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Malnutrition significantly alters the pharmacokinetics of medications, particularly in vulnerable populations such as children, pregnant women, elderly individuals, and individuals in low- and middle-income countries. These populations are often more vulnerable to the effects of malnutrition because of physiological, metabolic and socioeconomic factors. Changes in body composition, organ function and plasma protein levels associated with malnutrition can impact drug absorption, distribution, metabolism and excretion. In malnourished individuals, decreased serum albumin levels may increase the free (unbound) fraction of highly protein-bound acidic drugs, potentially elevating the risk of toxicity. However, this relationship is not universally straightforward, as it depends on the drug’s protein-binding characteristics, hepatic and renal function, volume of distribution and compensatory changes in drug clearance. In addition, malnutrition’s effects on liver enzymes, such as cytochrome P450 isoforms, and kidney function can result in unpredictable drug clearance, particularly for narrow-therapeutic-index medications. Emerging evidence also highlights the interplay between malnutrition and pharmacogenomics, with genetic variations further modulating drug metabolism and response. Addressing these complexities requires the development of tailored dosing regimens and adaptive therapeutic strategies to optimise treatment outcomes in these at-risk groups. This review accentuates the critical need for more robust research to inform clinical guidelines and improve health equity in managing malnourished populations globally.
Key Points
Malnutrition significantly alters drug pharmacokinetics by affecting absorption, distribution, metabolism and excretion, leading to an increased risk of subtherapeutic effects or toxicity.
Vulnerable populations such as children, elderly individuals and pregnant women are particularly vulnerable to these pharmacokinetic changes owing to their unique physiological states, compounded by malnutrition.
Individualised drug dosing and therapeutic drug monitoring are essential in malnourished patients to ensure safe and effective pharmacotherapy, especially during nutritional rehabilitation.
1 Introduction
Malnutrition, defined as an imbalance between nutrient intake and the body’s physiological needs, encompasses a spectrum of conditions including protein-energy malnutrition (PEM), micronutrient deficiencies and undernutrition. It remains a persistent global health challenge, particularly in low- and middle-income countries, where it disproportionately affects vulnerable populations such as children, pregnant women and elderly individuals [1, 2]. Beyond its detrimental impact on overall health and disease susceptibility, malnutrition induces a series of physiological alterations that can profoundly influence the pharmacokinetics of many commonly prescribed medications. These changes may disrupt drug absorption, distribution, metabolism and excretion, potentially resulting in subtherapeutic responses, increased toxicity or therapeutic failure [3].
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Importantly, malnutrition presents in diverse clinical forms, including kwashiorkor, marasmus, stunting and wasting, each associated with distinct physiological consequences that may influence drug disposition. The relationship between malnutrition and pharmacotherapy is complex and often under-recognised in clinical guidelines (refer to Fig. 1). Malnourished patients frequently require individualised and closely monitored pharmacological interventions, as standard dosing regimens may not account for the altered physiological state. A deeper understanding of how malnutrition affects drug disposition is therefore essential to inform safer and more effective treatment strategies [3‐5]. This article critically examines the interplay between malnutrition and drug pharmacokinetics, providing clinical insights and evidence-based recommendations to optimise pharmacological care in malnourished populations.
Fig. 1
Impact of malnutrition on pharmacokinetics: physiological changes and clinical consequences. GFR glomerular filtration rate, GI gastrointestinal, ↓ decreased, ↑ increased
This narrative review examines the impact of malnutrition on drug pharmacokinetics. A comprehensive literature search was conducted across major scientific databases, including PubMed, ScienceDirect and Scopus, to identify relevant peer-reviewed articles published in English, primarily between 2015 and 2025. The search strategy utilised key terms such as malnutrition, pharmacokinetics, pregnant women, paediatrics, older persons and pharmacotherapy.
Studies were included based on their relevance to the effects of malnutrition on drug absorption, distribution, metabolism and excretion, as well as their implications for therapeutic efficacy and safety. Articles focusing solely on general pharmacokinetics without reference to malnutrition or vulnerable populations were excluded. A thematic analysis approach was used to synthesise the data, with findings categorised according to pharmacokinetic changes observed across different patient groups.
3 Types of Malnutrition and Clinical Relevance
Malnutrition is a multifaceted condition that manifests in various clinical forms, each with distinct pathophysiological mechanisms and implications for pharmacological management (refer to Table 1). The type and severity of nutrient deficiencies, whether protein, energy or micronutrient related, determine the clinical presentation and potential impact on drug pharmacokinetics [3, 6].
Table 1
Clinical features and pharmacokinetic implications of different types of malnutrition
Type of malnutrition
Clinical features
Pharmacokinetic implications
Kwashiorkor
Oedema
Fatty liver
Dermatitis
Anaemia
Hair changes
↓ Plasma protein levels → altered protein binding
Impaired hepatic metabolism, potential ↓ drug clearance
Marasmus
Severe muscle wasting
Loss of subcutaneous fat
Growth retardation
↓ Volume of distribution for lipophilic drugs
Altered absorption
↓ Renal clearance (from reduced lean body mass)
Stunting
Chronic growth failure
Short stature
Result of prolonged undernutrition
Altered gut mucosa and barrier function
↓ CYP enzyme activity
Variable oral bioavailability
Wasting
Acute weight loss
Muscle and fat loss
Often infection associated
Hepatic steatosis affects metabolism
↓ Immune function (may alter drug response)
Possible ↓ metabolic clearance
Micronutrient deficiencies (often co-occurring)
Depends on the specific nutrient (e.g. iron, zinc, vitamin A, B12)
May impair enzyme cofactor availability
Affects metabolic enzyme function and tissue repair
Modifies the therapeutic efficacy and toxicity of some drugs
CYP cytochrome P450, ↓ decreased, → leads to
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Protein-energy malnutrition is broadly categorised into kwashiorkor and marasmus, which are especially prevalent in paediatric populations in low-resource settings [7]. Kwashiorkor, results primarily from protein deficiency and is characterised by clinical features such as oedema, fatty liver, skin and hair changes, and anaemia. These manifestations may be associated with alterations in plasma protein binding and hepatic metabolism, thereby influencing drug distribution and biotransformation [3, 7, 8].
Marasmus, in contrast, arises from a general deficiency in both protein and calories. It presents with marked muscle wasting, loss of subcutaneous fat and impaired growth. The reduction in lean body mass and fat stores in individuals with marasmus can significantly affect drug distribution volumes and fat-soluble drug kinetics [3, 7, 8].
Stunting, typically a consequence of chronic nutritional deprivation during critical growth periods in children, is associated with long-term changes in gastrointestinal function and mucosal integrity. These changes may affect the expression and activity of drug-metabolising enzymes, such as cytochrome P450 (CYP) isoenzymes, and transport proteins, which can alter oral drug bioavailability [9].
Wasting, a more acute form of malnutrition, results from an insufficient food intake, increased metabolic demands or persistent infections. It is characterised by rapid weight loss and a marked decline in muscle and fat tissue [10]. Clinically, wasting is linked to hepatic steatosis, reduced immune function and altered metabolic clearance of drugs. These physiological alterations necessitate a careful adjustment of drug dosing, particularly for medications with narrow therapeutic indices.
It is also important to recognise that these forms of malnutrition often overlap in clinical practice and may be compounded by micronutrient deficiencies. Such complexity places an emphasis on the need for individualised pharmacotherapy based on nutritional status and clinical presentation.
4 Pharmacokinetics in Malnutrition
The effects of malnutrition on drug pharmacokinetics span multiple physiological processes, including absorption, distribution, metabolism and excretion. While detailed tables outlining each phase will be provided, the table below summarises these core alterations to highlight their interconnected nature and clinical relevance (refer to Table 2). This concise overview is intended to serve as a practical reference for clinicians when considering pharmacological adjustments in malnourished patients.
Table 2
Summary of the effects of malnutrition on pharmacokinetic processes
Pharmacokinetic parameter
Malnutrition effect
Absorption
↓ Gastric enzymes, altered pH → ↓ bioavailability
May be reduced/delayed (especially for fat-soluble drugs)
Distribution
↓ Albumin, altered body composition → ↑ toxicity risk
Most affected: altered body composition → changes in Vd and plasma protein binding
Metabolism
Impaired liver enzyme function → ↓ drug clearance
Reduced hepatic enzyme function → slower metabolism
Excretion
↓ Renal function → drug accumulation and toxicity
Potential renal impairment → reduced clearance
↓ decreased, ↑ increased, → lead to , Vd volume of distribution
4.1 Impact of Malnutrition on Drug Absorption
The gastrointestinal tract undergoes both structural and functional changes during malnutrition, which can significantly impair drug absorption. These alterations include reduced mucosal surface area and inflammation of the intestinal lining, particularly in individuals with severe wasting and diarrhoea [3, 11, 12]. Although changes in the rate of absorption may not always have clinical significance, reductions in the extent of absorption, reflected in decreased bioavailability, can substantially affect drug exposure and therapeutic efficacy [13].
Hypochlorhydria, commonly observed in malnourished individuals, reduces gastric acid secretion, thereby altering the solubility and bioavailability of pH-dependent drugs [14]. Additionally, malnutrition leads to atrophy of the intestinal mucosa and a reduction in villous height, which diminishes the absorptive surface area [12]. This is further compounded by delayed gastric emptying and disrupted gut motility, leading to unpredictable drug transit times. The prevalence of gastrointestinal infections and parasitic infestations in malnourished populations further exacerbates the problem by compromising mucosal integrity and introducing competition for nutrient and drug absorption [15, 16]. Collectively, these alterations may result in suboptimal plasma concentrations of orally administered drugs, necessitating dose modifications or alternative routes of administration (refer to Table 3).
Table 3
Impact of malnutrition on drug absorption
Population
Impact of malnutrition on drug absorption
Example
Children
Immature GI tract + mucosal atrophy → ↓ enzyme activity and nutrient transporter function
Poor absorption of antibiotics (e.g. ampicillin) or fat-soluble vitamins (e.g. vitamin A)
Elderly individuals
Age-related ↓ gastric acid + malnutrition-induced gut mucosal changes
Reduced absorption of calcium carbonate, iron and vitamin B12
Pregnant women
Hyperemesis + malnutrition → reduced oral bioavailability of nutrients and oral medications
↓ Absorption of oral iron supplements and prenatal vitamins during severe vomiting episodes
GI gastrointestinal, ↓ decreased, → lead to
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4.2 Impact on Drug Distribution
Malnutrition markedly alters the distribution of drugs within the body because of changes in body composition and plasma protein levels (refer to Table 4). The significant reduction in adipose tissue and lean body mass observed in marasmus and marasmic-kwashiorkor affects the volume of distribution for lipophilic and hydrophilic drugs, respectively [3]. Evidence from multiple studies reviewed by Verrest et al. indicates that malnutrition, particularly kwashiorkor, influences drug distribution. A decreased volume of distribution has been reported for lipophilic drugs such as isoniazid, as well as for chloroquine and nevirapine, in malnourished patients [3]. Conversely, an increased volume of distribution has been observed for the hydrophilic drug streptomycin in individuals with kwashiorkor [3]. These pharmacokinetic changes appear to be specific to severe forms of malnutrition, as similar effects were not observed for isoniazid and streptomycin in cases of moderate malnutrition.
Table 4
Impact of malnutrition on drug distribution
Population
Impact of malnutrition on drug distribution
Example
Children
↓ Albumin levels + less fat → ↑ free drug concentrations
Increased risk of toxicity with phenytoin (highly protein bound)
Elderly individuals
Sarcopenia + ↓ albumin + increased fat → altered Vd of both hydrophilic and lipophilic drugs
Enhanced CNS effects of diazepam due to increased Vd and prolonged half-life
Pregnant women
Increased plasma volume + malnutrition-induced ↓ albumin
↑ Free concentration of antiretroviral drugs such as lopinavir/ritonavir in malnourished pregnant patients with HIV
CNS central nervous system, HIV human immunodeficiency virus, Vd volume of distribution, ↓ decreased, ↑ increased, → lead to
A hallmark of protein-energy malnutrition is hypoalbuminemia, which reduces the protein-binding capacity of drugs that are normally bound to serum albumin [4, 17]. Interestingly, some highly albumin-bound drugs, including chloroquine, quinine, ethambutol, rifampicin, lopinavir and efavirenz, have shown increased excretion in moderate malnutrition, likely due to higher unbound fractions from hypoalbuminemia [18‐20]. This may reduce the free (active) fraction of the drug, potentially lowering its therapeutic efficacy despite higher total plasma concentrations.
Consequently, the free (active) fraction of these drugs increases, potentially enhancing both their therapeutic and toxic effects. Furthermore, in kwashiorkor, generalised oedema and expanded extracellular fluid volume may dilute hydrophilic drugs, further complicating dose predictions. These complex alterations in drug distribution highlight the importance of individualised dosing and careful monitoring in malnourished patients [3, 17].
4.3 Impact on Drug Metabolism
The liver, the primary site of drug metabolism, is particularly susceptible to the effects of malnutrition. In kwashiorkor, hepatic steatosis is common and may impair hepatic function [21, 22]. Malnutrition has been shown to downregulate CYP enzymes, especially those involved in phase I metabolic pathways such as oxidation, reduction and hydrolysis [3, 23]. This enzymatic downregulation leads to reduced metabolic clearance of many drugs, thereby prolonging their half-life and increasing the risk of accumulation and toxicity (refer to Table 5). Although phase II reactions, such as glucuronidation and sulfation, may be less affected, prolonged or severe malnutrition can compromise these pathways as well.
Accumulation of propranolol or benzodiazepines (e.g. lorazepam)
Pregnant women
Hormonal changes usually ↑ CYP3A4 activity, but malnutrition may blunt this upregulation
Altered metabolism of drugs such as nifedipine or methyldopa in malnourished pregnancies
CYP cytochrome P450, ↓ decreased, ↑ increased, → lead to
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For isoniazid, increased area under the curve (AUC) and slower clearance are likely related to impaired acetylation, although the precise impact of malnutrition on this metabolic pathway remains unclear [3]. Drugs primarily metabolised by CYP enzymes, such as quinine and saquinavir, also exhibit reduced metabolism, potentially due to both CYP suppression and increased α1-acid glycoprotein, which decreases the unbound fraction available for hepatic uptake [3]. Hepatic enzyme immaturity in children and an age-related decline in elderly individuals can exacerbate these effects, further complicating drug metabolism in malnourished individuals across the age spectrum.
4.4 Impact on Drug Excretion
Renal excretion, the primary elimination pathway for many drugs, may also be compromised in malnourished patients. Malnutrition is associated with reduced renal blood flow, decreased glomerular filtration rate (GFR) and impaired tubular function [3, 24]. These changes reduce the kidneys’ ability to eliminate drugs and their metabolites, leading to drug accumulation and an increased toxicity risk, particularly for renally excreted medications such as aminoglycosides and certain beta-lactam antibiotics. Additionally, electrolyte imbalances common in malnourished states, such as hyponatremia and hypokalaemia, can influence drug transport and reabsorption mechanisms in the renal tubules, further affecting drug clearance [25]. These alterations highlight the need for renal function monitoring and potential dose adjustments in malnourished patients receiving nephrotoxic or renally cleared drugs.
Evidence from pharmacokinetic studies supports these concerns. Impaired GFR in severe malnutrition can significantly affect drug elimination [3]. Decreased clearance has been observed for hepatically and renally eliminated drugs across various malnourished states. For instance, isoniazid shows reduced elimination in individuals with kwashiorkor and other forms of malnutrition, while similar reductions have been noted for saquinavir, zidovudine, chloroquine and quinine as reported by Verrest et al. [3] For the renally cleared drug streptomycin, excretion was reduced in kwashiorkor but remained unchanged in moderate malnutrition. These findings highlight the importance of an individualised pharmacokinetic assessment in malnourished patients, especially when using drugs with narrow therapeutic indices or renal clearance pathways (refer to Table 6).
Table 6
Impact of malnutrition on drug excretion
Population
Impact of malnutrition on drug excretion
Example
Children
↓ GFR and immature kidneys → prolonged drug elimination
Increased nephrotoxicity risk from aminoglycosides such as gentamicin
Elderly individuals
Age-related ↓ renal function + malnutrition → ↓ renal clearance
Accumulation of digoxin or lithium, leading to toxicity
Pregnant women
Pregnancy ↑ GFR, but malnutrition can mask or reverse this effect
Reduced excretion of beta-lactams or magnesium sulphate in pre-eclamptic malnourished patients
GFR glomerular filtration rate, ↓ decreased, ↑ increased, → lead to
5 Clinical Implications for Pharmacotherapy in Vulnerable Populations
Malnutrition significantly alters pharmacokinetic and pharmacodynamic processes, particularly in vulnerable populations such as children, pregnant women and elderly individuals. These groups exhibit unique physiological states that are further complicated by nutrient deficiencies, necessitating a more cautious and individualised approach to pharmacological care.
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In children, malnutrition presents substantial challenges to drug therapy owing to developmental immaturity compounded by nutrient deficits [22]. Malnourished children, particularly those with marasmus or kwashiorkor, often exhibit delayed gastric emptying, reduced bile salt secretion and impaired intestinal integrity, all of which negatively affect drug absorption to a certain extent [22, 26, 27]. Furthermore, reductions in plasma proteins such as albumin alter the binding and distribution of protein-bound drugs such as phenytoin and diazepam [28]. Hepatic metabolism, already immature in early life, is often further compromised by malnutrition, particularly through downregulation of CYP enzymes [29]. Mukherjee et al. investigated the pharmacokinetic profiles (both maximum concentration and AUC from 0 to 4 h) of isoniazid, rifampicin, ethambutol and pyrazinamide in both severely malnourished and well-nourished children following administration of both the standard and revised World Health Organization-recommended paediatric doses [30]. Their findings revealed no statistically significant differences in these pharmacokinetic parameters between the two groups. Despite these observations, dosing of isoniazid and other anti-tuberculosis medications in children continues to follow age-specific weight bands as outlined in the updated World Health Organization guidelines. According to these guidelines, all children with tuberculosis should receive combination therapy comprising rifampicin, isoniazid, pyrazinamide and ethambutol.
A study by Dayal et al. showed no significant differences in isoniazid exposure (both maximum concentration and AUC from 0 to 8 h) between underweight, stunted, wasted, or severely malnourished children and their well-nourished peers [31]. In contrast, pyrazinamide exposure was significantly lower in severely malnourished older children with a low body mass index when compared with well-nourished children of similar age. Additionally, while the maximum concentration for pyrazinamide did not differ in underweight, stunted or wasted groups, the AUC from 0 to 8 h was significantly reduced in the stunted and wasted children.
Despite these findings, the study did not establish a clear link between reduced pyrazinamide exposure and tuberculosis treatment outcomes in malnourished children. The authors emphasised that malnutrition should not be treated as a single condition, as its various forms can affect drug disposition differently. They advocated for a more nuanced and evidence-based approach to evaluating how different malnutrition types influence pharmacokinetics in children. Thus, there remains a substantial gap in knowledge regarding how these drugs are processed in severely malnourished paediatric populations. Thus, there is an urgent need for more robust studies to better understand the pharmacokinetics of these drugs in malnourished children and to ensure accurate dosing.
Renal excretion, too, may be diminished because of reduced lean body mass and renal function. Consequently, therapeutic drug monitoring becomes essential, especially for drugs with narrow therapeutic indices [32]. It is important to base dosing on weight and developmental stage, with frequent reassessment, particularly in children who are severely wasted [33]. Moreover, micronutrient deficiencies, especially zinc and vitamin A, should be corrected to support enzyme function and optimise drug response [34].
Pregnant women present another layer of complexity. Pregnancy itself induces physiological changes such as increased plasma volume, altered gastric motility, enhanced renal clearance and fluctuating hepatic metabolism [35, 36]. When coupled with malnutrition, particularly protein-energy malnutrition, these changes can dramatically affect pharmacokinetics. The increase in extracellular fluid and total body water during pregnancy leads to an expanded volume of distribution for hydrophilic drugs, often resulting in reduced plasma concentrations [37, 38]. Concurrently, maternal adipose tissue increases by approximately 4 kg, which may enlarge the volume of distribution for lipophilic drugs [37]. However, the specific impact of increased fat stores on drug disposition in pregnancy remains poorly characterised, as available data are limited.
During pregnancy, plasma protein binding of drugs is reduced because of declining levels of both albumin and α1-acid glycoprotein [37, 39]. Physiologically, albumin levels decrease progressively as gestation advances by approximately 1% at 8 weeks, 10% at 20 weeks and 13% by 32 weeks of pregnancy [37]. These reductions may be further exacerbated by certain pathophysiological conditions that lower albumin levels beyond typical pregnancy-associated changes. Reduced protein binding increases the free (unbound) fraction of drugs, particularly for those with limited clearance, thereby enhancing their distribution into tissues [38]. For some medications, this shift has significant clinical implications. For instance, drugs such as phenytoin and tacrolimus exhibit increased unbound plasma concentrations during pregnancy due to both lower albumin levels and elevated clearance rates [38, 40]. As the pharmacological activity and toxicity of these agents are closely linked to their unbound concentrations, relying solely on total plasma concentrations for dose adjustments may result in unintended drug toxicity.
Alterations in CYP450 enzyme activity during pregnancy can significantly affect drug metabolism. For instance, enhanced CYP3A4 activity leads to the increased metabolism of drugs such as glyburide, nifedipine and indinavir. In contrast, the activity of certain other CYP isoforms, including CYP1A2 and CYP2C19, tends to decline progressively throughout gestation [36, 38, 41]. However, the clinical implications of these reductions remain uncertain and may vary depending on the specific drug involved. Therefore, a more accurate and safer approach in pregnant patients is to monitor free drug concentrations and tailor dosing accordingly, ensuring the unbound drug remains within the therapeutic window.
In Uganda, malnourished pregnant women experiencing food insecurity showed a 33% lower exposure to lopinavir compared with previously studied, well-nourished pregnant women. This reduction was attributed to decreased lopinavir bioavailability. However, increasing the dose of lopinavir/ritonavir to 600 mg/150 mg during pregnancy, using the tablet formulation, was found to restore lopinavir plasma concentrations to those typically observed in non-pregnant adults receiving the standard dose [42, 43].
Additionally, micronutrient deficiencies in pregnancy (such as folate, iron and iodine) may interfere with the efficacy and safety of prescribed drugs while simultaneously affecting foetal development [44]. Clinical care should therefore include routine nutritional assessments during antenatal visits, and where deficiencies are identified, appropriate supplementation should precede or accompany drug therapy. Drug selection and dosing should also take into account gestational age, organ function and foetal safety, using the lowest effective dose for medications with narrow therapeutic margins.
In elderly patients, age-related physiological decline is frequently magnified by malnutrition, contributing to altered pharmacokinetics and increased vulnerability to adverse drug reactions [10]. Malnutrition related to disease typically results in rapid skeletal muscle wasting, while age-associated malnutrition leads to a slower yet progressive decline in muscle mass. This protein catabolism manifests as reduced muscle mass, strength and function, significantly impairing physical performance [45]. Additionally, both malnutrition and insufficient dietary protein intake on their own have been linked to decreased bone mineral density in older adults [10, 46]. When combined with diminished physical performance and poor coordination factors that heighten the risk of falls, these changes further accelerate the development of osteoporosis and increase the likelihood of osteoporotic fractures [10]. Collectively, these consequences substantially raise the risk of falls, functional decline, loss of independence and long-term disability in elderly individuals.
Sarcopenia and a loss of adipose tissue affect the volume of distribution, altering the pharmacokinetics of both hydrophilic and lipophilic drugs [47, 48]. Malnourished elderly individuals also experience decreased renal clearance, reduced hepatic enzyme activity and hypoalbuminemia, all of which may lead to drug accumulation and toxicity [49]. Moreover, polypharmacy is highly prevalent in this group, increasing the risk of drug–drug and drug–nutrient interactions [50]. Cognitive decline, frailty and social challenges often compromise medication adherence, highlighting the need for a multidisciplinary approach [10]. Clinical strategies should include comprehensive geriatric assessments that incorporate nutritional screening, regular medication reviews, and the use of tools such as the Beers Criteria or STOPP/START guidelines to identify and minimise potentially inappropriate medications. Dose adjustments based on renal and hepatic function are crucial, as is ongoing education and support for both patients and caregivers to enhance adherence and therapeutic outcomes.
Across all populations, several cross-cutting strategies are vital to optimising pharmacological care (refer to Table 7). Individualised dosing based on nutritional status, organ function and body composition must be prioritised over standardised regimens. The integration of clinical decision-support tools can aid in identifying risks associated with specific drugs or dosing patterns in malnourished individuals. Interdisciplinary collaboration among pharmacists, clinicians, nurses and dietitians is critical to ensuring that both pharmacological and nutritional needs are met holistically. Routine screening using tools such as mid-upper arm circumference, body mass index for age or the Mini Nutritional Assessment - Short Form for elderly individuals should guide therapeutic planning [51‐53]. Finally, patient and caregiver education is essential for promoting understanding of treatment regimens, enhancing adherence and ultimately improving health outcomes in these nutritionally vulnerable groups.
Table 7
Cross-cutting strategies for all populations
Strategy
Rationale
Individualised dosing
Adjust based on nutritional status, body composition and renal/hepatic function
Use of clinical decision-support tools
Helps flag inappropriate or high-risk drugs in vulnerable populations
Interdisciplinary care
Collaboration between pharmacists, clinicians, dietitians and nurses ensures holistic management
Routine nutritional screening
Use tools such as MUAC, BMI for age and MNA-SF (elderly patients) to guide interventions
Patient and caregiver education
Improves understanding of drug therapy and promotes adherence
BMI body mass index, MNA-SF Mini Nutritional Assessment - Short Form, MUAC mid-upper arm circumference
6 Limitations of Traditional Creatinine-Based Estimated GFR Equations in Malnutrition
The accurate assessment of renal function in malnourished patients represents a significant clinical challenge that has profound implications for pharmacokinetic considerations and drug dosing. Traditional creatinine-based estimated glomerular filtration rate (eGFR) equations, including the widely used CKD-EPI and MDRD formulas, are fundamentally flawed when applied to malnourished populations because of their reliance on serum creatinine as a marker of kidney function [54]. These equations were developed and validated in populations with normal nutritional status and fail to account for the physiological alterations that occur in malnutrition. The primary limitation stems from the fact that creatinine is produced by muscle metabolism through the non-enzymatic conversion of creatine and creatine phosphate [55]. In malnourished patients, particularly those with protein-energy malnutrition, muscle wasting (sarcopenia) results in significantly reduced muscle mass, leading to decreased creatinine production and low serum creatinine levels. Consequently, creatinine-based eGFR calculations systematically overestimate kidney function in these patients, potentially leading to inappropriate drug dosing and an increased risk of nephrotoxicity [56, 57].
The problem is particularly pronounced in paediatric populations, where malnutrition significantly impairs growth and development. Children affected by malnutrition often exhibit stunted growth and reduced muscle mass for their age, rendering age-based serum creatinine reference ranges unreliable. Additionally, the constantly evolving physiology of children, including shifting body composition and maturing renal function, further complicates an accurate assessment of kidney function. In this context, eGFR is often overestimated in malnourished children, leading to serious clinical implications such as inappropriate dosing of renally excreted medications, missed diagnoses of acute kidney injury and delayed recognition of progressive chronic kidney disease. These challenges are particularly acute in resource-constrained settings where malnutrition is common and access to precise renal function testing is limited.
This impaired estimation of renal function has direct consequences for pharmacotherapy, particularly for drugs primarily eliminated by the kidneys. Several studies have shown significantly reduced renal clearance of antibiotics such as cefoxitin and penicillin in children with PEM [17]. While clearances of other renally eliminated drugs such as gentamicin, amikacin, ethambutol and streptomycin were also lower in these children, the differences were not statistically significant compared to healthy children or post-nutritional rehabilitation values [17]. Despite these alterations, none of these drugs reached toxic plasma concentrations, though it is important to note that multi-dose pharmacokinetic studies were not conducted. Moreover, the renal excretion mechanisms of these agents in the context of PEM have not been thoroughly explored. Overall, the renal impairment observed in malnourished children appears to cause only mild drug retention, insufficient to provoke toxicity typically associated with renal failure. Based on this, it has been proposed that drug dosing in malnourished individuals may be more accurately determined using relative body weight rather than total weight or body surface area. This concept may hold true for paediatric patients with PEM as well.
Cystatin C has emerged as a superior alternative biomarker for renal function assessment in malnourished patients, offering several distinct advantages over creatinine-based measurements [58]. Unlike creatinine, cystatin C is a low-molecular-weight protein produced by all nucleated cells at a relatively constant rate, regardless of muscle mass, sex or nutritional status. Studies have consistently demonstrated that cystatin C-based eGFR equations provide more accurate estimates of kidney function in patients with extremes of body composition, including those with muscle wasting conditions such as malnutrition [58, 59].
The clinical utility of cystatin C extends beyond its independence from muscle mass [58, 59]. Research has shown that combined creatinine-cystatin C equations offer superior accuracy compared with either marker alone, particularly in vulnerable populations such as malnourished patients and children. The CKD-EPI creatinine-cystatin C equation has been shown to improve the accuracy of eGFR estimation and reduce the bias associated with single-marker approaches [59, 60]. Additionally, cystatin C may serve as an earlier indicator of kidney function decline, as its levels begin to rise when GFR falls below 90 mL/min/1.73 m2, compared with creatinine, which typically remains within normal limits until GFR drops below 60 mL/min/1.73 m2 [61]. This enhanced sensitivity is particularly valuable in malnourished patients, where early detection of kidney dysfunction is crucial for preventing further deterioration and optimising therapeutic interventions.
Despite a growing awareness, significant gaps remain in our understanding of the pharmacokinetic consequences of malnutrition. There is an urgent need for clinical studies that quantify these effects across different drug classes and patient populations. Moreover, population-specific dosing algorithms that incorporate nutritional status would greatly aid clinicians in delivering personalised medicine. Emerging fields such as pharmacogenomics and systems pharmacology offer promising avenues to integrate nutrition as a variable in pharmacokinetic modelling. Ultimately, addressing the pharmacological implications of malnutrition requires an interdisciplinary research agenda that bridges clinical pharmacology, nutrition science and public health.
Malnutrition exerts profound and multifactorial effects on the pharmacokinetics of medications, often resulting in altered therapeutic outcomes. Understanding the pathophysiological changes associated with malnutrition, particularly in absorption, distribution, metabolism and excretion, is critical for optimising drug therapy in affected individuals. Clinicians must remain vigilant to these changes and adopt a flexible patient-centred approach that includes dose adjustment, therapeutic drug monitoring and nutritional support. By integrating a nutritional assessment into routine pharmacological care, we can improve medication safety and therapeutic efficacy in one of the most medically fragile populations.
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Funding
Open access funding provided by University of KwaZulu-Natal. No funding was received for the preparation of this article.
Conflicts of Interest/Competing Interests
Nokwanda N. Ngcobo has no conflicts of interest that are directly relevant to the content of this article.
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Authors’ Contributions
NN contributed to the design, data collection, and analysis of the results and to the writing of the manuscript. NN approved the final version to be reviewed and possibly published.
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