Opportunities for Precision Dosing of Cytotoxic Drugs in Non-Small Cell Lung Cancer: Bridging the Gap in Precision Medicine

Open Access
05.03.2025
Review Article

Erschienen in:

Verfasst von: M. P. Kicken; M. J. Deenen; A. J. van der Wekken; B. E. E. M. van den Borne; M. M. van den Heuvel; R. ter Heine
Erschienen in: Clinical Pharmacokinetics | Ausgabe 4/2025

Abstract

Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic agents continue to play a critical role in NSCLC treatment. However, the current body surface area (BSA)-based dosing of these agents fails to adequately address interindividual variability in pharmacokinetics. By better considering patient characteristics, treatment outcomes can be improved, reducing risks of under-exposure and over-exposure. This narrative review explores opportunities for precision dosing for key cytotoxic agents used in NSCLC treatment: cisplatin, carboplatin, pemetrexed, docetaxel, (nab-)paclitaxel, gemcitabine, and vinorelbine. A comprehensive review of regulatory reports and an extensive literature search were conducted to evaluate current dosing practices, pharmacokinetics, pharmacodynamics, and exposure-response relationships. Our findings highlight promising developments in precision dosing, although the number of directly implementable strategies remains limited. The most compelling evidence supports using the biomarker cystatin C for more precise carboplatin dosing and adopting weekly dosing schedules for docetaxel, paclitaxel, and nab-paclitaxel. Additionally, we recommend direct implementation of therapeutic drug monitoring (TDM)-guided dosing for paclitaxel. This review stresses the urgent need to reassess conventional dosing paradigms for classical cytotoxic agents to better align with the principles of the precision dosing framework. Our recommendations show the potential of precision dosing to improve NSCLC treatment, addressing gaps in the current dosing of classical cytotoxic drugs. Given the large NSCLC patient population, optimising the dosing of these agents could significantly improve treatment outcomes and reduce toxicity for many patients.

Key Points

Classical cytotoxic agents are vital in treating lung cancer, but conventional dosing fails to account for interindividual variability, resulting in under-exposure and over-exposure.

Directly implemental opportunities exist for precision dosing in lung cancer based on established pharmacokinetic and pharmacodynamic relationships.

Precision dosing for classical cytotoxic agents can enhance treatment efficacy, reduce toxicity, and significantly improve treatment for the large lung cancer patient population.

1 Introduction

Lung cancer is the second most common cancer in the world. In 2022, a total of 2.5 million people worldwide were diagnosed with lung cancer, followed by an estimated 1.8 million deaths that year, indicating much-needed treatment improvement [1]. Lung cancer is categorised based on histological categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Around 80–85% of lung cancers are NSCLC, divided mainly into adenocarcinoma (40–45%) of the small airway epithelium and type II alveolar cells, squamous cell lung carcinoma (25–30%) of the epithelial cells of the bronchial tubes and large cell carcinoma (5–10%) targeting the central parts of the lungs [2].

The type of treatment for NSCLC depends on the tumour stage. In the treatment of stage I–III NSCLC, surgery is preferred and often combined with (neo)-adjuvant treatment using classic cytotoxic agents, immune checkpoint inhibitors, or targeted therapy [3]. Treatment of stage IV NSCLC is based on patient and tumour characteristics such as performance score (i.e., Eastern Cooperative Oncology Group [ECOG] – performance score), molecular profiling of the tumour, and immunohistochemistry (i.e., Programmed Death Ligand 1 [PD-L1] expression). Its treatment includes targeted therapy, immunotherapy, and chemotherapy [4]. However, while recent developments in targeted therapy have shown promising results in specific patient populations, classical cytotoxic therapy will remain an important pillar of the treatment of stage IV NSCLC for the coming decade.

For cytotoxic drugs, there is always a complex balance between subtherapeutic therapy (i.e., under-exposure) and toxicity (i.e., over-exposure) to find the individual optimal therapeutic effective dose. Since systemic exposure to the drug largely determines its effect and toxicity, prediction of individual pharmacokinetics (PK) can be used to tailor the dose. Historically, the dosing of cytotoxic drugs has been adapted to body size, for example, by using the estimated body surface area (BSA). This approach is based on early studies by Pinkel (1958) and Freireich (1966) showing a “reasonable” relationship between BSA and the pharmacokinetics of various chemotherapeutic drugs [5]. However, since body size only modestly correlates with the metabolic capacity of the liver and the glomerular filtration rate—the two main organ systems responsible for drug elimination—BSA is a poor predictor for individual pharmacokinetics [6]. Moreover, using BSA for dosing is only based on correlation (which disappears in the pharmacokinetic interindividual variability) and not on a causal physiological relationship with the clearance of cytotoxic drugs [7].

Nonetheless, the current dosing of cytotoxic agents for NSCLC treatment is still primarily BSA-based. This may lead to unwanted interindividual variability, as two patients with the same BSA may experience different drug exposures (and consequently, different treatment responses) due to variances in individual patient characteristics, such as hepatic or renal function, age, and genetic polymorphisms. High interindividual variability in clearance and exposure for many anticancer drugs has been observed, showing that dosing based on BSA leads to over- or under-exposure for the individual patient [7]. Over-exposure is unwanted since it may lead to severe toxicity, early treatment discontinuation, and reduced quality of life. Under-exposure is unwanted since it may negatively impact the efficacy of anticancer treatment. Precision dosing is adjusting the dose based on the patient’s characteristics already known before the start of treatment (e.g., hepatic and renal function, genetic factors) or during treatment through assessment of the drug’s exposure, i.e., pharmacokinetically guided dosing using therapeutic drug monitoring (TDM)-guided or toxicity-guided dosing [8]. In the era of advancing precision medicine, the tailoring of dosing of classical cytotoxic drugs to individual patients' characteristics is lagging and remains insufficient [8]. Regulatory agencies, such as the Food and Drug Administration (FDA), have also realised that the current paradigm for the dose selection of new oncology drugs is inadequate and needs improvement [9]. Through project Optimus, the FDA aims for a paradigm shift to identify optimal doses of new oncology drugs [10]. However, this initiative does not extend to older oncology drugs, which remain largely unexamined under the current shifting framework, creating a significant knowledge gap. We postulate that existing oncological drugs, especially classical cytotoxic drugs, should not be neglected and should undergo the same re-evaluation to optimise their dosing strategies. As the population of patients with NSCLC is large, an even slight improvement in dosing can affect and improve the treatment of many patients. Therefore, the aim of this narrative review is to describe opportunities for precision dosing of classical cytotoxic drugs for improved safety and efficacy of chemotherapeutic treatment of NSCLC.

2 Methods

The scope of this narrative review was limited to the treatment of NSCLC with classical cytotoxic agents, including platinum (cis- or carboplatin) and taxane (docetaxel, paclitaxel, or nab-paclitaxel) compounds, pemetrexed, gemcitabine, and vinorelbine [3, 4]. First, we assessed the European Public Assessments Reports (EPARs) from the European Medicines Agency (EMA) and pharmacology and PK reviews of the FDA gather regulatory insights on approved indications, dosing recommendations, and available pharmacokinetic/pharmacodynamic (PK/PD) data. From these regulatory documents, we extracted relevant information on each drug. Next, we examined the PK, PD, exposure-response relationships, and dose-treatment optimisation strategies for each cytotoxic agent. After that, we queried PubMed to identify additional relevant literature on personalised medicine of these cytotoxic agents. For example, when a PK relationship was found between BSA and exposure for a specific agent, we searched for “BSA” AND “exposure” AND “[drug-name]” (e.g., cisplatin, carboplatin). Filters were applied to include only English-language publications, with a priority given to studies in NSCLC populations, clinical trials, meta-analyses, and reviews, in that order. Lastly, we employed citation snowballing, specifically backward snowballing, by examining the reference lists of key studies to identify other potentially relevant publications.

The general approach for dose individualisation of selected cytotoxic agents starts with the current state of dosing and general PK and PD characteristics (“PKs, PDs and current practice in dosing”), followed by “Promising developments” of opportunities and research already performed for optimising and personalising of dosing, followed by our recommendation to improve precision dosing of these cytotoxic agents. All directly implementable opportunities and proposed PK/PD relationships of these cytotoxic agents in treating NSCLC were summarised in Table 1.

Table 1

Characteristics, proposed PK/PD relationships and opportunities for precision dosing strategies for classical cytotoxic drugs in treatment of NSCLC

Cytotoxic drug	Target	Approved dose	Proposed PK/PD relationships		Precision dosing
Cytotoxic drug	Target	Approved dose	Efficacy	Toxicity	Opportunities for treatment optimisation to be directly implemented	Promising developments
Cisplatin	Bind to DNA-adducts in cells	75 mg/m² IV Q3W	AUC	AUC C_max	–	Dosing based on renal function^a Neutrophil-guided dosing^a TDM-guided dosing in paediatric patients and 5-day continuous infusion^b
Carboplatin	Bind to DNA-adducts in cells	400 mg/m² IV Q3W Dose = AUC_target * (GFR +25)	AUC	AUC	Dosing based on cystatin C as novel biomarker for estimating carboplatin clearance For example Schmitt et al. carboplatin clearance = 117.8(Cr_serum/75)^− 0.450 cystatin C^− 0.385(body weight/65)^+ 0.504 (age/56)^− 0.366* 0.847^sex with sex = 0 for male [58]	TDM-guided dosing in paediatric and high-dose carboplatin protocols Improved estimation of carboplatin clearance using: 1. CT derived body composition and serum creatinine^a 2. Pro-enkephalin
Pemetrexed	Folate antimetabolite needed for DNA and RNA synthesis	500 mg/m² IV Q3W	AUC	AUC Time above threshold	Dose individualization (for patients with CrCL ≥ 45 mL/min) based on renal function to target an AUC of 164 mg/L*h	TDM-guided dosing for normal renal function based on proposed target AUC of 164 mg/L*h [66, 68]^a Dosing adjustment in patients with impaired renal function (< 45 mL/min) and potentially adding folinic acid prophylaxis therapy^a
Docetaxel	Binding site GTP on microtubules	75 mg/m² IV Q3W	AUC	AUC	Weekly dosing	Neutrophil-guided dosing^a TDM-guided dosing in specific populations such as patients with mCRPC Genotyping and metabolic phenotyping (e.g., CYP3A and ABCB1)
Paclitaxel		175 mg/m² IV Q3W	Time above threshold	Time above threshold	TDM-guided dosing at time-above-threshold of 0.05 μmol/L (T_>0.05) Weekly dosing	Genotyping and metabolic phenotyping (e.g., CYP2C8*3 and ABCB1)
Nab-paclitaxel		100 mg/m² IV Q1W	Time above threshold	Time above threshold	Weekly dosing	Neutrophil-guided dosing^b TDM-guided dosing Genotyping and metabolic phenotyping (e.g., CYP2C8*3 and ABCB1)
Gemcitabine	Pyrimidine antagonist	1250 mg/m² IV Q3W	Inconclusive		–	Prolonged infusion times Genotyping (e.g., dCK and hENT^a,b) Neutrophil-guided dosing
Vinorelbine	Binding site β-tubulin on microtubules	25–30 mg/m² IV 60 mg/m² PO	Inconclusive		–	Neutrophil-guided dosing^a

AUC area under the curve, CrCL creatinine clearance, C_max maximum concentration, dCK deoxycytidine kinase, GFR glomerular filtration rate, hENT human equilibrative nucleoside transporters, IV intravenously, PK/PD pharmacokinetic/pharmacodynamic, PO per os (by mouth), mCRPC metastatic castration-resistant prostate cancer, NSCLC non-small cell lung cancer, Q1W weekly dosing, Q3W 3-weekly dosing, TDM therapeutic drug monitoring

^aNo prospective studies available

^bNot investigated in NSCLC population

3 Platinum-Based Compounds (Cisplatin, Carboplatin)

After intravenous administration, cis- and carboplatin are hydrolysed to active platinum metabolites, which bind to proteins through sulfide bonds of albumin and globulins. Hence, only a small part of elimination depends on protein turnover [11]. Compared to cisplatin, carboplatin is chemically more stable and less reactive, hydrolysed at a lower constant rate, and forms fewer complexes with plasma proteins. Both cisplatin and carboplatin are cleared by the kidneys as free platinum, with carboplatin being excreted up to 65–77% within 24 hours versus 28% for cisplatin [11]. Hence, the dosing of carboplatin is adjusted for renal function, while adjustment of the dosing of cisplatin in patients with renal impairment is only advised [12].

Both drugs are considered interchangeable for the treatment of NSCLC, as a large meta-analysis (n = 2048) including 12 randomised controlled trials (RCTs) showed no significant differences in survival outcomes between first-line cisplatin- and carboplatin-based chemotherapy. Nevertheless, differences in toxicity profiles exist, with a higher incidence of thrombocytopenia and anaemia for carboplatin and an increased risk of nausea and vomiting for cisplatin [13]. Furthermore, cisplatin shows higher incidences of ototoxicity and neurotoxicity compared to carboplatin. The specific mechanism underlying this difference in sensitivity is still poorly understood. However, studies have found a higher accumulation of cisplatin in the cochlea, resulting in reactive oxygen species (ROS) overload and an impaired antioxidant system [14].

The cytotoxic mode of action of platinum drugs has been linked to forming DNA-crosslinks, causing DNA damage, and inducing apoptosis of tumour cells, but as a side effect also in healthy cells [11]. Most chemotherapy-induced toxicity encompasses rapidly dividing cells, including in the bone marrow. Neutropenia is the most common form of bone marrow toxicity, as neutrophils are especially vulnerable to cell-diving toxicity due to their extremely short circulating half-life (6–8 h) and the need for continuous replenishment by the bone marrow [15]. The nadir neutrophil count occurs 8–10 days after administration and is associated with, among others, systemic exposure to the specific cytotoxic drug [16]. An exception to this rule is carboplatin, where carboplatin-associated haematological toxicity mainly manifests as thrombocytopenia. This difference in haematological toxicity might be explained by the downregulation of the JAK2/STAT2 pathway critical for megakaryocyte proliferation and differentiation by carboplatin [17].

Platinum-based drugs not only function as cytotoxic drugs but may also exert immunomodulatory effects that contribute to their efficacy and synergetic effect in chemoimmunotherapy. For example, cisplatin in vitro increases the number of effector cells (i.e., natural killer [NK] cells, cytotoxic T-cells, antigen presenting cells [APCs], and macrophages) while decreasing the number of myeloid-derived suppressor cells (MDSCs) and regulatory T-cells [18]. Moreover, cisplatin seems to enhance the effect of immunotherapy by remodelling the tumour microenvironment (by ferroptosis and neutrophil polarisation) and enhancing T-cell infiltration and Th1 differentiation [19]. The same synergistic effect was found for carboplatin and PD-1 inhibitors (i.e., pembrolizumab and nivolumab) in NSCLC cell lines [20].

4 Cisplatin

4.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Cisplatin entered the market in 1978 as an anticancer drug for the first-line treatment of several malignant tumours, including lung, ovarian, and colorectal cancers [21]. The cumulative exposure to unbound cisplatin (expressed as area under the curve [AUC]) is strongly correlated with the formation of DNA-adducts in tumour cells and tumour response [22] as well as toxicity [23]. The main cisplatin-induced toxicities are nephrotoxicity, ototoxicity, myelotoxicity, nausea, and peripheral neuropathy [23]. Specifically, an increased systemic drug exposure (AUC) and maximal plasma concentration (C_max) of unbound platinum are correlated with an increased risk of cisplatin-induced nephrotoxicity [24]. Slow infusion rates may prevent nephrotoxicity and myelotoxicity in addition to hyperhydration and diuresis [25]. Incidences of neuropathy and ototoxicity are only preventable by dose reduction or cessation of cisplatin [26]. Although BSA only weakly correlates with cisplatin systemic exposure [27], cisplatin is still dosed based on BSA 75–100 mg/m² every three weeks (Q3W) in NSCLC treatment [12].

4.2 Promising Developments

Since cisplatin is eliminated by the kidneys, dosing in patients with renal impairment should be adjusted. At the moment, dose adjustment in patients with impaired renal function is only advised by the label and not mandatory [12]. However, recent guidelines, including the International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD), recommend avoiding the administration of cisplatin in patients with renal impairment (estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73 m²) and exercising extra caution in those with an eGFR of 45–59 mL/min/1.73 m² [28]. Limited prospective data in NSCLC are available, and the best approach for adjusting cisplatin dosage in patients with impaired renal function has yet to be determined [29]. Interestingly enough, a study investigating dose reduction of cisplatin for patients (n = 151) with metastatic urothelial carcinoma and renal dysfunction, 30–60 mL/min found no negative impact or significant differences in severe toxicity or survival outcomes compared to standard dosing in patients with renal function > 60 mL/min [30]. Since cisplatin and carboplatin are considered interchangeable in treating NSCLC [13], changing treatment to carboplatin may also be an option to adjust treatment to individual renal function more easily (see chapter Carboplatin).

An increasing number of pharmacogenomic studies of cisplatin-induced toxicity have been published, especially regarding cisplatin-induced ototoxicity [31] and nephrotoxicity [32]. For example, a large genome-wide study (GWAS) of 608 European patients found an association between a predisposition of the BACH2 gene and an increased risk of cisplatin-induced nephrotoxicity [33]. At the moment, there is no place for PGx for cisplatin-induced toxicity due to the lack of consistency in study results. Nevertheless, pharmacogenomics remains highly relevant and important for future research.

Neutrophil-guided dosing of cisplatin could be a potential opportunity for treatment optimisation. A large retrospective study by Di Maio et al based on three RCTs (n = 1265) found the degree of cisplatin-induced neutropenia to be associated with increased overall survival (OS) [34]. Unfortunately, to our knowledge, no prospective studies have confirmed this relationship between the incidence of neutropenia and survival outcomes in cisplatin treatment.

As cisplatin exposure is related to its efficacy and toxicity, TDM-guided dosing of cisplatin based on reaching a specific AUC or C_max would be possible, especially in specific populations (e.g., paediatric, high-dose treatment) and for treatment that is administered over several days [35]. To date, no studies have investigated the added value of TDM-guided dosing of cisplatin in NSCLC patients. In patients with other types of solid tumours, TDM-guided dosing of cisplatin (n = 58) as a 5-day continuous infusion successfully reached the target C_max and reduced interindividual variability of PK parameters [36]. Another PK study in 19 patients with different solid tumours also successfully achieved targeted C_max, with little grade III–IV toxicities (10% leukocytopenia, 6% anaemia, and thrombocytopenia) and no nephrotoxicity and neurotoxicity, and all patients are still alive and disease-free after a follow-up of 15 years [37].

4.3 Recommendations and Opportunities for Treatment Optimisation

Currently, dosing is still based on BSA, and there is insufficient evidence to adjust cisplatin dosing based on renal function or to use cisplatin-induced haematological toxicity, a potential opportunity for neutrophil-guided dosing. For specific NSCLC patient populations like paediatric patients or 5-day continuous infusion of cisplatin, we recommend further exploring TDM-guided dosing based on the limited promising results in other tumours.

5 Carboplatin

5.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Carboplatin entered the market roughly ten years after cisplatin in 1986 as a potential substitution for cisplatin [38]. Carboplatin was initially approved on BSA-based dosing [39]. However, studies showed carboplatin clearance to be linearly correlated with glomerular filtration rate (GFR) [40]. The toxicity of carboplatin treatment showed high variability and higher incidences of (haematological) toxicity with decreasing renal function [41]. Since carboplatin systemic drug exposure correlates well with toxicity, Calvert et al developed the following dosing formula for dosing based on AUC: Dose (mg) = AUC_target * (GFR + 25) [40]. In this formula, the GFR is based on the measured GFR using chromium 51-ethylenediaminetetra-acetic acid (⁵¹Cr-EDTA). In daily practice, directly measuring the GFR using exogenous markers is complex, expensive, and inconvenient [42], and the GFR is frequently substituted by the estimated creatine clearance (CrCL) [43]. However, creatinine is not 100% cleared by the glomerulus but also undergoes active tubular secretion, resulting in a 10–20% systematic overestimation of GFR [42]. Moreover, besides biased estimation, serum creatinine-based estimations of renal function have proven to be imprecise. A study by Ekhart et al showed that adjusting carboplatin dose using estimated renal function based on serum creatinine provided similar drug exposure levels as administering a flat dose to patients with normal renal function [44]. This finding can be explained by the fact that serum creatinine correlates with muscle mass and that in advanced cancer patients, muscle mass deviates from the population where equations for estimation of renal function were developed [45]. For example, cachectic patients, often seen in oncological populations, have an abnormally low creatinine production, and assessing the creatinine clearance in this population will provide an overestimation of GFR [46, 47]. Directly measuring (24-hour) creatinine clearance as a proxy for GFR might be more accurate than relying on estimated GFR for carboplatin dosing. Still, this has been proved inaccurate for carboplatin dose individualisation [48].

5.2 Promising Developments

Since carboplatin is dosed to a specific target AUC, TDM-guided dosing may aid in dosing carboplatin to improve target attainment. An extensive review by Maillard et al [35] found multiple small studies demonstrating that TDM-guided carboplatin dosing in children with retinoblastoma successfully achieved target AUC, leading to remission without reported renal toxicity [49, 50]. Similarly, high-dose carboplatin has been shown to reach target AUC in adults with advanced germ cell tumours [51]. Looking at carboplatin toxicity and treatment outcomes, the association between (haematological) toxicity and survival outcomes of carboplatin treatment has not been established [52]. However, there is still potential for improvement in carboplatin dosing by adjusting for baseline haematological status (i.e., low platelets or absolute neutrophil counts at baseline), concomitant therapy, and better estimation of renal function [53].

As stated earlier, estimating renal function based on the creatinine clearance (i.e., carboplatin clearance) in patients with an abnormal body composition gives an under- or over-estimation of the eGFR. However, developments in deep learning and medical imaging allow accurate assessment of an individual’s body composition, including muscle mass, using X-ray computed tomography (CT) scans [54]. As muscle mass correlates with creatinine production, creatinine clearance might be accurately estimated using a CT-scan assessment of body composition and serum creatinine to improve carboplatin dosing [55]. Other biomarkers, cystatin C and pro-enkephalin (PENK), are more effective in estimating the GFR than creatinine clearance [56, 57]. Using cystatin C for dosing of carboplatin better attains target AUC compared to serum creatinine-based assessments of renal function in individualising the dose [58, 59]. White-Koning et al combined three previously published clinical studies of 491 patients receiving carboplatin and compared various formulas for estimating carboplatin clearance to actual clearance. They found that cystatin C (used in the CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration]) was the best predictor (i.e., least bias, highest precision) of carboplatin clearance, independent of other patient characteristics such as sex, body mass index (BMI) (only significant at the 1% level), and age [60]. See Table 2 for different cystatin C formulae tested for estimating carboplatin clearance.

Table 2

Different cystatin C formulas for estimating carboplatin clearance

Schmitt et al [58]	\(\text{CL }[\text{mL}/\text{min}]=117.8{\left(\frac{{\text{Cr}}_{\text{SERUM}}}{75}\right)}^{-0.450}{\left(\frac{{\text{cystatin C}}_{\text{SERUM}}}{1.0}\right)}^{-0.385}{\left(\frac{\text{WEIGHT}}{65}\right)}^{+0.504}{\left(\frac{\text{AGE}}{56}\right)}^{-0.366}*0.847\, [\text{IF FEMALE}]\)
Thomas et al [59]	\(\text{CL }[\text{mL}/\text{min}]=110.0{\left(\frac{{\text{Cr}}_{\text{SERUM}}}{75}\right)}^{-0.512}{\left(\frac{{\text{cystatin C}}_{\text{SERUM}}}{1.0}\right)}^{-0.327}{\left(\frac{\text{WEIGHT}}{65}\right)}^{+0.474}{\left(\frac{\text{AGE}}{56}\right)}^{-0.387}*0.854\, [\text{IF FEMALE}]\)
CKD-EPI (creatinine + cystatin C) [57]	\(\text{eGFR }[\text{mL}/\text{min}/1.73 \,{\text{m}}^{2}]=135{\left(\frac{{\text{Cr}}_{\text{SERUM}}}{\text{A}}\right)}^{\text{B}}{\left(\frac{{\text{cystatin C}}_{\text{SERUM}}}{\text{C}}\right)}^{\text{D}}{0.9961}^{\text{AGE}}0.963\, [\text{IF FEMALE}]\)
	If male and: Serum creatinine ≤ 0.9 and serum cystatin C ≤ 0.8: A = 0.9, B = −0.144, C = 0.8, and D = −0.323 Serum creatinine ≤ 0.9 and serum cystatin C > 0.8: A = 0.9, B = −0.144, C = 0.8, and D = −0.778 Serum creatinine > 0.9 and serum cystatin C ≤ 0.8: A = 0.9, B = −0.544, C = 0.8, and D = −0.323 Serum creatinine > 0.9 and serum cystatin C > 0.8: A = 0.9, B = −0.544, C = 0.8, and D = −0.778	If female and: Serum creatinine ≤ 0.7 and serum cystatin C ≤ 0.8: A = 0.7, B = −0.219, C = 0.8, and D = −0.323 Serum creatinine ≤ 0.7 and serum cystatin C > 0.8: A = 0.7, B = −0.219, C = 0.8, and D = −0.778 Serum creatinine > 0.7 and serum cystatin C ≤ 0.8: A = 0.7, B = −0.544, C = 0.8, and D = −0.323 Serum creatinine > 0.7 and serum cystatin C > 0.8: A = 0.7, B = −0.544, C = 0.8, and D = −0.778

5.3 Recommendations and Opportunities for Treatment Optimisation

Dosing of carboplatin is already adjusted for exposure (AUC) and clearance (GFR) using the Calvert formula. We recommend implementing and using cystatin C as a marker for renal clearance and adjusting dosage for baseline haematological status and concomitant therapy. Cystatin C has the most evidence as an ideal estimator of carboplatin clearance independent of patient characteristics (see Table 1). Moreover, prospective studies in cystatin C have already shown that it is a better approximation of carboplatin clearance compared to conventional creatinine clearance formulae. However, its impact on clinical outcomes has yet to be evaluated. Finally, TDM-guided dosing could be an option in specific patient groups, such as paediatrics or high-dose protocols.

6 Pemetrexed

6.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Pemetrexed is a folate antimetabolite, moderately protein bound (81%), and is almost entirely eliminated as unchanged drug by the kidneys (70–90% within 24 h in patients with adequate renal function) [61]. After uptake in the (tumour) cell, a polyglutamate chain is added by folylpolyglutamate synthetase (FPGS) increasing the affinity and inhibition by pemetrexed of enzymes used in purine and pyrimidine synthesis, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Inhibiting these enzymes disrupts DNA and RNA synthesis, thus blocking cell replications and growth [62]. Thymidylate synthase inhibition and consequential cell death of tumour and healthy cells are the most important factors for both the efficacy and toxicity effects of pemetrexed (mainly nephrotoxicity and haematological toxicity) [62]. Furthermore, pemetrexed acts synergetically when combined with immunotherapy. By inactivating TS in tumour cells, pemetrexed stimulates the upregulation of PD-L1 by activating CD274 through upregulating NF-κB signalling [63], and the addition of pemetrexed to platinum-pembrolizumab doublet chemotherapy significantly improves OS in patients with stage IV NSCLC [64], as well as for platinum-atezolizumab [65].

Since pemetrexed is mainly excreted by the kidneys by both tubular secretion and glomerular filtration, clearance of pemetrexed correlates linearly with renal function [66]. Hence, a decrease in renal function will lead to an increase in pemetrexed exposure and risk of (haematological) toxicity [67, 68]. Even though pemetrexed exposure primarily depends on renal function, dosing is individualised based on BSA, with an approved dose of 500 mg/m² every 3 weeks [69].

The primary haematological toxicity for pemetrexed is neutropenia, as observed in early trials with a 39–42% incidence for grade III–IV neutropenia for pemetrexed monotherapy (500–600 mg/m² without vitamin supplementation) [70, 71]. Pemetrexed-induced neutropenia is caused by the inhibition of proliferation of progenitor cells to fully differentiated leukocytes [72] and follows the maturation and life cycle of neutrophils with the nadir absolute neutrophil count at 8–10 days after administration [69]. An extensive study by Niyikiza et al showed that vitamin B12 deficiency is associated with increased myelotoxicity [73]. These findings resulted in adding folic acid (vitamin B9) and vitamin B12 as standard supplementation in pemetrexed treatment. After introducing vitamin supplementation, a Phase III study showed a decrease in haematological toxicity to 5.8% grade III–IV neutropenia and 1.9% febrile neutropenia [74]. However, real-world data show a higher incidence of 26% for grade III–IV neutropenia [75]. Haematological toxicity of pemetrexed is driven by a “time above a toxicity concentration threshold” [76], comparable to methotrexate [77]. Consequently, patients with decreased pemetrexed elimination (i.e., impaired renal function) are prone to haematological toxicity. Moreover, cumulative exposure to pemetrexed was found to be a risk factor for the development of renal injury, consequently associated with an increased incidence of treatment discontinuation related to renal events of 4% to 33% increasing with age, pre-existing condition, and use of nephrotoxic drugs [78, 79]. Hence, patients with impaired renal function (< 45 mL/min) cannot be administered an effective dose without risk for severe toxicity [80], and dosing in patients with renal function < 45 mL/min is contraindicated [69]. Other non-haematological toxicities for pemetrexed, besides nephrotoxicity, include gastro-intestinal and skin toxicities [69]. Cells in the gastro-intestinal tracts and skin contain both highly proliferating cells and are therefore more prone to cytotoxic effects of pemetrexed. For skin toxicities, it is still unclear if these reactions are immunologically mediated or arise from the direct cytotoxic effect on keratinocytes [81].

6.2 Promising Developments

For efficacy, higher dosing of pemetrexed up to 900 or 1000 mg/m² every 3 weeks did not improve survival outcomes compared to 500 mg/m² dosing, but came with greater toxicity [82, 83]. While pemetrexed exposure largely depends on renal function, dosing based on BSA proves to be effective and generally safe in patients with adequate renal function (CrCL ≥ 45 mL/min) [84]. However, a recent study applying dose individualisation for pemetrexed based on renal function (dose = 109 × [weight/70]^0.75 + 561 × [eGFR/75]) showed the potential to reduce the incidence of toxicity (i.e., neutropenia) and decrease the costs of pemetrexed-associated neutropenia without compromising effective exposure [85]. Recently, it was found that the CKD-EPI equation to estimate the GFR using serum creatinine and cystatin C could best predict the pemetrexed PKs, showing opportunities for better dose individualisation [86].

Large interindividual variability in pemetrexed plasma concentration is observed, and TDM-guided dosing could be used to reduce variability in specific cases (e.g., high risk of toxicity, interaction with concomitant medication) [87]. A proposed target AUC for effective and safe treatment has already been determined for pemetrexed at 164 mg/L*h [66, 68]. However, the target AUC is not a reliable predictor of toxicity in patients with impaired renal function. Instead, time above the threshold concentration is a more accurate measure for predicting pemetrexed toxicity in these patients. Boosman et al identified pemetrexed threshold concentrations of 0.030 mg/L for non-supplemented patients and 0.110 mg/L for vitamin-supplemented patients for daily dosing of pemetrexed [76].

Finally, the timing of pemetrexed administration may be an important factor in optimising pemetrexed efficacy, especially since NSCLC expresses various circadian genes that play key roles in DNA synthesis and nucleotide metabolism [88]. A retrospective study in 78 advanced NSCLC patients showed that patients who received pemetrexed and platinum in the morning (n = 26) had a higher PFS compared to patients receiving chemotherapy after 2 pm (n = 52; 13 vs 43 months, respectively) [89].

6.3 Recommendations and Opportunities for Treatment Optimisation

For patients with adequate renal function (CrCL ≥ 45 mL/min), dose individualisation based on renal function to target an AUC of 164 mg/L*h could already be implemented in clinical practice, similar to carboplatin dosing based on target AUC. Preferably, the CKD-EPI equation using serum creatinine and cystatin C should be used. However, caution is warranted for patients with impaired renal function, as data in this population remain limited. We align with regulatory guidelines contra-indicating the administration of pemetrexed to patients with CrCL < 45 mL/min.

7 Taxanes (Docetaxel, Paclitaxel, Nab-Paclitaxel)

Taxanes are plant isolates used as anticancer drugs for NSCLC. It started with the discovery of paclitaxel in 1971 from the yew tree: Taxus brevifolia. At that time, the direct extraction of the highly lipophilic paclitaxel from the Taxus brevifolia was not economically viable, needing at least 2–3 full-grown yew trees to treat one patient [90]. Only 20 years later, the preparation of economically viable quantities of paclitaxel was possible by a semisynthetic approach of modification of the precursor 10-deacetyl-baccatin III naturally and in high quantities available from the extraction of the needles of the European Taxus Baccata. From 1996 onwards, another semisynthetic derivative of 10-deacetyl-baccatin III was developed: docetaxel [91].

Both docetaxel and paclitaxel are highly lipophilic and extensively bound to plasma proteins [92, 93]. They are metabolised in the liver by cytochrome P450 (CYP) enzymes and excreted through the bile. Additionally, both drugs are substrates for ATP-binding cassette (ABC) transporters, which facilitate their efflux from cells, a process that affects treatment efficacy (e.g., tumour resistance due to the efflux of taxanes by cancer cells) and toxicity (e.g., reduced efflux of taxanes by healthy cells) [91]. Solvents are added to their formulations to improve the solubility of docetaxel and paclitaxel. Docetaxel is made soluble by adding polysorbate 80 [92]. Paclitaxel uses the micelle-forming cremophor EL to increase its water solubility [93]. Both compounds are associated with high rates of hypersensitivity and infusion reactions and require the addition of prophylactic antihistamines and dexamethasone [94, 95]. Moreover, polysorbate 80 and cremophor EL can hinder circulating taxane molecules from crossing the endothelial barrier of blood vessels or penetrating tumour tissue [96]. To tackle these problems and reduce toxicity while increasing efficacy, nano-formulation of albumin-bound paclitaxel (nab-paclitaxel) was developed [91]. A large Phase III trial compared docetaxel (60 mg/m² Q3W) with nab-paclitaxel (100 mg/m² weekly) in 503 patients with advanced NSCLC and found no significant differences in OS (adjusted hazard ratio (aHR) = 0.85 (95% confidence interval [CI]: 0.68–1.07). However, nab-paclitaxel showed an increased progression-free survival (PFS; aHR = 0.76; 95% CI 0.63–0.92, p = 0.0042) compared to docetaxel and a lower incidence of grade III–IV febrile neutropenia (2% vs 22%), although with a higher incidence of grade III–IV peripheral sensory neuropathy (10% vs 1%) [97]. The same trend was seen in 1052 patients with advanced NSCLC treated with paclitaxel (200 mg/m² Q3W) or nab-paclitaxel (100 mg/m² weekly), finding no significant differences in OS and PFS, but significantly less neutropenia grade III (32% vs 26%) and grade IV (33% vs 14%) and neuropathy grade III (11% vs < 1%) and grade IV (3% vs 0%) for nab-paclitaxel. Nab-paclitaxel was associated with a significantly increased incidence of thrombocytopenia grade III (13% vs 5%) and IV (7% vs 2%) and anaemia grade III (22% vs 5%) and IV (6% vs < 1%) [98]. Due to the lack of improved survival outcomes with nab-paclitaxel and its higher incidence of severe peripheral sensory neuropathy, paclitaxel and docetaxel are typically preferred. In this chapter, paclitaxel and nab-paclitaxel are discussed together since the active compound of nab-paclitaxel in tumour cells is still paclitaxel.

Taxanes bind to the binding site for GTP on microtubules (β-tubulin) and stabilise the peeling off and polymerisation of the protofilaments of microtubules, leading to G2-M arrest, resulting in cell apoptosis [91]. Different effects are observed depending on taxane concentration, with docetaxel having a higher binding site affinity than paclitaxel. At high concentrations, taxanes induce cell apoptosis. However, at low concentrations (or high concentrations after adaptation to taxane treatment), taxanes alter mitosis and disturb the formation of micronuclei and aggregation of chromosomes, leading to DNA damage and the activation of the cGAS/STING pathway [91]. The cGAS/STING pathway activates the innate immune system and stimulates macrophage activity, providing a synergetic effect with immune checkpoint inhibitors [99]. Additionally, paclitaxel binds toll-like receptor 4 (TLR-4), leading to the secretion of pro-inflammatory cytokines and enhancing inflammation response by activating dendritic, NK- and cytotoxic T-cells [100]. Moreover, paclitaxel and docetaxel inhibit the accumulation of endothelial progenitor cells (EPC) and induce the expression of thrombospondin-1 (TSP-1) in the tumour microenvironment, leading to the inhibition of angiogenesis [101].

8 Docetaxel

8.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Docetaxel is hydrophobic, and more than 90% is bound in plasma to albumin, α1-acid glycoprotein (AAG), and lipoprotein (mainly high-density and low-density lipoprotein) [102]. Docetaxel is primarily eliminated by CYP3A4 enzymes and excreted through biliary excretion into the faeces with less than 5% renal excretion [92]. The PK of docetaxel appear to be linear over the clinically relevant range of doses, with exposure to docetaxel increasing proportionately with the dose [92]. Covariates that influence docetaxel clearance are age, BSA, albumin and AAG concentrations, and hepatic function [103]. Although many covariates for docetaxel PKs have been identified, most variability in exposure remains unexplained. In clinical practice, docetaxel is dosed based on BSA at 75 mg/m² Q3W [95]. Nevertheless, administration of docetaxel solely on BSA results in a negligible reduction in interindividual variability of the PK of docetaxel [104].

Systemic docetaxel drug exposure significantly correlates with the risk of toxicity, specifically with neutropenia, but also with better survival outcomes [105]. Moreover, the degree of neutropenia is associated with the efficacy of docetaxel [106]. A large study involving 885 patients with advanced or metastatic NSCLC identified grade I–II and grade III–IV docetaxel-induced neutropenia as independent factors associated with improved time to progression (TTP) and OS compared to patients without neutropenia [107].

8.2 Promising Developments

As docetaxel is mainly metabolised by CYP3A enzymes in the liver, genotyping and phenotyping of the metabolic activity of the liver could be an option. However, evidence for genotyping is limited. A study of 92 patients with solid tumours found no association between CYP3A polymorphisms and docetaxel PK [108]. Another candidate for genotyping could be ABC-transporters. Studies found an association between carriers of ABCB1 gene polymorphisms and increased exposure [108] and risk of docetaxel-associated neutropenia [109].

Regarding metabolic phenotyping, an erythromycin breath test (ERMBT; ¹⁴C-labelled erythromycin is administered and exhaled ¹⁴C-labelled CO₂ is measured as an indicator for CYP3A activity) was found to explain 67% of interindividual variability of docetaxel exposure [110]. Other studies showed no correlation between CYP3A(4) probes like midazolam and docetaxel clearance [111, 112]. A study by Yamamoto et al found the renal excretion of 6-β-hydroxy cortisol (6-β-OHF) to be significantly and highly correlated with docetaxel clearance (r = 0.867; p < 0.001) [113]. A subsequent prospective randomised study found the use of 6-β-OHF reduced docetaxel interindividual variability by 46.2% compared to BSA-based dosing [114]. Similar results were found for other non-invasive methods to determine the patient individual CYP3A4 phenotyping using 6-β-OHF to cortisol ratio or other endogenous markers [115]. Clearance of a microdose of docetaxel before treatment could potentially be linearly extrapolated to therapeutically relevant doses. However, docetaxel clearance showed no linear increase from 0.1 and 1 mg microdoses to a therapeutic dose, presumable because of plasma protein binding to AAG and other lipoproteins, which might be saturated at therapeutic doses [116, 117].

Another promising development is the change from docetaxel administration Q3W to weekly dosing. A meta-analysis including 6 RCTs in 1018 advanced NSCLC patients investigating weekly versus Q3W of docetaxel showed a significant decrease in grade III–IV neutropenia, while OS (relative risk [RR] = 1.01; 95% CI 0.76–1.42, p = 0.785) and objective response rate (RR = 0.81; 95% CI 0.47–1.40, p = 0.465) remained unaffected [118].

Evidence on the effectiveness of TDM-guided dosing for docetaxel in NSCLC patients is still limited. A small study (n = 30) across multiple tumour types showed that TDM-guided dosing, compared to standard BSA-based dosing, reduced interindividual variability in docetaxel exposure by 39% and variability of neutropenia by 50% when targeting at a docetaxel exposure (AUC) of 4.9 mg/L*h [119]. Lastly, TDM-guided dosing could potentially be utilised for subsequent cycles in specific patient populations, such as metastatic castration-resistant prostate cancer (mCRPC) patients. A large meta-analysis of 26 RCTs (n = 1150) identified a 1.8-fold lower docetaxel exposure and 2.2-fold lower odds of developing grade III–IV neutropenia for mCRPC patients compared to patients with other solid tumours [120].

Research data suggest a link between patient survival and neutrophil count in the first cycle, showing a potential benefit for dose reduction after the first cycle of docetaxel [106]. In clinical practice, neutrophil counts are measured as part of the standard of care one day before the next cycle. Yet, the most accurate estimate of the neutrophil nadir would be obtained by measuring it approximately 8–10 days after docetaxel administration. Interestingly, a simulation study showed that one extra neutrophil measurement is sufficient to limit severe neutropenia while increasing dose intensity [121]. However, to our knowledge, this has not yet been prospectively tested in clinical practice. Although promising, at present we are still hesitant to recommend docetaxel dosing based on neutrophil counts. The available evidence is based on older studies conducted when docetaxel was given as an earlier line of treatment. Currently, however, docetaxel is generally used as a third- or fourth-line therapy, where any added toxicity could be especially risky and potentially life-threatening. Moreover, an extra neutrophil measurement during treatment comes with additional logistic consequences.

8.3 Recommendations and Opportunities for Treatment Optimisation

We recommend weekly dosing of docetaxel, as it decreases the incidence of severe neutropenia while similar efficacy is maintained. However, this will impact hospital infusion care and patient visits. With regard to other promising developments, including neutrophil-guided dosing, metabolic genotyping and phenotyping, and TDM-guided dosing, more clinical evidence is needed before further recommendations can be made.

9 Paclitaxel and Nab-Paclitaxel

9.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Paclitaxel clearance is non-linear, which is especially apparent in up to 3-hour infusions. Its non-linear clearance is attributed to the saturation of paclitaxel transport, binding (albumin and AAG), CYP2C8-mediated metabolism, and by the formulation of paclitaxel using the solvent cremophor EL mixed 1:1 with ethanol [96, 122]. Different PK parameters have been tested for association with clinical outcome parameters of paclitaxel treatment: AUC, C_max, and time above threshold concentration (T_{>concentration}). Time above paclitaxel plasma concentration of 0.05 μmol/L (T_>0.05) appeared to be the best predictor of paclitaxel-associated neutropenia, paclitaxel-induced polyneuropathy (cumulative chemotherapy-induced peripheral neuropathy [CIPN]), and clinical outcomes [123]. Some studies even suggest a higher time above the threshold (T_>0.10) [124]. Like docetaxel, paclitaxel is primarily cleared by the liver and eliminated through biliary excretion. Hence, patients with impaired liver function or liver metastases have a decreased paclitaxel clearance, leading to increased exposure and an increased risk of paclitaxel-induced toxicity [125].

Nab-paclitaxel is albumin-bound paclitaxel. The albumin part binds to albondin (gp60) receptors on endothelial cells and paclitaxel-albumin complexes are carried across the endothelial membrane (transcytosis) into surrounding tissues, including tumour tissue. Accumulation of albumin-paclitaxel complexes is increased by a high amount of leaky tumour vasculature and by the albumin binding activity of secreted protein acidic and rich in cysteine (SPARC) in tumour tissue [96]. The albumin-paclitaxel formulation rarely shows infusion or hypersensitivity reactions. Therefore, nab-paclitaxel does not require prophylactic medication and can be administered by intravenous infusion 30 minutes faster compared to 1- or 3-h paclitaxel and 1-h docetaxel infusions [126]. Nab-paclitaxel PK show linear elimination with a higher free fraction of paclitaxel (6.2%) [127] compared to paclitaxel cremophor EL (2.3%) [128]. Still, since albumin has multiple times higher molecular weight compared to paclitaxel, nab-paclitaxel is administered at a higher dose of 300 mg/m² versus 175 mg/m² for paclitaxel cremophor EL Q3W [96]. At high dosages of nab-paclitaxel, elimination is non-linear, indicating a possible saturation of metabolism at high paclitaxel concentrations [122]. Clearance of nab-paclitaxel is equal to clearance of its active component paclitaxel. Hence, clearance is mainly by the liver, and dose reduction is recommended for patients with impaired liver function [126].

Exposure to nab-paclitaxel is associated with toxicity, including (febrile) neutropenia and alopecia, but without acute or infusion-related hypersensitivity systemic reactions [129]. Moreover, nab-paclitaxel is still associated with cumulative CIPN, even though the formulation of nab-paclitaxel was developed to reduce peripheral neuropathy compared to paclitaxel and docetaxel. However, studies have been conflicting. The latest meta-analysis, including 24 studies, found a significantly higher incidence of peripheral neuropathy for nab-paclitaxel versus paclitaxel (16% vs 5%) [130].

9.2 Promising Developments

Paclitaxel's time above plasma concentration of 0.05 μmol/L (T_>0.05) is associated with both efficacy and toxicity outcomes, suggesting the potential for TDM-guided dosing. Several prospective RCTs in patients with advanced NSCLC have been conducted, aiming for a target time above 0.05 μmol/L paclitaxel plasma concentration between 26 and 31 hours or ≥ 15 h without a clearly defined upper limit for 0.10 μmol/L (T_>0.10) [123]. All studies demonstrated reduced paclitaxel-associated toxicity, primarily neuropathy, while efficacy was not significantly different compared to BSA-based dosing. For nab-paclitaxel, literature concerning TDM-guided dosing in NSCLC patients based on a specific plasma concentration is limited. A study by Chen et al in 150 patients with various tumours receiving either 100 mg/m² weekly or 300 mg/m² Q3W nab-paclitaxel found time above the C_threshold of 720 μg/L (0.86 and 3.75 h, respectively) to be associated with a ≥ 50% decrease in neutrophils and that the development of neutropenia to be positively associated with age (but not with hepatic function, tumour type, gender or dosing schedule) [127].

Genotyping and metabolic phenotyping for paclitaxel, and thus nab-paclitaxel, may also be an opportunity, although to a lesser extent. Ovarian cancer patients (n = 93) carrying the CYP2C8*3 allele showed a significantly increased paclitaxel AUC and 11% lower clearance than non-carriers [131]. Unsurprisingly, patients carrying the CYP2C8*3 allele were associated with an increased risk of paclitaxel-associated neurotoxicity and higher incidences of complete response compared to non-carriers (55% vs 23%) [132]. Lastly, having an ABCB1 dysfunctional allele was associated with an increase in paclitaxel-associated neuropathy [133], gastro-intestinal toxicity, and possibly increased survival outcomes relative to non-carriers [134].

Weekly dosing of paclitaxel instead of Q3W has shown favourable results. A meta-analysis including 10 RCTs in 3504 advanced solid tumour patients showed that weekly paclitaxel treatment reduces severe neutropenia and sensor neuropathy (10 RCTs; odds ratio [OR] = 0.49; 95% CI 0.30–0.82) and improves response rates (5 NSCLC RCTs; OR = 1.24; 95% CI 1.01–1.53) compared to Q3W [135]. For nab-paclitaxel, multiple studies show that reducing the dosing interval of nab-paclitaxel to 100 mg/m² weekly resulted in improved efficacy and less toxicity compared to 300 mg/m² Q3W [136, 137].

In pancreas cancer studies, the grade of nab–paclitaxel-induced neutropenia of weekly dosing seems to be an independent predictive for grade III–IV versus grade I–II neutropenia (19.2 vs 11.3 months, p < 0.001) and prognostic factor (HR = 0.79; 95% CI 0.69–0.91, p = 0.001) associated with increased OS [138]. In a prospective study by Scheithauer et al, 421 patients with metastatic pancreas cancer receiving nab-paclitaxel 125 mg/m² weekly. 172 (41%) patients received a dose reduction and 300 (71%) received a dose delay. Patients who had a dose reduction and dose delay completed more cycles and received higher cumulative dosing compared to patients not receiving a dose reduction. Furthermore, patients receiving no dose reduction and dose delay were significantly associated with decreased OS compared to patients receiving dose reduction (6.9 vs 11.4 months, HR = 1.93; 95% CI 1.53–2.44, p < 0.0001) and dose delay (6.2 vs 10.1 months, HR = 2.05; 95% CI 1.60–2.63, p < 0.0001) [139].

9.3 Recommendations and Opportunities for Treatment Optimisation

For paclitaxel, we recommend starting the first cycle using BSA-based dosing for Q3W dosing of paclitaxel, followed by blood sampling around 24 h after the start of infusion and a TDM-guided dose aiming at the time above plasma concentration of 0.05 μmol/L (T_>0.05) of 26–31 h based on the recommendation by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) [123]. A validated commercial assay is readily available including a decision support tool for routine paclitaxel TDM [140]. If neutropenia grade III–IV occurred in the previous cycle, the dose of paclitaxel is reduced. Moreover, weekly dosing of paclitaxel may ameliorate the toxicity profile of paclitaxel without compromising efficacy (see Table 1). We recommend weekly dosing of nab-paclitaxel, as it offers similar opportunities to reduce toxicity while enhancing efficacy, as with paclitaxel.

10 Gemcitabine

10.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Gemcitabine (dFdC) is an analogue of cytidine with the addition of two fluorine substituents on the 2’ position of the furanose ring [141]. As dFdC is a hydrophilic prodrug, it must first be transported into the cell by membrane nucleoside transporters (mainly human equilibrative nucleoside transporters [hENTs]). Once inside the cell, dFdC is activated through intracellular phosphorylation to gemcitabine monophosphate (dFdCMP) primarily by the rate-limiting enzyme deoxycytidine kinase (dCK) [141, 142]. Additional phosphorylation creates the active metabolites gemcitabine di-(dFdCDP) and triphosphate (dFdCTP) and prevents them from being excreted from the cell [143].

Gemcitabine clearance from plasma is linear and independent of dosing up to 3650 mg/m² [144]. However, the phosphorylation of gemcitabine intracellular to dFdCDP and dfdCTP is saturated at high concentrations of gemcitabine [145]. Gemcitabine is inactivated mainly by deoxycytidine deaminase (dCDA) to di-fluoro-deoxyuridine (dFdU) or phosphorylated gemcitabine by deoxycytidylate deaminase to phosphorylated uridine (e.g., dFdCMP to dFdUMP) and subsequently to dFdU [141]. Gemcitabine and dFdU are excreted from the cell since they are not a substrate for pyrimidine nucleoside phosphorylases [144]. The dCDA is expressed at high levels in the plasma and the liver [142]. Hence, clearance of gemcitabine is fast (t_1/2 = 2–15 min), with 50–95% of gemcitabine metabolised into dFdU and excreted via the urine within 24 h (> 90% within one week as either gemcitabine [1%] or dFdU [99%]) [143]. Since dCK is the rate-limiting enzyme for activation of gemcitabine, saturation or deficiency of dCK decreases the effectiveness of gemcitabine [142]. Moreover, phosphorylated dFdU still present in the (tumour) cell can again be incorporated in DNA (and RNA) and is associated with cytotoxicity, increasing with prolonged exposure [146]. Covariates that influence gemcitabine clearance, and thus exposure, are creatinine clearance, sex, dCDA polymorphisms, and BSA [147], while age seems to have no influence [148]. Currently, gemcitabine is administered based on BSA 1000–1250 mg/m² weekly and administrated in 30 min (40 mg/m²/min), resulting in dFdC plasma concentration of 20–60 μM, whereas saturation of dCK is already reached at 15–20 μM [145].

The phosphorylated gemcitabine anabolites have multiple intracellular targets influencing DNA synthesis. Gemcitabine monophosphate inhibits ribonucleotide reductase (RNR) needed for producing deoxynucleotides, further stimulating the incorporation of gemcitabine anabolites into DNA [149]. dFdCTP inhibits DNA polymerase and is incorporated into DNA, leading to direct termination of chain elongation, preventing DNA repair enzymes from detecting DNA chain termination and inducing apoptosis [141, 142].

10.2 Promising Developments

To avoid dCK saturation and to increase intracellular accumulation of dFdCTP, prolonged gemcitabine infusion times at 10 mg/m²/min have been proposed. Indeed, administration at 10 mg/m²/min increased the accumulation of dFdCTP. However, at the same time, gemcitabine-induced toxicity was increased compared to conventional 30-minute infusion without affecting survival outcomes [150]. Literature on this topic is conflicting. A study by Lee et al (n = 48) examining the toxicity and efficacy of prolonged gemcitabine infusion (1000 mg/m²) combined with cisplatin (25 mg/m²) in elderly or poor performance status patients with NSCLC found comparable response rates and toxicity levels to those in patients with good performance status [151]. Similarly, an observational study (n = 39) by Locher et al reported similar outcomes for elderly patients (≥ 70 years) with pancreatic cancer [152]. As survival outcomes remain unaffected, but toxicity increases, this suggests that the intracellular concentrations of gemcitabine achieved with the current dosage are within the therapeutic range. Therefore, administering a reduced dose of gemcitabine over an extended period could maintain similar efficacy (being within the therapeutic exposure range) while reducing toxicity. Hence, another proposed treatment regimen for gemcitabine is the prolonged infusion of weekly low-dose gemcitabine (PLDG) for 250 mg/m² over 6 h (= 0.7 mg/m²/min). Compared to the standard administration of gemcitabine, an extensive study by Patil et al in 308 advanced SCLC patients showed no significant difference in median OS, PFS, and adverse event rate for PLDG compared to standard weekly gemcitabine dosing of 1000 mg/m² in 30 min [153].

Likewise, for gemcitabine, dosing based on neutropenia as a prognostic factor for treatment outcome is possible [34, 138]. A large study by Pallis et al looked at docetaxel-gemcitabine treatment in advanced NSCLC patients (n = 885) and found a significantly increased median OS of 12.5 (95% CI 11.3–13.7) and 11.2 months (95% CI 9.2–13.2) for mild (grade I–II) and severe (grade III–IV) neutropenia compared to 7.9 months (95% CI 6.9–8.8) for absence (grade 0) of neutropenia [107]. However, to our knowledge, only one large RCT (Phase III) has been conducted, describing 402 metastatic pancreas cancer patients receiving gemcitabine monotherapy and showed a significant association between decreased OS and gemcitabine-induced toxicity [139].

Genotyping for dCK [154] and tumour expression analysis of hENT [155] show promising results as a predictor of gemcitabine treatment outcomes. A meta-analysis including 29 studies of 253 patients with advanced pancreatic carcinoma found an association between higher hENT1 tumour expression and increased OS (HR = 0.674; 95% CI 0.509–0.893, p = 0.006), without an increase in PFS (HR = 0.740; 95% CI 0.517–1.059, p = 0.100) [156]. To further reduce interpatient variability, TDM-guided dosing for gemcitabine could be possible with a target concentration of 20 μM (~ 5 μg/mL) corresponding with saturation levels of dCK [157] or C_max correlated with gemcitabine-induced toxicity [158]. However, gemcitabine’s standard of care is administrated in 30 min, making the blood sampling needed hours after administration difficult. Moreover, immunoassays for gemcitabine are still being developed and optimised [157].

10.3 Recommendations and Opportunities for Treatment Optimisation

At present, we cannot recommend prolonging the gemcitabine infusion time, as more research is needed to determine whether a prolonged infusion of low-dose gemcitabine can maintain efficacy while reducing toxicity. Moreover, whether extended hospital stays due to longer infusion times outweigh the costs has yet to be investigated.

11 Vinorelbine

11.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

Vinorelbine is a semisynthetic vinca alkaloid that reversibly binds to the positive end of a microtubule, destabilising its function. The primary binding site of vinorelbine is β-tubulin, which induces a conformational change that increases the affinity of tubulin for itself and influences the dynamics of lengthening and shortening and increases of the microtubule. At high concentrations, vinorelbine stimulates microtubule depolymerisation and mitotic spindle destruction, and at low concentrations, it blocks mitotic progression [159]. Vinorelbine is highly lipophilic and primarily metabolised in the liver (< 20% through urinary excretion) and excreted unchanged in bile to vinorelbine N-oxide and deacetyl-vinorelbine [160]. Vinorelbine clearance is shown to be correlated with creatinine clearance but not with age and BSA [161]. However, administration of vinorelbine is currently still based on BSA. Due to a relatively low oral bioavailability of 40%, a higher dose is given per os compared to intravenous administration (60 mg/m² vs 25–30 mg/m², respectively) [162].

The hepatic clearance of vinorelbine is shown to be associated with ABCB1 [161] and partly with CYP3A genotypes [163]. Nevertheless, clearance of vinorelbine in plasma is high and approaches hepatic blood flow, indicating that the overall capacity of the liver in removing vinorelbine is high (i.e., maximised to hepatic blood flow) [160]. Only small prospective studies have investigated the relationship between vinorelbine clearance and hepatic function and have found no effect of liver impairment on the PK of vinorelbine [161, 164]. The primary vinorelbine-induced toxicity is neutropenia, anaemia, and thrombocytopenia, with the maximum dose of vinorelbine intravenously set at 35 mg/m² due to the dose-limiting toxicity of neutropenia [162].

11.2 Promising Developments

Body surface area is associated with the degree of myelosuppression (i.e., neutropenia) in vinorelbine treatment [161]. A study in metastatic breast cancer patients (n = 25) showed fixed-dose vinorelbine (+ capecitabine) to be more effective and safer compared to dosing based on BSA and found no association between vinorelbine clearance and BSA [165]. Gusella et al (n = 82) found high blood concentrations of vinorelbine and its metabolites associated with increased toxicity but not efficacy in NSCLC patients [166]. Another study (n = 201) found high BMI to be associated with increased vinorelbine-induced toxicity but found no association for the covariates sex, chemotherapeutic regimen (monotherapy vs combination therapy), prior chemotherapy, and dose of vinorelbine (< 40 vs ≥ 40 mg) [167]. In contrast, Nobili et al (n = 83) found an association between vinorelbine toxicity and covariates age and sex [168].

The clearance of technetium labelled sestamibi (^99mTc-MIBI) and midazolam could be used for phenotyping of ABCB1 and CYP3A, and clearance of both substances significantly correlated to vinorelbine clearance. However, as vinorelbine clearance is associated with creatinine clearance, the partial correlation between vinorelbine clearance and hepatic ^99mTC-MIBI clearance was 0.44 after adjusting for creatinine clearance [161].

Metronomic dosing of vinorelbine has also been investigated with promising results. A meta-analysis including 509 stage IIIb/IV NSCLC (11 RCTs) identified a similar efficacy compared to monotherapy vinorelbine, with a median PFS of 3.5 months (95% CI 2.5–4.4) and OS of 8.2 months (95% CI 7.2–9.2), and fewer and lighter adverse events with only a 16% incidence of grade III–IV adverse events (95% CI 10–22) with 9% neutropenia (95% CI 2–20) [169]. Furthermore, adding granulocyte colony-stimulating factor (G-CSF) could increase the dose intensity of vinorelbine for both daily and weekly dosing without a corresponding increase in toxicity [170].

The limited and conflicting data, particularly in NSCLC patients, prevent a definitive conclusion regarding the relationship between PK parameters and PD efficacy and toxicity endpoints of vinorelbine treatment. In addition, while prolonged infusion of vinorelbine over 96 h in a dose of 8 mg/m² has demonstrated considerable therapeutic activity, it is associated with severe toxicities, affecting half of the patients treated [171]. These results do not indicate an advantage of prolonged infusion compared to conventional weekly administration.

11.3 Recommendations and Opportunities for Treatment Optimisation

Currently, we still recommend dosing at BSA. There is insufficient evidence to suggest dosing differently, especially since BSA seems to correlate with toxicity. However, a clear PK/PD relationship between plasma exposure and response to vinorelbine has yet to be found (see Table 1), and TDM-guided dosing is not advised.

12 Concluding Remarks

Currently, all classical cytotoxic drugs, except for carboplatin, in NSCLC are dosed based on BSA. In this review, we showed many opportunities for precision dosing of classical anticancer drugs to improve NSCLC treatment outcomes in which the incidence of severe toxicity can be reduced, and efficacy can be improved (see Table 1). An important point to note is that while the type of cancer may not necessarily alter PK, it could impact efficacy (PD), making extrapolation to NSCLC patients potentially unfeasible. To address this concern, we have added footnotes to highlight the recommendations that were not investigated in NSCLC populations.

While multiple promising developments exist for cisplatin, pemetrexed, and vinorelbine, these opportunities are not yet for direct implementation and require further research. In the case of carboplatin, we recommend immediately adopting cystatin C to individualise the dose of carboplatin. We suggest weekly dosing for docetaxel, paclitaxel, and nab-paclitaxel to minimise toxicity while maintaining treatment efficacy. Specifically, for paclitaxel, when administered in a 21-day cycle, we recommend the use of TDM-guided dosing following the international IATDMCT guidelines. Finally, we advise investigating prolonging infusion times for gemcitabine to reduce toxicity without compromising effectiveness.

Although dose individualisation strategies have been shown to significantly improve health outcomes and reduce side effects, implementing precision dosing opportunities may also pose challenges. For example, individualised dosing based on TDM requires extra time and sampling, clear PK/PD relationships (often tumour-specific), logistical planning, dosing decision support, and facilities [172, 173]. Therefore, further research is needed to ensure that these strategies are both cost effective and feasible for routine clinical settings without overstraining existing healthcare systems.

Currently, much of the effort toward dose optimisation remains within the academic sphere. A major barrier to the implementation of precision dosing recommendations, based on readily available evidence, is that academic research is often not integrated or adopted by regulatory agencies or license holders. The findings of this review, alongside other academic dose optimisation studies, should reach governments, regulatory agencies, license holders, and key healthcare professionals. These recommendations should not be confined to stay as an academic exercise but should be actively considered by all stakeholders. However, there is limited commercial incentive for license holders to adjust their labelling. This is why initiatives by regulatory agents like the FDA’s Project Renewal, which aims to update prescribing information (i.e., labelling) for older oncology drugs, are so critical [174]. Such initiatives help to ensure that information remains clinically meaningful and scientifically up-to-date.

In conclusion, this narrative review provided a comprehensive overview of studies focused on individualised dosing opportunities of classical cytotoxic drugs in patients with NSCLC and outlined the most promising, readily implementable dose optimisation strategies. Some of these approaches have already been proven in multiple prospective studies and can be directly implemented into clinical practice, requiring minimal further research. Finally, although there is still much to be done to optimise classical cytotoxic therapy dosing strategies to individual patients’ characteristics in the era of precision medicine, promising developments and opportunities are numerous and encouraging.

Acknowledgements

The authors declare that there are no acknowledgements, including no funding or grants.

Declarations

Conflict of interest

The authors declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Funding

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics approval

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Availability of data and material

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Code availability

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Author contributions

M.P. Kicken contributed to conceptualisation, formal analysis, investigation, methodology, project administration, supervision, validation, visualization, writing—original draft and writing—review & editing. R. ter Heine, and M.J. Deenen contributed to conceptualization, formal analysis, investigation, methodology, supervision, validation, writing—original draft and writing—review & editing. B.E.E.M. van den Borne, A.J. van der Wekken, and M.M. van den Heuvel contributed to investigation, writing—review & editing.

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Titel: Opportunities for Precision Dosing of Cytotoxic Drugs in Non-Small Cell Lung Cancer: Bridging the Gap in Precision Medicine
Verfasst von: M. P. Kicken
M. J. Deenen
A. J. van der Wekken
B. E. E. M. van den Borne
M. M. van den Heuvel
R. ter Heine
Publikationsdatum: 05.03.2025
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 4/2025
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-025-01492-6

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Springer Medizin

Abstract

1 Introduction

2 Methods

3 Platinum-Based Compounds (Cisplatin, Carboplatin)

4 Cisplatin

4.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

4.2 Promising Developments

4.3 Recommendations and Opportunities for Treatment Optimisation

5 Carboplatin

5.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

5.2 Promising Developments

5.3 Recommendations and Opportunities for Treatment Optimisation

6 Pemetrexed

6.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

6.2 Promising Developments

6.3 Recommendations and Opportunities for Treatment Optimisation

7 Taxanes (Docetaxel, Paclitaxel, Nab-Paclitaxel)

8 Docetaxel

8.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

8.2 Promising Developments

8.3 Recommendations and Opportunities for Treatment Optimisation

9 Paclitaxel and Nab-Paclitaxel

9.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

9.2 Promising Developments

9.3 Recommendations and Opportunities for Treatment Optimisation

10 Gemcitabine

10.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

10.2 Promising Developments

10.3 Recommendations and Opportunities for Treatment Optimisation

11 Vinorelbine

11.1 Pharmacokinetics, Pharmacodynamics and Current Practice in Dosing

11.2 Promising Developments

11.3 Recommendations and Opportunities for Treatment Optimisation

12 Concluding Remarks

Acknowledgements

Declarations

Conflict of interest

Funding

Ethics approval

Consent to participate

Consent for publication

Availability of data and material

Code availability

Author contributions

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