Imti Sammons

Choonara

Oshikoya Ka

Sammons Hm

Dr K A Oshikoya

A systematic review of pharmacokinetics studies in children with protein-energy malnutrition

Keywords: protein-energy malnutrition, drug, absorption, distribution, protein-binding, metabolism, children protein-energy malnutrition, drug, absorption, distribution, protein-binding, metabolism, children

Background: Protein-energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics.

Methods: Literature search in MEDLINE and EMBASE databases (January 1960-December 2009) was performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite stimulating drugs.

Results: Altogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was however unaffected for most of the drugs. The effect of PEM on total clearance and half-life of drugs primarily metabolised by the liver was studied for eight drugs. There was decreased total clearance and an associated increased half-life of five drugs.

For two drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs but significantly decreased for two drugs (cefoxitin and penicillin).

Conclusions:

Considering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.

Introduction

Protein energy malnutrition (PEM), also referred to as protein calorie malnutrition (PCM), has long been recognised as a common problem, especially of children in the developing countries, whose inadequate nutritional intake is deficient for socioeconomic reasons [1]. PEM is a range of deficiency states, from mild to severe, defined as a range of pathological conditions arising from coincident deficiency of protein and calories in varying proportions, occurring most frequently in infants and young children, and commonly associated with infections [2].

PEM is responsible, directly or indirectly, for approximately half of the 10.8 million deaths per year in children under five. It also contributes to many deaths associated with infectious diseases among children in developing countries [3]. Infection is one of the major complications of PEM; malaria, bronchopneumonia and measles being the most frequently associated infections with PEM in African children [4]. HIV/AIDS and tuberculosis frequently co-exist with PEM but begin to manifest when the immunity is lowered [5]. The World Health Organization (WHO) has recommended empirical treatment of all children admitted for PEM with ampicillin and gentamicin [6], even in the absence of overt signs and symptoms of sepsis. Considering the wide range of pathophysiological derangements in children with PEM [7][8][9], the pharmacokinetics of many of the drugs used for their treatments is likely to be affected and this may require dose modification. This systematic review was therefore performed to determine the effects of PEM on drug pharmacokinetic parameters.

Methods

Identification of relevant literature

Articles describing drug absorption and disposition in malnourished children were searched using EMBASE and MEDLINE (January 1960-December 2009) and by reference tracking. In both methods, the search strategies involved an initial search for all relevant abstracts using the medical subject heading (MeSH) descriptor 'drug absorption' OR 'drugs absorption', limited to children between 0-17 years. Similar searches were done for drug distribution, metabolism and clearance by substituting the term 'absorption' with each of the terms 'distribution', 'pharmacokinetics', 'pharmacodynamic', 'metabolism', 'elimination' and 'clearance', respectively. Another search was made using the MeSH descriptors 'malnutrition' OR 'mal-nutrition' OR 'undernutrition' OR 'undernutrition' OR 'underweight' OR 'under-weight' OR 'protein energy malnutrition' OR 'protein-energy F o r P e e r R e v i e w 4 malnutrition' OR 'protein calorie malnutrition' OR 'protein-calorie malnutrition' OR 'marasmus' OR 'marasmic-kwashiorkor' OR 'kwashiokor'. The searches were later combined to give the desired abstracts. Abstracts that appeared in both EMBASE and MEDLINE searches were hand searched to avoid duplication and to judge whether they met the inclusion criteria.

Inclusion criteria were abstracts that assessed or discussed pharmacokinetics, pharmacodynamics, absorption, distribution, metabolism, elimination or clearance of drugs in children who are underweight, marasmic, marasmic-kwashiorkor, and/or kwashiorkor. Abstracts that assessed or discussed disposition of micronutrients and appetite stimulating drugs in malnourished children were excluded. Full articles of the relevant abstracts were then searched and retrieved. The references of the retrieved articles were searched manually in order to identify additional appropriate studies. The relevant additional articles that met the inclusion criteria were accessed.

Data abstraction

Two researchers (KAO and IC) reviewed each study independently, and using a standard form, extracted data on the number and year of studies; characteristics of the subjects and controls; types of drug studied; and the number of blood samples collected. The pharmacokinetic parameters studied (rate and extent of absorption, volume of distribution, protein-binding, metabolism, clearance and half-life) were extracted. We also extracted from each study data on the methods of PEM classification.

Results

Publications

The EMBASE search yielded 731 abstracts and MEDLINE546 abstracts of potential use. 50 abstracts met the inclusion criteria. Most abstracts were excluded because they assessed serum macroand micro-nutrients and serum proteins in the malnourished children. The abstracts were mainly original research (40), review articles (4) and letters to the editor (6). Both the original research articles and letters to the editor (46 publications) were included in this study. Five publications were further excluded because there were either insufficient details (no documentation of mean value of the data or the control data) or the data was published in more detail in a subsequent paper which was included in the final analysis [10][11][12][13][14]. Altogether, 41 publications were analysed in this study. The majority of the studies were published in 1970s (14) and 1980s (17), thereafter the number progressively decreased over the next two decades (Figure 1). Thirty of the studies involved one drug only. A total of 34 different drugs were studied.

Methodology of trials

The age range of the patients and control subjects used for the studies was three months to 16 years. The number of patients in individual studies varied from five to 41. Age matched, healthy children were the control subjects in 25 studies. Nutritionally rehabilitated children were used as additional control subjects in four studies and as the only control subjects in seven studies. Five studies had no control subjects. PEM was classified in the subjects according to Wellcome Trust Party classification [8] (22 studies) and Gomez classification [9] (seven studies). Co-existing infections, including tuberculosis (4), bacterial sepsis (3), malaria (2) and HIV with tuberculosis (1) were reported in the patients in 10 studies. One to 17 blood samples were collected from individual children.

Drug absorption

Table 1 shows the effect of PEM on absorption of 18 drugs [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The extent of absorption of most of the drugs (10) was not significantly affected. Ideally, in pharmacokinetic studies, rate is measured as K a (hr -1 ) and extent of absorption, F (%), as AUC oral xDose i.v /AUC i.v xDose oral . The extent of absorption was reported in this review as AUC oral or AUC i.m since most of the drugs were administered either orally or intramuscularly. The extent of absorption of eight drugs was found to be significantly increased. This was probably due to the effects of decreased clearance as all these drugs were shown to have either a prolonged half-life or decreased clearance (see below). The extent of absorption of aspirin [15], oral penicillin [19] and chloramphenicol [45], measured in terms of F (%), was reported only in one study each. F was significantly decreased for chloramphenicol in kwashiorkor by 85% compared to 44% in seven controls, P<0.05 and marasmic-kwashiorkor by 85% compared to 30% in seven controls, P<0.05 [45]. However, the difference in the F values for aspirin in both malnourished children and controls (92% and 90%, respectively) was not statistically significant [15].

In the case of oral penicillin administered to fasted PEM children, F was decreased in underweight children by 36% compared to 55% in six controls, P<0.05; increased in marasmus by 66% compared to 55% in six controls and in kwashiorkor by 83% compared to 55% in six controls, P<0.05 [19]. The statistical significance level of the decreased or increased F values for penicillin in PEM was however [45] are in contrast to the increased extent of absorption in all forms of PEM reported in another study [27]. In addition, contrasting results were also documented for quinine. The extent of absorption of oral quinine was increased [30] whereas the extent of IM absorption was not significantly affected [21]. K a was reported only for chloramphenicol [45] and six other drugs (Table 1). It was significantly increased for sulphadiazine [31] and significantly decreased for sulphamethoxazole [32] in children with PEM. In the studies involving children with different categories of PEM, the K a of chloramphenicol was significantly decreased in children with marasmic-kwashiorkor only [45] whereas it was significantly increased for oral penicillin in children suffering from kwashiorkor only [19].

Protein binding and distribution

The plasma protein binding of 20 drugs was evaluated by eight in vitro studies [21,[33][34][35][36][37][38][39].

Serum or plasma of children with kwashiorkor was used for studies of protein binding of the drugs.

The number of patients studied and their ages were not provided except for the study that involved quinine [21]. Fresh pooled adult serum and plasma were used as controls, except for the quinine study where plasma from healthy children was used as a control. The protein binding of 12 drugs was significantly reduced in kwashiorkor (Table 2). The plasma binding of quinine, expressed as a percentage of bound drugs, was however not significantly different in both the control group (94%) and PEM children (93%) [21].

The volume of distribution (Vd) of 13 drugs was evaluated in 19 studies (Table 3) [16,18,19,21,22,[40][41][42][43][44][45][46][47][48][49][50][51][52]. There were contrasting results for four drugs (gentamicin, quinine, streptomycin and theophylline). In the case of gentamicin, a study involving children with kwashiorkor documented decreased Vd [52]. In contrast, a study involving children who were underweight, marasmic or experiencing marasmic-kwashiorkor had an increased Vd of gentamicin [50]. In the case of theophylline, children with marasmus and kwashiorkor were found to have an increased Vd [49] whereas children who were underweight had no change in their Vd [49]. A separate study where the degree of malnutrition was undefined showed no effect of PEM on the Vd of theophylline [22]. In the case of streptomycin, children with kwashiorkor exhibited an increased Vd [48] whereas children with marasmus or underweight had a decreased Vd [48]. A decreased Vd for quinine in children with undefined PEM in one study [51] was in contrast to a separate study involving children with marasmus and marasmic-kwashiorkor where the Vd was unaffected [21]. 4 shows the effect of PEM on the total clearance and half-life of seven drugs that are primarily metabolised in the liver. The total clearance of five drugs was significantly decreased with a correspondingly increased half-life [18,26,40,[42][43][44]. The total clearance of quinine was significantly decreased in two studies involving poorly categorised malnourished children [51] and kwashiorkor [30], but significantly increased in another study involving children with all categories of PEM except kwashiorkor [21]. Similarly, in one study, the total clearance of chloramphenicol was either significantly decreased in kwashiorkor or unaffected in marasmus and marasmic-kwashiorkor [45].

The effects of PEM on total clearance of six drugs that are primarily eliminated by the kidneys are presented in Table 5. The total CL of two drugs only was significantly decreased [19,47,53]. The t½ of one of the drugs, cefoxitin, was not significantly increased in association with a significantly decreased CL in kwashiorkor [53]. One study documented a significant decrease in the total CL in association with a non-significant increase in t½ of penicillin in all categories of PEM [19]. This was in contrast to a separate study that documented a significant decrease in the total CL and a corresponding significant increase in the t½ of penicillin in children with kwashiorkor only [47]. There was no influence of PEM on the total clearance of the three aminoglycoside antibiotics studied [41,48,50,52]. One of these studies involving streptomycin documented an increased plasma half-life in children with kwashiorkor but no change in children who were underweight or had marasmus only [48]. This was probably as a result of presence of oedema in kwashiorkor which enhances the volume of distribution of streptomycin. There were 11 studies where the plasma half-life was calculated without any clearance values (Table 6) [15,17,20,23,25,28,29,31,32,54,55]. Five studies documented an increase in the plasma half-life of five separate drugs whereas the other studies showed no significant effect of PEM on the plasma half-life of the remaining six drugs.

Discussion

PEM is a public health problem affecting a great number of children throughout the world [1][2][3]. It is thought to be a contributory factor in the deaths of five million children under the age of five each year [3]. It is very surprising that, despite the global burden of PEM and treatment of the affected children with numerous medicines, there have been so few studies that looked at the effect of PEM on pharmacokinetics of drugs in children. It is also concerning that there are now fewer pharmacokinetic support for medicines particularly used for the treatment of infectious diseases such as HIV/AIDS, tuberculosis and malaria that frequently co-exist with PEM, the WHO has noted the lack of regular access to essential medicines for these diseases in some parts of Asia and Africa [56]. Unfortunately, Africa and Asia are two of the continents with a high burden of PEM [57]. Approximately 70% of the world's malnourished children live in Asia [58]. Lack of access to essential medicines for children, especially those suffering from PEM, might have contributed to the decline in the number of pharmacokinetic studies of drugs in PEM children.

Many of the neglected diseases in the developing world may be associated with PEM. It is well recognised that there is a lack of effective, safe, and affordable medicines to control the neglected diseases [59]. This may also be another contributory factor to the dearth of pharmacokinetic studies of drugs in PEM. It is to be hoped that the European Union research fund for neglected diseases [60] will impact positively on research on drug pharmacokinetics in PEM.

The majority of the studies did not report the effect of PEM on the rate of drug absorption.

However, where these were studied, K a was either unaffected [18,28], increased [31] or decreased [32] in children with PEM. Only two studies looked at the differential effects of marasmus, marasmickwashiorkor and kwashiorkor on the rate of drug absorption [19,45] and based on this small number of studies, it is impossible to draw firm conclusions on the effects of PEM on drug absorption rate.

Further studies may therefore be required in this area. The extent of absorption, measured in terms of AUC, was determined in most of the studies. Although, the AUC was not significantly affected for most of the drugs, it was significantly decreased for two drugs and significantly increased for another eight drugs, thus suggesting an altered bioavailability of oral drugs in PEM. This may be explained by the pathophysiological changes in the gastrointestinal system of children with PEM [7][8][9].

A major effect of PEM on drug disposition is decreased total clearance with an associated increased plasma half-life [18, 25, 26, 30, 40, 42-45, 47, 51]. Other drugs that are primarily metabolised by the liver had increased half-lives in association with PEM [28,29,31,54], although their clearances were not reported. This would suggest that lower doses or alternatively less frequent administration of drugs in PEM may be required.

PEM appears not to affect the total clearance of most drugs primarily eliminated by the kidneys as their values remained almost unchanged in the subjects and controls [16,41,48,50,52]. This was probably because most of these drugs are rarely metabolised as they are known to be eliminated unchanged via the kidneys [61]. Decreased total clearance was, however, demonstrated for two drugs [19,47,53] and in view of the small number of drugs studied (six), it is impossible to draw firm conclusions about the effect of PEM on renal drug elimination. Further studies may therefore be required.

It should be recognised that PEM is not a single disease entity but rather a disease spectrum.

The wide range of pathophysiological changes in PEM probably explains the wide variations in the findings from different researchers who have studied the same drug in different categories of PEM. The presence of oedema in association with kwashiorkor or marasmic-kwashiorkor [7] is more likely to result in changes in volume of distribution of drugs as observed with gentamicin [50,52] and quinine [21,51]. Only one group of researchers (Eriksson and co-workers) [19,45,48,49] have systematically investigated the effects of different categories and severities of PEM on drug disposition. Their studies have shown that PEM is a disease spectrum with varying effects on drug pharmacokinetics.

Few antibiotics were studied relative to the wide spectrum of infections that may affect children with PEM. Only two antimalarials; chloroquine [25,39] and quinine [21,30,51], were studied. Resistance to chloroquine has necessitated the use of artemesinin based combined therapy as first line treatment for malaria in sub-Saharan African countries [62] and the WHO has recommended artemether and lumefantrine combination in malaria endemic developing nations [63]. Artemether and lumefantrine, like chloroquine, are metabolised by hepatic microsomal enzymes (CYP 3A4) [64,65].

Given the effects of PEM on chloroquine metabolism, artemether and lumefantrine metabolism may be affected by PEM; therefore the pharmacokinetics of these antimalarials may need to be studied in children with PEM so as to determine their appropriate dosing and safety.

The pharmacokinetics of antituberculosis drugs have been extensively studied in PEM. Their rates and extents of absorption [16], protein-binding [34,36], Vd [16,46] and total clearance [16] remain unaffected. Antiretroviral drugs, however, have not been studied in PEM and this is probably due to lack of access to these drugs in developing countries in the 1980s when most of the studies were performed. Additionally, antiretroviral drugs are rarely commenced in the acute phase management of PEM.

Lack of detailed information about the patients, using blood samples of adults as controls, and limiting the studies to only kwashiorkor patients would suggest that the data on protein binding in PEM F o r P e e r R e v i e w 10 be interpreted with caution. Although information on drug protein binding in older children is lacking, a qualitative and quantitative decrease in plasma protein binding has been documented in newborns compared to adults [66]. This emphasises the significance of age and the use of appropriate controls in a study of protein binding in PEM. Many of the studies showed decreased protein binding in PEM [33][34][35][36][37][38]. Although the decreased plasma binding was statistically significant, it was felt that the clinical significance of these findings was likely to be minimal since most of the drugs studied were not highly protein bound [67]. Further research in this area may be required for only highly protein-bound drugs.

Most of the studies described in this review used traditional methods of studying pharmacokinetics. These involved taking multiple blood samples from each patient. Alternative approaches that involve the use of population pharmacokinetics where a fewer number of blood samples are collected from a larger number of patients [68] or non-invasive methods such as the caffeine breath test [69,70] may be necessary.

The World Health Organization (WHO), in collaboration with UNICEF, Save the Children, Médicins Sans Frontières and the International Paediatric Association has launched a major campaign entitled "Make Medicines Child Size" [71]. This welcome initiative will result in increased research in relation to medicines for children in developing countries. It is to be hoped that this initiative will increase interest in the relationship between PEM and pharmacokinetics of drugs in children which has been neglected in the last decade.

Conclusion

Despite the enormous global burden of PEM and its association with a wide spectrum of infections, the pharmacokinetics of drugs used for its treatment has not been extensively studied. PEM significantly decreased total clearance and increased the half-life of many drugs primarily metabolised in the liver which may indicate a need for modifications of the doses of these drugs in acute phase management of PEM. Further pharmacokinetic studies are required to determine appropriate doses and safety of drugs used for PEM children. These studies need to recognise that PEM is a disease spectrum and should evaluate the differential effects of kwashiorkor and marasmus on drug disposition in children.

Acknowledgement

F o r P e e r R e v i e w 20

Table 2 Effect of kwashiorkor on drug protein binding or free unbound drug (f u )

Drug Drug

Decreased protein binding (Increased f u ) Increased protein binding (Decreased f u )

Chloramphenicol [33,34] Chloroquine [39] Cloxacillin [34] Digoxin [34 35] Unaffected protein binding (Unaffected f u ) Ethionamide [34,36] Flucloxacillin [34] Dicumarol [34] Para-amino salicylic acid [34,36] Ethambutol [34,36] Penicillin [34] Gentamicin [34] Phenobarbitone [34] Isoniazid [33,34] Salicylate [37] Rifampicin [34,36] Streptomycin [34,36] Phenytoin [34] Sulphamethoxazole [34] Quinine [21] Thiopentone [34,38]

F o r P e e r R e v i e w 21

F o r P e e r R e v i e w 23

F o r P e e r R e v i e w 25

Introduction

Protein energy malnutrition (PEM), also referred to as protein calorie malnutrition (PCM), has long been recognised as a common problem, especially of children in the developing countries, whose inadequate nutritional intake is deficient for socioeconomic reasons [1]. PEM is a range of deficiency states, from mild to severe, defined as a range of pathological conditions arising from coincident deficiency of protein and calories in varying proportions, occurring most frequently in infants and young children, and commonly associated with infections [2].

PEM is responsible, directly or indirectly, for approximately half of the 10.8 million deaths per year in children under five. It also contributes to many deaths associated with infectious diseases among children in developing countries [3]. Infection is one of the major complications of PEM; malaria, bronchopneumonia and measles being the most frequently associated infections with PEM in African children [4]. HIV/AIDS and tuberculosis frequently co-exist with PEM but begin to manifest when the immunity is lowered [5]. The World Health Organization (WHO) has recommended empirical treatment of all children admitted for PEM with ampicillin and gentamicin [6], even in the absence of overt signs and symptoms of sepsis. Considering the wide range of pathophysiological derangements in children with PEM [7][8][9], the pharmacokinetics of many of the drugs used for their treatments is likely to be affected and this may require dose modification. This systematic review was therefore performed to determine the effects of PEM on drug pharmacokinetic parameters.

Methods

Identification of relevant literature

Articles describing drug absorption and disposition in malnourished children were searched

Data abstraction

Two researchers (KAO and IC) reviewed each study independently, and using a standard form, extracted data on the number and year of studies; characteristics of the subjects and controls; types of drug studied; and the number of blood samples collected. The pharmacokinetic parameters studied (rate and extent of absorption, volume of distribution, protein-binding, metabolism, clearance and half-life) were extracted. We also extracted from each study data on the methods of PEM classification.

Results

Publications

The EMBASE search yielded 731 abstracts and MEDLINE546 abstracts of potential use. 50 abstracts met the inclusion criteria. Most abstracts were excluded because they assessed serum macroand micro-nutrients and serum proteins in the malnourished children. The abstracts were mainly original research (40), review articles (4) and letters to the editor (6). Both the original research articles and letters to the editor (46 publications) were included in this study. Five publications were further excluded because there were either insufficient details (no documentation of mean value of the data or the control data) or the data was published in more detail in a subsequent paper which was included in the final analysis [10][11][12][13][14]. Altogether, 41 publications were analysed in this study. The majority of the studies were published in 1970s ( 14) and 1980s (17), thereafter the number progressively decreased over the next two decades (Figure 1). Thirty of the studies involved one drug only. A total of 34 different drugs were studied.

Methodology of trials

The age range of the patients and control subjects used for the studies was three months to 16

Drug absorption

Table 1 shows the effect of PEM on absorption of 18 drugs [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. The extent of absorption of most of the drugs (10) was not significantly affected. Ideally, in pharmacokinetic studies, rate is measured as K a (hr -1 ) and extent of absorption, F (%), as AUC oral xDose i.v /AUC i.v xDose oral . The extent of absorption was reported in this review as AUC oral or AUC i.m since most of the drugs were administered either orally or intramuscularly. The extent of absorption of eight drugs was found to be significantly increased. This was probably due to the effects of decreased clearance as all these drugs were shown to have either a prolonged half-life or decreased clearance (see below). The extent of absorption of aspirin [15], oral penicillin [19] and chloramphenicol [45], measured in terms of F (%),

was reported only in one study each. F was significantly decreased for chloramphenicol in kwashiorkor by 85% compared to 44% in seven controls, P<0.05 and marasmic-kwashiorkor by 85% compared to 30% in seven controls, P<0.05 [45]. However, the difference in the F values for aspirin in both malnourished children and controls (92% and 90%, respectively) was not statistically significant [15].

In the case of oral penicillin administered to fasted PEM children, F was decreased in underweight children by 36% compared to 55% in six controls, P<0.05; increased in marasmus by 66% compared to 55% in six controls and in kwashiorkor by 83% compared to 55% in six controls, P<0.05 [19]. [45] are in contrast to the increased extent of absorption in all forms of PEM reported in another study [27]. In addition, contrasting results were also documented for quinine. The extent of absorption of oral quinine was increased [30] whereas the extent of IM absorption was not significantly affected [21].

K a was reported only for chloramphenicol [45] and six other drugs (Table 1). It was significantly increased for sulphadiazine [31] and significantly decreased for sulphamethoxazole [32] in children with PEM. In the studies involving children with different categories of PEM, the K a of chloramphenicol was significantly decreased in children with marasmic-kwashiorkor only [45] whereas it was significantly increased for oral penicillin in children suffering from kwashiorkor only [19].

Protein binding and distribution

The plasma protein binding of 20 drugs was evaluated by eight in vitro studies [21,[33][34][35][36][37][38][39].

Serum or plasma of children with kwashiorkor was used for studies of protein binding of the drugs.

The number of patients studied and their ages were not provided except for the study that involved quinine [21]. Fresh pooled adult serum and plasma were used as controls, except for the quinine study where plasma from healthy children was used as a control. The protein binding of 12 drugs was significantly reduced in kwashiorkor (Table 2). The plasma binding of quinine, expressed as a percentage of bound drugs, was however not significantly different in both the control group (94%) and PEM children (93%) [21].

The volume of distribution (Vd) of 13 drugs was evaluated in 19 studies (Table 3) [16,18,19,21,22,[40][41][42][43][44][45][46][47][48][49][50][51][52]. There were contrasting results for four drugs (gentamicin, quinine, streptomycin and theophylline). In the case of gentamicin, a study involving children with kwashiorkor documented decreased Vd [52]. In contrast, a study involving children who were underweight, marasmic or experiencing marasmic-kwashiorkor had an increased Vd of gentamicin [50]. In the case of theophylline, children with marasmus and kwashiorkor were found to have an increased Vd [49] whereas children who were underweight had no change in their Vd [49]. A separate study where the degree of malnutrition was undefined showed no effect of PEM on the Vd of theophylline [22]. In the case of streptomycin, children with kwashiorkor exhibited an increased Vd [48] whereas children with marasmus or underweight had a decreased Vd [48]. A decreased Vd for quinine in children with undefined PEM in one study [51] was in contrast to a separate study involving children with marasmus and marasmic-kwashiorkor where the Vd was unaffected [21]. Table 4 shows the effect of PEM on the total clearance and half-life of seven drugs that are primarily metabolised in the liver. The total clearance of five drugs was significantly decreased with a correspondingly increased half-life [18,26,40,[42][43][44]. The total clearance of quinine was significantly decreased in two studies involving poorly categorised malnourished children [51] and kwashiorkor [30], but significantly increased in another study involving children with all categories of PEM except kwashiorkor [21]. Similarly, in one study, the total clearance of chloramphenicol was either significantly decreased in kwashiorkor or unaffected in marasmus and marasmic-kwashiorkor [45].

The effects of PEM on total clearance of six drugs that are primarily eliminated by the kidneys are presented in Table 5. The total CL of two drugs only was significantly decreased [19,47,53]. The t½ of one of the drugs, cefoxitin, was not significantly increased in association with a significantly decreased CL in kwashiorkor [53]. One study documented a significant decrease in the total CL in association with a non-significant increase in t½ of penicillin in all categories of PEM [19]. This was in contrast to a separate study that documented a significant decrease in the total CL and a corresponding significant increase in the t½ of penicillin in children with kwashiorkor only [47]. There was no influence of PEM on the total clearance of the three aminoglycoside antibiotics studied [41,48,50,52]. One of these studies involving streptomycin documented an increased plasma half-life in children with kwashiorkor but no change in children who were underweight or had marasmus only [48]. This was probably as a result of presence of oedema in kwashiorkor which enhances the volume of distribution of streptomycin.

There were 11 studies where the plasma half-life was calculated without any clearance values (Table 6) [15,17,20,23,25,28,29,31,32,54,55]. Five studies documented an increase in the plasma half-life of five separate drugs whereas the other studies showed no significant effect of PEM on the plasma half-life of the remaining six drugs.

Discussion

PEM is a public health problem affecting a great number of children throughout the world [1][2][3]. It is thought to be a contributory factor in the deaths of five million children under the age of five each year [3]. It is very surprising that, despite the global burden of PEM and treatment of the affected children with numerous medicines, there have been so few studies that looked at the effect of PEM on pharmacokinetics of drugs in children. It is also concerning that there are now fewer pharmacokinetic support for medicines particularly used for the treatment of infectious diseases such as HIV/AIDS, tuberculosis and malaria that frequently co-exist with PEM, the WHO has noted the lack of regular access to essential medicines for these diseases in some parts of Asia and Africa [56]. Unfortunately, Africa and Asia are two of the continents with a high burden of PEM [57]. Approximately 70% of the world's malnourished children live in Asia [58]. Lack of access to essential medicines for children, especially those suffering from PEM, might have contributed to the decline in the number of pharmacokinetic studies of drugs in PEM children.

Many of the neglected diseases in the developing world may be associated with PEM. It is well recognised that there is a lack of effective, safe, and affordable medicines to control the neglected diseases [59]. This may also be another contributory factor to the dearth of pharmacokinetic studies of drugs in PEM. It is to be hoped that the European Union research fund for neglected diseases [60] will impact positively on research on drug pharmacokinetics in PEM.

The majority of the studies did not report the effect of PEM on the rate of drug absorption.

However, where these were studied, K a was either unaffected [18,28], increased [31] or decreased [32] in children with PEM. Only two studies looked at the differential effects of marasmus, marasmickwashiorkor and kwashiorkor on the rate of drug absorption [19,45] and based on this small number of studies, it is impossible to draw firm conclusions on the effects of PEM on drug absorption rate.

Further studies may therefore be required in this area. The extent of absorption, measured in terms of AUC, was determined in most of the studies. Although, the AUC was not significantly affected for most of the drugs, it was significantly decreased for two drugs and significantly increased for another eight drugs, thus suggesting an altered bioavailability of oral drugs in PEM. This may be explained by the pathophysiological changes in the gastrointestinal system of children with PEM [7][8][9].

A major effect of PEM on drug disposition is decreased total clearance with an associated increased plasma half-life [18, 25, 26, 30, 40, 42-45, 47, 51]. Other drugs that are primarily metabolised by the liver had increased half-lives in association with PEM [28,29,31,54], although their clearances were not reported. This would suggest that lower doses or alternatively less frequent administration of drugs in PEM may be required.

PEM appears not to affect the total clearance of most drugs primarily eliminated by the kidneys as their values remained almost unchanged in the subjects and controls [16,41,48,50,52]. This was probably because most of these drugs are rarely metabolised as they are known to be eliminated unchanged via the kidneys [61]. Decreased total clearance was, however, demonstrated for two drugs [19,47,53] and in view of the small number of drugs studied (six), it is impossible to draw firm conclusions about the effect of PEM on renal drug elimination. Further studies may therefore be required.

It should be recognised that PEM is not a single disease entity but rather a disease spectrum.

The wide range of pathophysiological changes in PEM probably explains the wide variations in the findings from different researchers who have studied the same drug in different categories of PEM. The presence of oedema in association with kwashiorkor or marasmic-kwashiorkor [7] is more likely to result in changes in volume of distribution of drugs as observed with gentamicin [50,52] and quinine [21,51]. Only one group of researchers (Eriksson and co-workers) [19,45,48,49] have systematically investigated the effects of different categories and severities of PEM on drug disposition. Their studies have shown that PEM is a disease spectrum with varying effects on drug pharmacokinetics.

Few antibiotics were studied relative to the wide spectrum of infections that may affect children with PEM. Only two antimalarials; chloroquine [25,39] and quinine [21,30,51], were studied. Resistance to chloroquine has necessitated the use of artemesinin based combined therapy as first line treatment for malaria in sub-Saharan African countries [62] and the WHO has recommended artemether and lumefantrine combination in malaria endemic developing nations [63]. Artemether and lumefantrine, like chloroquine, are metabolised by hepatic microsomal enzymes (CYP 3A4) [64,65].

Given the effects of PEM on chloroquine metabolism, artemether and lumefantrine metabolism may be affected by PEM; therefore the pharmacokinetics of these antimalarials may need to be studied in children with PEM so as to determine their appropriate dosing and safety.

The pharmacokinetics of antituberculosis drugs have been extensively studied in PEM. Their rates and extents of absorption [16], protein-binding [34,36], Vd [16,46] and total clearance [16] remain unaffected. Antiretroviral drugs, however, have not been studied in PEM and this is probably due to lack of access to these drugs in developing countries in the 1980s when most of the studies were performed. Additionally, antiretroviral drugs are rarely commenced in the acute phase management of PEM.

Lack of detailed information about the patients, using blood samples of adults as controls, and limiting the studies to only kwashiorkor patients would suggest that the data on protein binding in PEM a qualitative and quantitative decrease in plasma protein binding has been documented in newborns compared to adults [66]. This emphasises the significance of age and the use of appropriate controls in a study of protein binding in PEM. Many of the studies showed decreased protein binding in PEM [33][34][35][36][37][38]. Although the decreased plasma binding was statistically significant, it was felt that the clinical significance of these findings was likely to be minimal since most of the drugs studied were not highly protein bound [67]. Further research in this area may be required for only highly protein-bound drugs.

Most of the studies described in this review used traditional methods of studying pharmacokinetics. These involved taking multiple blood samples from each patient. Alternative approaches that involve the use of population pharmacokinetics where a fewer number of blood samples are collected from a larger number of patients [68] or non-invasive methods such as the caffeine breath test [69,70] may be necessary.

The World Health Organization (WHO), in collaboration with UNICEF, Save the Children, Médicins Sans Frontières and the International Paediatric Association has launched a major campaign entitled "Make Medicines Child Size" [71]. This welcome initiative will result in increased research in relation to medicines for children in developing countries. It is to be hoped that this initiative will increase interest in the relationship between PEM and pharmacokinetics of drugs in children which has been neglected in the last decade.

Conclusion

Despite the enormous global burden of PEM and its association with a wide spectrum of infections, the pharmacokinetics of drugs used for its treatment has not been extensively studied. PEM significantly decreased total clearance and increased the half-life of many drugs primarily metabolised in the liver which may indicate a need for modifications of the doses of these drugs in acute phase management of PEM. Further pharmacokinetic studies are required to determine appropriate doses and safety of drugs used for PEM children. These studies need to recognise that PEM is a disease spectrum and should evaluate the differential effects of kwashiorkor and marasmus on drug disposition in children. Chloramphenicol [33,34] Chloroquine [39] Cloxacillin [34] Digoxin [34 35] Unaffected protein binding (Unaffected f u ) Ethionamide [34,36] Flucloxacillin [34] Dicumarol [34] Para-amino salicylic acid [34,36] Ethambutol [34,36] Penicillin [34] Gentamicin [34] Phenobarbitone [34] Isoniazid [33,34] Salicylate [37] Rifampicin [34,36] Streptomycin [34,36] Phenytoin [34] Sulphamethoxazole [34] Quinine [21] Thiopentone [34,38] F o r P e e r R e v i e w 21 Note: U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified † Clearance and half-life of the drug were provided in the study, clearance was apparently decreased in PEM but the level of significance was not provided when compared with normal control children.

Acknowledgement

F

F o r P e e r R e v i e w 20

F o r P e e r R e v i e w 23

F o r P e e r R e v i e w 25

  in PEM children than 20 years ago. Despite the provision of international aid and

Figure 1 :

 1 Figure 1: Frequency of publication of pharmacokinetic studies of drugs in children with protein-energy malnutrition

  years. The number of patients in individual studies varied from five to 41. Age matched, healthy children were the control subjects in 25 studies. Nutritionally rehabilitated children were used as additional control subjects in four studies and as the only control subjects in seven studies. Five studies had no control subjects. PEM was classified in the subjects according to Wellcome Trust Party classification[8] (22 studies) and Gomez classification[9] (seven studies). Co-existing infections, including tuberculosis (4), bacterial sepsis (3), malaria (2) and HIV with tuberculosis (1) were reported in the patients in 10 studies. One to 17 blood samples were collected from individual children.

  in PEM children than 20 years ago. Despite the provision of international aid and

  caution. Although information on drug protein binding in older children is lacking,

Figure 1 :

 1 Figure 1: Frequency of publication of pharmacokinetic studies of drugs in children with protein-energy malnutrition

  The decreased extents of chloramphenicol absorption reported byEriksson et al

	not reported.
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	6

Table 1

 1 Effect of protein-energy malnutrition on drug absorption (AUC and K a )

	Mean AUC (µg/ml/hr)	Mean absorption rate
		(K a /hr)

Note: †= significant difference in K a values at P<0.05 *= unit uncertain; **= values in µg/ml/min; IM = intramuscular; U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ψ= drug administered to fasted patients; R-rehabilitated patients; H= healthy children with normal weight; NH= non-healthy children with normal weight.

Table 3

 3 Effect of protein-energy malnutrition on drug distribution (Vd) = values for adult reference; U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ¶= drug administered intravenously; §= values in litres; R-rehabilitated patients; H= healthy children with normal weight; NH= non-healthy children with normal weight.

	Mean Vd (L/kg)

Table 4

 4 Effect of protein-energy malnutrition on total clearance (CL) and half-life (t½) of drugs primarily metabolised by the liver M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ¶= drug administered intravenously; ┼= median value; ∫= value in l/hr; ∫∫= value in ml/hr/kg; ∫∫*= value in ml/min/kg; ∫∫∫= value in ml/min; ∫∫∫∫= unit of the value was not given; ∫∫∫∫∫= value in mg/min; ∫∫∫∫∫∫= value in L/kg/hr.

	Mean CL (ml/min/kg)	Mean t½ (hr)

Table 5

 5 Effect of protein-energy malnutrition on total clearance (CL) and half-life (t½) of drugs primarily eliminated by the kidneys ∫∫∫= value in ml/min; ∫∫∫∫∫∫= value in L/kg/hr; § §= value in litres/hr.

	Mean CL in (ml/min/kg)	Mean t½ (hr)

Table 6

 6 Effect of protein-energy malnutrition on drug half-life (t½) Note: U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified † Clearance and half-life of the drug were provided in the study, clearance was apparently decreased in PEM but the level of significance was not provided when compared with normal control children.

	Mean t½ (hr)

  Full articles of the relevant abstracts were then searched and retrieved. The references of the retrieved articles were searched manually in order to identify additional appropriate studies. The relevant additional articles that met the inclusion criteria were accessed.

	malnutrition' OR 'protein calorie malnutrition' OR 'protein-calorie malnutrition' OR 'marasmus' OR
	'marasmic-kwashiorkor' OR 'kwashiokor'. The searches were later combined to give the desired
	abstracts. Abstracts that appeared in both EMBASE and MEDLINE searches were hand searched to
	avoid duplication and to judge whether they met the inclusion criteria.
	Inclusion criteria were abstracts that assessed or discussed pharmacokinetics,
	pharmacodynamics, absorption, distribution, metabolism, elimination or clearance of drugs in children
	who are underweight, marasmic, marasmic-kwashiorkor, and/or kwashiorkor. Abstracts that assessed
	or discussed disposition of micronutrients and appetite stimulating drugs in malnourished children were
	excluded.
	F o r
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	w
	using EMBASE and MEDLINE (January 1960-December 2009) and by reference tracking. In both
	methods, the search strategies involved an initial search for all relevant abstracts using the medical
	subject heading (MeSH) descriptor 'drug absorption' OR 'drugs absorption', limited to children
	between 0-17 years. Similar searches were done for drug distribution, metabolism and clearance by
	substituting the term 'absorption' with each of the terms 'distribution', 'pharmacokinetics',
	'pharmacodynamic', 'metabolism', 'elimination' and 'clearance', respectively. Another search was
	4

made using the MeSH descriptors 'malnutrition' OR 'mal-nutrition' OR 'undernutrition' OR 'undernutrition' OR 'underweight' OR 'under-weight' OR 'protein energy malnutrition' OR 'protein-energy

  The decreased extents of chloramphenicol absorption reported byEriksson et al

	not reported.
	F o r
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	6

The statistical significance level of the decreased or increased F values for penicillin in PEM was however

Table 1

 1 Effect of protein-energy malnutrition on drug absorption (AUC and K a )

	Mean AUC (µg/ml/hr)	Mean absorption rate
		(K a /hr)

Note: †= significant difference in K a values at P<0.05 *= unit uncertain; **= values in µg/ml/min; IM = intramuscular; U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ψ= drug administered to fasted patients; R-rehabilitated patients; H= healthy children with normal weight; NH= non-healthy children with normal weight.

Table 2

 2 Effect of kwashiorkor on drug protein binding or free unbound drug (f u )

	Drug

Table 3

 3 Effect of protein-energy malnutrition on drug distribution (Vd) Note: *= values for adult reference; U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ¶= drug administered intravenously; §= values in litres; R-rehabilitated patients; H= healthy children with normal weight; NH= non-healthy children with normal weight.

	Mean Vd (L/kg)

Table 4

 4 Effect of protein-energy malnutrition on total clearance (CL) and half-life (t½) of drugs primarily metabolised by the liver U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ¶= drug administered intravenously; ┼= median value; ∫= value in l/hr; ∫∫= value in ml/hr/kg; ∫∫*= value in ml/min/kg; ∫∫∫= value in ml/min; ∫∫∫∫= unit of the value was not given; ∫∫∫∫∫= value in mg/min; ∫∫∫∫∫∫= value in L/kg/hr.

	Mean CL (ml/min/kg)	Mean t½ (hr)

Table 5

 5 Effect of protein-energy malnutrition on total clearance (CL) and half-life (t½) of drugs primarily eliminated by the kidneys Note: *= significant difference in t½ values; **= values for adult reference; ¶= drugs administered intravenously; U= underweight; M= marasmus; K= kwashiorkor; M-K= marasmic-kwashiorkor; Undefined= PEM not classified; ∫∫∫= value in ml/min; ∫∫∫∫∫∫= value in L/kg/hr; § §= value in litres/hr.

	Mean CL in (ml/min/kg)	Mean t½ (hr)

F o r P e e r R e v i e w

Table 6

 6 Effect of protein-energy malnutrition on drug half-life (t½)

	Mean t½ (hr)

European Journal of Clinical Pharmacology

Abstract

Background: Protein-energy malnutrition (PEM) is a nutritional problem affecting many children world-wide. Its association with a wide spectrum of infections necessitates multiple drug therapies. A systematic review was performed to determine the effects of PEM on drug pharmacokinetics.

Methods: Literature search in MEDLINE and EMBASE databases (January 1960-December 2009) was performed. Malnutrition, undernutrition, underweight, protein-energy malnutrition, protein-calorie malnutrition, marasmus, marasmic-kwashiorkor or kwashiorkor was the medical subject heading (MeSH) descriptor used. Inclusion criteria were abstracts that assessed or discussed absorption, distribution, metabolism, elimination, clearance, pharmacokinetics or pharmacodynamics of drugs, except micronutrients and appetite stimulating drugs.

Results: Altogether, 41 publications were identified. A total of 34 drugs were studied. The absorption of 18 drugs was studied; the extent of absorption (AUC) was unaffected for 10 drugs. The plasma protein binding of 20 drugs was evaluated; it was significantly reduced for 12 drugs. The volume of distribution (Vd) of 13 drugs was evaluated; it was however unaffected for most of the drugs. The effect of PEM on total clearance and half-life of drugs primarily metabolised by the liver was studied for eight drugs. There was decreased total clearance and an associated increased half-life of five drugs.

For two drugs (chloramphenicol and quinine), different degrees of PEM affected total clearance differently. The total clearance of six drugs primarily eliminated by the kidneys was studied; it was unaffected for four drugs but significantly decreased for two drugs (cefoxitin and penicillin).

Conclusions:

Considering the proportion of children affected with PEM world-wide, there have been relatively few pharmacokinetic studies of drugs frequently used for their treatment. More studies are therefore required to establish the appropriate dose and safety of these drugs for PEM children. The studies need to recognise that PEM is a disease spectrum and should further look at the differential effects of kwashiorkor and marasmus on drug pharmacokinetics in children.