Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab

The complement system is an important part of innate immunity and consists of three different pathways, all converging at C3, the central complement component (Fig. 1). The classical pathway (CP) and lectin pathway (LP) are, respectively, triggered by antibodies (such as the case in gMG) and mannose-containing sugars on pathogens. The alternative pathway (AP) is unique since spontaneous autoactivation is always present and can be further triggered by bacterial components such as lipopolysaccharide and bacterial toxins [14]. Activation of each pathway leads to the formation of the C3 convertase (C3bBb) which can cleave C3, leading to chemotaxis and opsonization with C3a and C3b, respectively. The generation of large amounts of C3b results in the formation of C5 convertase (C3bBbC3b). In turn, C5 convertase can cleave C5, thereby producing the second anaphylatoxin C5a, and C5b, which can bind complement proteins C6, C7, C8 and C9 to form the end product of the complement system, the membrane attack complex or C5b-C9 (C5b-C9), which causes cell lysis (Fig. 1). Normally, the complement system is tightly controlled by regulatory proteins present in both the fluid phase and on the cell surface [14, 15].

Together with our growing knowledge of the complement system and its role in different diseases, evidence has emerged for complement blockage with drugs. Eculizumab was approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as standard treatment for PNH, aHUS and gMG in 2007, 2011, and 2017, respectively [1, 6, 16, 17]. Eculizumab administration is reported in two disease situations: primarily in diseases resulting from complement dysregulation (e.g. PNH and aHUS) and subsequently in diseases with extensive complement activation with inflammation (e.g. gMG) [18‐30]. For the purpose of this review, the most prominent diseases with reported eculizumab therapy are described, in light of sufficient PK and PD data being available.

((“Eculizumab” [Supplementary Concept] OR eculizumab[tiab] OR soliris[tiab]) AND (“pharmacology” [Subheading] OR “Pharmacology, Clinical”[Mesh] OR “Pharmacokinetics”[Mesh] OR “Drug Interactions”[Mesh] “Dose-Response Relationship, Drug”[Mesh] OR Pharmaco*[tiab] OR exposure*[tiab] OR drug monitoring[tiab] OR drug concentration*[tiab] OR target concentration*[tiab] OR clinical pharmacolog*[tiab] OR drug interact*[tiab] OR adverse effect*[tiab] OR adverse event*[tiab] OR adverse drug event*[tiab] OR contraindication*[tiab] OR contra-indication*[tiab] OR dose-response[tiab]))

[Adverse Drug Reaction, Drug Administration, Drug Concentration, Drug Dose, Drug Therapy, Drug Toxicity, Intravenous Drug Administration, Pharmaceutics, Pharmacokinetics, Pharmacology]

(exp eculizumab/ae, ad, cr, do, dt, to, iv, pr, pk, pd) OR (Eculizumab OR soliris).ti,ab,kw.

AND exp drug exposure/ or exp drug safety/ or exp pharmacodynamics/ or exp pharmacokinetics/ or exp clinical pharmacology/ or pharmacokinetic*.ti,ab,kw. or pharmacodynamic*.ti,ab,kw. or drug interact*.ti,ab,kw. or adverse effect*.ti,ab,kw. or adverse event*.ti,ab,kw. or adverse drug event*.ti,ab,kw. or contraindication*.ti,ab,kw. or contra-indication*.ti,ab,kw. or dose-response.ti,ab,kw.

The characteristics of eculizumab are similar to other monoclonal antibodies. Eculizumab is administered as an intravenous infusion in 25–45 min, with a maximum of 2 h and 4 h in patients > 12 and < 12 years of age, respectively (see Table 2 for different dosage regimens for each disease) [41]. After intravenous administration, eculizumab is primarily distributed in blood plasma. Limited distribution in cerebrospinal fluid has been described, with concentrations 5000-fold lower than in plasma [45]. Distribution to other tissues has not been described in human studies. In vivo animal studies and in vitro studies with normal human tissues showed intracellular distribution to a wide variety of cells, consistent with expected C5 localization.

As described for other monoclonal antibodies, eculizumab is internalized by either pinocytosis or binding to the Fcγ receptor, and is subsequently degraded by lysosomes to peptides and amino acids. Recycling of eculizumab can occur via binding to the neonatal Fc receptor (FcRn). However, the eculizumab–C5 complex does not dissociate efficiently in the endosome. Hence, eculizumab catabolism is mainly driven by target-mediated drug disposition [49]. Eculizumab contains no known active metabolites [41, 50, 51]. Due to its molecular size, eculizumab is not excreted in urine, except in patients with heavy proteinuria, where eculizumab concentrations as high as 56 µg/ml have been detected [52, 53].

The eculizumab concentration in serum depends on various factors. The dose is based on weight and the underlying disease, with the exception of patients with a body weight < 40 kg; this group receives a weight-based regimen. To identify the optimal dose of eculizumab necessary to block complement, six single-dose studies were performed in patients with RA (C97-001-01) and SLE (C97-002-01) [3]. Patients were infused with a single dose, ranging from 0.1 to 8 mg/kg of eculizumab in 30 min (Tables 3, 4). As reported in the scientific discussion of the EMA, these single-dose studies in RA patients yielded a mean clearance (CL) of 0.26 ml/kg/h, with a central volume of distribution (Vd1) of 15 ml/kg and peripheral volume of distribution (Vd2) of 20 ml/kg [42]. The estimated Vd at steady state was calculated at 35 ml/kg, and, with this Vd, the estimated half-life was 93 h (3.9 days). The area under the curve (AUC) was calculated at 24,467.6 µg·h/ml. A twofold increase in the eculizumab dose from 4 to 8 mg/kg in RA and SLE yielded an increase of 60% and 15% in mean maximum concentration (C_max), respectively (Table 3). Furthermore, the AUC increased by 70% and 103% in RA and SLE, respectively (Table 3). Both distribution and half-life were dose-dependent (Table 3) [3, 42]. One highly interesting observation was the presence of a second peak after 2 days postdose, which was most likely related to drug recycling from the endosome back into the bloodstream, as described for other monoclonal antibodies [54]. This peak is most often seen in single-dose, phase I or II studies due to timing of blood sampling, which is more frequent. The concentration of this second peak is minimal compared with the first peak and does not impact the overall drug exposure or complement inhibition; thus, it is presumed not to be therapeutically significant (Alexion, personal correspondence) [54].

Multiple-dose studies were conducted in three patient groups with RA (C01-004), IMG (C99-004), and PNH (C02-001). With the use of a two-compartment model, PK parameters were calculated (see Table 4). At therapeutic doses, eculizumab shows linear PK, indicating saturation of the drug target [42].

The population PK of eculizumab in PNH patients have previously been described using a one-compartment model (Table 4). CL was estimated to be 0.3 ml/kg/h, with a Vd of 110.3 ml/kg, which was slightly larger than the estimated serum volume of patients [3]. The elimination rate (K) was 0.0028 l/h, which resulted in a half-life of approximately 271.7 h (11.3 days). Of note, in the study by de Latour et al., trough concentration (C_trough) varied from 18 to 643 µg/ml and half-life was highly variable, ranging from 4 to 21 days [55]. In PNH, eculizumab C_trough measured at week 26 was 97 ± 60 µg/ml. C_trough levels remained stable during the maintenance phase (see Table 2 for the dosing regimen) [3, 56]. During the follow-up of patients in both pivotal trials (extension study, E05-001), C_trough concentrations < 35 µg/ml were repeatedly observed in 10% of patients; this correlated with rapid eculizumab CL > 0.4 ml/kg/h or a shorter half-life < 130 h. In half of the patients, breakthrough hemolysis was successfully treated by decreasing the eculizumab dosing interval. Overall, 10% of patients needed frequent changes in dosing interval to sustain remission [57].

In the group of aHUS patients, PK were best described using a one-compartment model. In total, 57 patients from C08-002A/B, C08-003 A/B, and C09-001r were included in the analysis (see Tables 3 and 4). CL was estimated at 0.2 ml/kg/h and Vd was 87.7 ml/kg. C_trough concentrations measured at week 26 in aHUS were 242 ± 101 µg/ml, with an estimated half-life of 291 h (12.1 days) [56]. PK data of both prospective trials (C08-002 A/B and C08-003 A/B) showed C_trough levels of 93 and 113 µg/ml, respectively, in adults, and 104 and 109 µg/ml, respectively, in adolescent patients. The AUC during the maintenance phase in both trials was 77,693 µg·h/ml and 104,228 µg·h/ml, respectively, in adults, and 104,228 µg·h/ml and 99,956 µg·h/ml, respectively, in adolescents. The observed C_max was up to 431 µg/ml [56].

The PK properties of eculizumab in gMG were best described using a two-compartment model (see Table 4) [5, 38, 58]. Data from two studies were combined to best describe the PK. Fourteen participants from a double-blind, placebo-controlled, randomized, crossover trial (C08-001) and 126 participants from a double-blind, placebo-controlled, randomized trial (ECU-MG-301) were included in the analysis. CL was estimated at 0.09 ml/kg/h, with a Vd1 of 27.6 ml/kg and Vd2 of 30 ml/kg (median weight of 80 kg in the eculizumab arm). Eculizumab C_trough concentrations were approximately twofold different at steady state when comparing both studies. Following a maintenance dose of 1200 mg, C_max and C_trough levels reported at week 26 were 738 ± 288 µg/ml and 341 ± 172 µg/ml. Interindividual variability was high, and CL and Vd were up to 42% and 24%, respectively [5, 58].

Finally, another study assessed the PK properties of eculizumab in patients with HSCT-TMA. Eculizumab CL ranged from 0.23 to 3.39 mL/kg/h during the induction phase. Important to note is the high number of erythrocyte and platelet transfusions due to severe and persistent gastrointestinal bleeding, which explains the high CL rate. At the fifth week, CL decreased to a mean CL (± standard deviation [SD]) of 0.35 ml/kg/h (± 0.25). PK modeling with a one-compartment model of eculizumab therapy in HSCT recipients showed a high variability of eculizumab CL of 1.4 ml/kg/h (relative standard error 9%), especially within the first weeks of treatment [18].

Several covariates have been identified to impact the PK of eculizumab, including age, weight, C5 concentrations, C5b-C9 concentrations, human anti-human antibodies (HAHAs), plasma exchange therapy, and pregnancy. The impact of these covariates will be discussed in the next paragraphs.

In all trials conducted by the pharmaceutical company, hemolytic activity was used to determine the PD properties of eculizumab [6, 60]. Hemolytic activity reflects total complement activity (reported as CH50) by testing the capacity of patient serum to lyse sheep or chicken erythrocytes coated with antibodies. In case of a functional complement system, the CP will be activated, subsequently leading to C5b-C9 deposition on the erythrocytes and thus causing hemolysis. CH50 levels correlated with eculizumab serum trough levels, and a completely blocked complement (no hemolytic activity measured) was the aim of treatment.

It is important to realize that besides the classical hemolytic assay based on lysis of erythrocytes, various other assays have been introduced to measure CH50. Furthermore, C5 function and AP activity (AP50) are also reported as a marker of eculizumab effectiveness [71]. In case of eculizumab levels > 100 µg/ml, undetectable CH50, AP50, and normal C5 levels with inhibited C5 function have been reported [71]. There are different (commercial) assays available to measure these markers, of which the so called ‘Wieslab’ ELISA is quite commonly used. However, more studies are needed to explore the relation between AP50 and eculizumab trough levels since AP50 levels are not totally suppressed despite high eculizumab levels [71, 72].

The exposure–effect relationship in the phase I and II trials in RA, SLE, and IMG patients was mainly evaluated using the serum hemolytic activity to assess complement inhibition [3]. The results of the single-dose studies in RA (C97-001) and SLE (C97-002) showed a concentration-dependent inhibition of hemolytic activity, with an inverse relationship between eculizumab concentration and C5 complement blockade. Hemolytic activity was completely blocked within 15 min in almost all patients who received a 2.0 mg/kg dose, but hemolytic activity reappeared within 2 days. By increasing the dose to 4 or 8 mg/kg, complement activity was completely suppressed for 7–14 and 11–21 days, respectively. Complete blockade of complement hemolytic activity was measured at eculizumab concentrations as low as 29–55 µg/ml and 11–35 µg/ml in RA and SLE patients, respectively [3].

The maximum PD effect was modeled using a maximum effect (E_max) model using the above-described data from RA patients pooled with data of IMG and PNH patients, with a half maximal effective concentration (EC50) of 43 µg/ml (95% CI 39.04–47.78) [3]. Since eculizumab concentrations are reported in both the bound to C5 and unbound proportion of eculizumab, this could indicate an overestimation of the required eculizumab concentration for complement blockade [73]. The EMA scientific report using pooled data from all single- and multiple-dose studies (performed in various patient populations) suggested that an eculizumab serum concentration of 35 µg/ml is sufficient to completely block complement activation. Hence, the dosing schedule of 600 mg in the initiation phase, followed by 900 mg every 2 weeks, was selected as the most optimal dosing regimen to suppress complement inhibition in almost all PNH patients (Table 2) [3, 42].

Nonetheless, based on a meta-analysis of data from 177 PNH patients, a higher target exposure was recommended for patients with aHUS. In this cohort of PNH patients, some patients (up to 10%) had remaining complement activity [16, 57]. It was expected that this residual activity could result in clinical manifestations in the aHUS patient group. The main expected clinical manifestations reported were the potential rapid loss of kidney function in case of insufficient blockage, with ongoing active TMA [61]. In the FDA approval package, an analysis is shown that describes the necessity of a minimal eculizumab concentration of 50 µg/ml to achieve a > 90% decrease in free C5 [56]. Hence, in aHUS patients, higher eculizumab concentrations of 50–100 µg/ml for complete complement blockade are recommended (Table 2).

We have reviewed the basic pharmacology of eculizumab in all diseases for which this drug is currently licensed. Next, we described the PK and PK–PD relations, as well as covariates that impact both the PK and PD. Striking is the high interindividual variation. We advocate for an individualized approach to provide the best tailored care.

We hypothesize that by performing therapeutic drug monitoring (TDM), one could adjust the dose and/or dosing intervals and thereby maximize treatment response and reduce treatment costs. As an illustration, we performed a simulation study of the effect of TDM of eculizumab in PNH patients. We simulated a population of 1000 virtual adult patients based on the population PK and PD of eculizumab in PNH patients as described by the pharmaceutical company, with an average body weight of 70 kg (20% variation) [73]. After simulation of the virtual individuals, the individual PK parameters for each individual were used to predict the steady-state exposure after dose adaptation. We simulated the PK of eculizumab at steady state (after 8 weeks of standard treatment, including the induction phase) and applied a protocol for TDM based on the measurement of the steady state C_trough, using the following algorithm: the absolute dose at each administration (900 mg) remained the same, but the dosing interval was adjusted, based on the measured C_trough levels. When C_trough levels were below the target of 30 µg/ml, we decreased the dosing interval from 2 weeks to 1 week. When the C_trough was between 30 and 90 µg/ml, the usual 2-week interval was maintained. At higher exposure, the dosing intervals were extended: a C_trough of 90–120 resulted in a 3-week dosing interval, a C_trough between 120 and 210 µg/ml resulted in a 4-week interval, and a C_trough > 210 µg/ml resulted in an interval of 5 weeks. The results of the simulation are presented in Fig. 2, where the predicted C_trough and associated inhibition of C5 activity are shown before and after the TDM intervention. Without TDM, large interindividual variation in predicted exposure can be observed, with a median C_trough level of 76 µg/ml (range 4–362) when using the standard dose regimen. By using TDM, median C_trough levels decrease to 58 µg/ml (range 30–131) [Fig. 2a]. Furthermore, simultaneously with decreasing the range of C_trough levels, a decrease in the variation of C5 inhibition could be observed, with more patients reaching target attainment (Fig. 2b). Moreover, with our TDM regimen, an overall cost reduction of 11% in 1000 simulated patients was achieved by diminishing eculizumab administrations. We calculated the costs of eculizumab administrations alone per patient for 1 year of treatment and compared this with standard treatment (patients who are treated for 1 year according to the treatment scheme described in Table 2). Every patient received 8 weeks of standard therapy, after which TDM was applied with adjustment of the interval between eculizumab administrations. Costs largely depend on the cumulative dose per patient, ranging from €211,618 per patient per year with a 5-weekly interval, to €726,524 per patient per year with a 1-weekly interval.

Of note, studies reporting TDM in patients with aHUS and HSCT-TMA have increased substantially [9, 10, 18, 52]. However, remarkable is the lack of studies regarding TDM in patients with PNH. Future studies should give more insight into the possibility and potential risks of TDM in patients with PNH.

In conclusion, we would like to stress the potential of TDM for the use of eculizumab in various diseases. To fully determine the efficacy of therapy, we advise monitoring both eculizumab serum levels and complement blockade by CH50. One could argue that eculizumab levels alone would be sufficient since there seems to be a clear correlation between C_trough and complement blockade. In our opinion, CH50 is especially important in the case of clinical deterioration despite adequate exposure.