SYMPOSIUM ON PEDIATRIC TUBERCULOSIS

Pharmacokinetics of Anti-tuberculosis Drugs in Children

Geetha Ramachandran & A. K. Hemanth Kumar &

Soumya Swaminathan

Received: 4 October 2010 /Accepted: 23 November 2010 /Published online: 17 December 2010# Dr. K C Chaudhuri Foundation 2010

Abstract Tuberculosis (TB) is among the top 10 causes ofdeath among children worldwide. Recent reports suggestthat the currently recommended dosages of first-line anti-TB drugs are not adequate in children, particularly youngerchildren. The objective of this review was to synthesizeavailable pharmacokinetic data of anti-TB drugs in childrenfrom different settings that would help determine optimaldoses of anti-TB drugs, in order to provide evidence-basedrecommendations. A PubMed database was searched from1970 to present using the terms rifampicin, isoniazid,pyrazinamide, ethambutol, pharmacokinetics, HIV, TB,nutrition and children. References from identified articleswere also reviewed and abstract from recent meetings wereincluded. Available pharmacokinetic data from differentsettings suggest that age, nutritional status, HIV infectionand gene polymorphisms in drug metabolising enzymescould significantly influence the pharmacokinetics of first-line anti-TB drugs. However, most of the pharmacokineticstudies conducted so far in children have failed to associatedrug concentrations with treatment outcomes. Hence, morestudies to examine the relationship between drug pharma-cokinetics and response to anti-TB treatment are required.Studies to examine the impact of nutritional status and HIVinfection on the pharmacokinetics of anti-TB drugs inchildren are needed.

Keywords Pharmacokinetics . Children . TB

Introduction

Tuberculosis (TB) in children is an important public healthproblem, and among the 10 major causes of mortality, with aglobal estimate of >100,000 deaths per year [1]. There areabout one million estimated cases of TB in childrenworldwide, of which 75% occur in the 22 high burdencountries [1]. Further, in countries with a high prevalence ofHIV infection, there has been a marked increase in theincidence and a decrease in the peak age of prevalence ofinfectious TB [1]. In high TB burden countries, a substantialproportion of cases (20–40%) occur in children, posingmany challenges for diagnosis and treatment. Infants andyoung children (HIV infected and uninfected) exposed toadult infectious TB are a group at high risk for developmentof disease and rapid progression/dissemination.

Treatment of Tuberculosis The basic principles of treatmentand recommended standard anti-TB regimens for children aresimilar to those for adults [2]. Treatment for most forms ofpulmonary and extra pulmonary TB consists of a 6-monthshort course chemotherapy regimen with isoniazid (INH),rifampicin (RMP), pyrazinamide (PZA) and ethambutol(EMB) for 2 months followed by INH and RMP for thenext 4 months.

There are considerable variations in national recommen-dations for TB drug doses in children, particularly, for INH.Doses for children are based on body weight and largelyextrapolated from adult pharmacokinetic studies TheAmerican Thoracic Society guidelines recommend a dailyINH dose of 10–15 mg/kg body weight, whereas the WHOrecommendations till date are 4–6 mg/kg (these guidelines

G. Ramachandran :A. K. H. Kumar : S. SwaminathanTuberculosis Research Centre (Indian Council of MedicalResearch),Chennai, India

S. Swaminathan (*)UNICEF/UNDP/World Bank//WHO Special Programme forResearch & Training in Tropical Diseases,20, Avenue Appia, 27,Geneva 1211, Switzerlande-mail: swaminathans@who.int

Indian J Pediatr (April 2011) 78(4):435–442DOI 10.1007/s12098-010-0304-x

are currently undergoing revision and the dosage is likely tobe increased to 10 mg/kg). The South African TB controlprogram recommends daily INH doses of 4–6 mg/kg [3]. Inthe Revised National TB Control Program (RNTCP) inIndia, all new pediatric patients diagnosed with TB areinitiated on anti-TB treatment (ATT) provided in pediatricpatient-wise boxes (PWB). The recommended dosages are10 mg/kg for INH and RMP, 30–35 mg/kg for PZA and30 mg/kg for EMB given thrice weekly. For the purpose oftreatment, the pediatric population is divided into 4 weightbands: 6–10 kg, 11–17 kg, 18–25 kg and 26–30 kg. Thepatients receive the PWB appropriate for their body weight.The importance of adequate dosing and therapeutic bloodlevels of anti-TB drugs has received more attention recentlyin the light of recent reports suggesting that the currentlyrecommended dosages of RMP, INH, PZA and EMB arenot adequate in children [4–11].

Pediatric Pharmacotherapy Drug dosage selection inchildren is based upon stages of growth and development.Unlike adults, various factors specific to the pediatricpopulation dictate treatment options. Physiological changesthat occur with growth and development cause differences inabsorption, distribution, metabolism and excretion of drugs[12]. Several age related factors, including gastric acidsecretion, gastric emptying time, intestinal transit time andgastrointestinal motility influence absorption of drugs inchildren [12]. Body composition and tissue binding charac-teristics vary greatly with age and play a major role in thedistribution of drugs among children. Altered hepaticenzyme activity and elimination pattern in children couldhave a profound effect on the serum concentrations of drugs,depending on their metabolic pathways. It is thereforeimportant to study the influence of developmental changesin relation to the pharmacokinetics of anti-TB drugs inchildren, in order to optimize treatment strategies, minimisetoxicities and maximise therapeutic efficacy.

Factors Influencing Anti-TB Drug Pharmacokinetics

Good bioavailability leading to adequate plasma and tissueconcentrations of anti-TB drugs is an absolute pre-requisitefor the success of treatment of TB. Although several studieshave shown evidence of good treatment outcomes inchildren with drug dosages based on body weight [13,14], poor treatment response in childhood TB has also beenreported [15]. While response to treatment depends onmultiple factors, sub-therapeutic serum concentrations ofdrugs could potentially lead to unsatisfactory treatmentoutcomes. Serum concentrations of drugs are influenced byone or more factors such as age, ethnicity/genetic factors,

nutritional status, HIV infection, drug-drug interactions,drug-food interactions etc. (Table 1).

a) Age: Due to continual maturation of body systems inchildhood leading to changing drug disposition overtime, age becomes an important factor capable ofsignificantly altering the kinetic profile of an individualdrug and consequently its efficacy and side effects.Hence, drug therapy in infancy and childhood requiresspecial dose considerations due not only to continuouschange in body weight, surface area and bodycomposition but also enzyme maturation [25]. Changesare most rapid from birth to 2 years of age and slowdown thereafter. Table 2 gives a summary of fewstudies that have compared the pharmacokinetics ofRMP, INH, PZA and EMB among children belongingto different age groups.

The study of Schaaf et al. in South African children withTB showed that younger children eliminated INH fasterthan older children. Furthermore, exposure of children toINH (10 mg/kg dose) was significantly less than that ofadults who received the same mg/kg dose [4]. Thesignificantly faster elimination of INH by infants andyounger children has been attributed to the relativelygreater mass of the liver in proportion to total bodyweight and it is proposed that optimal doses could becalculated on the basis of body surface area rather thanbody weight. They suggested that young children <5 yearsof age should receive an INH dose of at least 10 mg/kgdaily to ensure that fast acetylators of INH maintainadequate serum concentration of INH.

Thee et al. compared serum concentrations of INHwhen administered according to body weight and bodysurface area. They observed that body weight-basedINH dose produced lower serum levels than adults,especially in children below 8 years. In contrast, afterdosing based on body surface area, similar serumconcentrations were achieved in children and adults[5]. A recent study from South Africa observed 58%lower peak INH concentrations in children whoreceived 4–6 mg/kg dose than those who received 8–10 mg/kg dose [6]. Peak concentrations were belowthe recommended lower limit of 3 μg/ml in 70% ofchildren prescribed a dose of 4–6 mg/kg, suggestingthat this dose is inadequate in younger children.

Children prescribed RMP at a dose of 10 mg/kgbody weight had lower concentrations compared toadults who received a similar dose. Decreased RMPexposure in the presence of EMB was also observed,though not significant [7]. The authors suggest thatRMP doses may be calculated on the basis of bodysurface area rather than body weight, especially inyounger children. An RMP dosage of 300 mg/m2

436 Indian J Pediatr (April 2011) 78(4):435–442

Table 1 Factors influencing pharmacokinetics of anti-TB drugs in children

Factor Drug Effect Reference. #

Acetylator status INH Decreased drug exposure in rapid compared to slow acetylators [4, 6, 9, 16]

Drug transporterpolymorphisms

RMP SLCO1B1 rs4149032 polymorphism has a significant effect on RMP exposurea [17, 18]

Age INH Younger children eliminate INH faster and have reduced blood levels [4–6, 9, 16]

RMP Low blood levels in young children [8, 19, 20]

PZA and EMB Lower blood levels in younger children [11]

EMB Lower blood levels in younger children [20]

RMP, INH & PZA Children <3 years have lower peak concentration and exposure than other age groups [9]

Body weight RMP, INH, PZAand EMB

Low body weight is associated with increased risk of sub optimal drugconcentrations in HIV and TB co-infected patientsa

[21]

EMB Heavier people at higher risk of toxicity and thinner people at greater risk oftherapeutic failurea

[22]

Sex RMP, INH, PZAand EMB

Male sex is associated with reduced drug exposure in HIV and TB co-infectedpatients a

[21]

Drug-druginteractions

RMP Decreased exposure in the presence of EMB [7]

Drug-foodinteractions

RMP, INH & EMB Food reduces peak concentrations [23]

Nutritional status RMP Malnutrition lowers protein binding capacity, increases renal clearance anddecreases drug levelsa

[24]

PZA and EMB Plasma levels are lower in malnourished children [11]

RMP, INH & PZA Stunting and underweight reduces peak concentration and exposure [9]

HIV infection RMP Low serum concentrations in HIV-infected children [8]

a Reported in adults

Drug Age (years) Cmax (μg/ml) AUC (μg/ml.h) Reference #

INH a 1.3 (0.41–5.10) 0.76 (0.69–2.24) 2.93 (1.56–7.20) [6]3.6 (1.97–5.51) 2.39 (1.59–3.40) 5.97 (4.00–9.39)

7.0 (2.04–11.97) 5.85 (5.70–6.00) 11.72 (11.09–12.35)

INH b 1–3 3.9±1.2* 16.5±6.1* [9]3.1–6 6.9±3.5 29.1±15.6

6.1–9 6.8±2.1 25.8±9.2

9.1–12 7.6±1.7 29.4 ±10.5

RMP b 2–<6 6.5 (1.2) 20.15 [7]6–<10 7.1 (1.2) 21.75

10–<14 6.6 (0.8) 22.75

1–3 4.5±1.5* 21.4±7.4* [9]3.1–6 7.1±2.4 33.8±12.7

6.1–9 7.6±1.5 36.4±8.2

9.1–12 6.9±1.5 33.2±7.7

PZA b 2–<6 37.9 (5.6) – [26]6–<10 31.9 (6.4) –

10–<14 33.3 (2.3) –

1–3 32.1±3.4* 182.3±16.4* [9]3.1–6 42.1±7.8 244.5±40.5

6.1–9 42.8±4.6 233.8±29.7

9.1–12 41.0±5.1 229.3±27.5

0–4 27.5 (16.6)* 327 (335) [11]≥5 47.9 (17.7) 416 (333)

EMBb 0–4 1.8 (1.2) 20.2 (18.9)

≥5 1.8 (1.2) 23.5 (8.8)

Table 2 Pharmacokinetics ofanti-TB drugs in children ofdifferent age groups

AUC values for INH: 0–6 h(6); 0–8 h (9), RMP: 0–7 h,PZA: 0–24 h, EMB: 0–∞a Values are Median (IQR); b Val-ues are Mean (SD)

*denotes p<0.05 vs. othergroup/s

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body surface area given to children at the age of3 months to 2.5 years produced mean serum concen-trations of 9.1 μg/ml, which is close to the desiredserum level of 10 μg/ml [19]. Similar findings havebeen reported by Schaaf et al. [8], who also observedvery low RMP concentrations in children whoreceived the recommended standard dose of 8–12 mg/kg body weight. The relatively low plasmaconcentration of RMP in children is also evident inother studies where RMP prescribed at 10–12 mg/kgproduced peak concentrations ranging from 3–9 μg/ml[20, 27, 28]. In the only study that observed RMPserum levels of 9–12 μg/ml, children received RMP ina suspension which could have caused improvedabsorption. Thus, Hussels et al. [27] suggested thatchildren under 6 years of age should receive a RMPdose of 15 mg/kg, and older children 10 mg/kg.However, a recent study presented at the InternationalWorkshop on Pharmacology of TB drugs, Boston,September 2010, Zvada et al. showed that even daily10 mg/kg doses of RMP did not achieve the sameexposure in children as in adults [29]. Further, basedon their population pharmacokinetic model, theyfound that though 15 mg/kg dose improved drugexposure, young children were still under-dosed,suggesting that RMP dosage needs to be re-evaluatedin children of different ages.

Pharmacokinetic studies of PZA and EMB havefound lower plasma drug levels and shorter half-livesin children than in adults using the same dosages, andhave suggested increasing the dosage for children [10,30, 31]. An older study compared mean peakconcentration of EMB among 28 European childrenof different age ranges who were prescribed 35 mg/kgdosage. This study observed lower levels for youngerchildren – 1.5 μg/ml for 2–5 year olds compared to2.3 μg/ml for 6–9 year olds and 3 μg/ml for 10–14 year olds [27]. However, a few studies havereported adequate serum concentrations of PZA inchildren who received 30 and 35 mg/kg dosages [26,32, 33]. The study of Thee et al. showed that EMBdosages based on body surface area produced thera-peutic serum levels in all age groups leading to a highefficacy of anti-TB treatment without increased oculartoxicity, and dosages based on body weight causedsub–therapeutic serum levels [34].

There are fewer reports of drug levels and treatmentoutcomes in children receiving intermittent anti-TBtherapy. A pharmacokinetic study done by our groupin Indian children in the age range of 1–12 years,receiving thrice-weekly anti-TB medications based onthe RNTCP guidelines showed that those below3 years of age had significantly lower peak concen-

tration and exposure of RMP, INH and PZA comparedto other age groups [9]. Graham et al. reported poorabsorption of PZA and EMB in Malawian children,demonstrating low serum drug levels with intermittenttherapy using the recommended doses of PZA of35 mg/kg and EMB 30 mg/kg, especially in youngerchildren [11].

There are conflicting reports on dose recommenda-tions for children based on pharmacokinetic studies. Sethet al. reported that RMP and INH at 12 and 10 mg/kg/daydoses respectively in children, produced serum concen-trations above those required for therapeutic efficacy [35].A similar finding has been reported by Mahajan et al.who observed serum concentrations of RMP adminis-tered at doses of 10 and 7.5 mg/kg body weight tochildren with TB meningitis to be several times higherthan the MIC against M. tuberculosis [36]. A compar-ative pharmacokinetic study of INH at two dose levels,10 mg/kg and 5 mg/kg daily showed that the latter dosewas adequate for treatment of pulmonary TB in children,who showed symptomatic and radiological improve-ments at 6 months [37].

Most of the pharmacokinetic studies conducted so farin children were observational and have failed toassociate drug concentrations with treatment outcomes.This could be due to the fact that assessment of responseto anti-TB treatment in a standardised manner is difficultin children because objective markers of treatmentresponse are lacking, unlike adults where sputum smearand culture is used as the gold standard [38]. Thesignificance of sub-therapeutic plasma concentrations inrelation to therapeutic efficacy remains a matter ofdebate. While Chang et al. found no correlation betweenpeak RMP serum concentrations and delayed sputumculture conversion in adults [39], the United StatesPublic Health System (USPHS) trial showed that withlower dosages such as 9 mg/kg leading to reducedplasma concentrations of RMP, the speed of sputumconversion was reduced, and that improved earlybactericidal activity and better treatment response wereassociated with higher doses of RMP [40]. In the era ofHIV/AIDS, reduced dosages of anti-TB medications,especially in severe forms of TB could be associatedwith an increased risk of relapse [41]. Hence, it remainsto be seen whether differences in exposure to lowerserum concentrations of anti-TB agents that arise fromusing the same mg/kg dose in children as in adultsmatter in terms of treatment response.

b) Nutritional Status: Drug disposition and nutritionalstatus of the child have a close interaction with eachother. Protein energy malnutrition is a major publichealth problem in the regions of the world where TB isendemic. It has been suggested that drugs used in

438 Indian J Pediatr (April 2011) 78(4):435–442

conventional doses, calculated on the basis of age orbody weight, may not produce the desired effect inmalnourished children [42]. The pathophysiologicalchanges associated with malnutrition can alter pharma-cokinetic processes, drug responses and toxicity [43].Patients with TB are often malnourished; the interac-tion between malnutrition and TB being dynamic andbi-directional. A significant association between mal-nutrition and severe forms of childhood TB has beenreported [44]. Poor nutritional status could causemalabsorption of drugs, presumably due to alteredlevels of drug metabolising enzymes in the liverleading to enhanced renal clearance and decrease inthe serum concentrations of protein bound drugs.

A few studies that have examined the effect ofmalnutrition on the pharmacokinetics of anti-TB drugshave had conflicting results (Table 3). Eriksson et al.observed that INH was well absorbed and producedtherapeutically active plasma levels in 45 Ethiopianchildren with TB, who belonged to different nutritionalgroups (normal, underweight, marasmus and kwashi-orkor) [45]. Similar findings have been reported bySeifart et al. who reported that changing conditions ofdisease or nutrition did not significantly influence INHelimination in children [46]. Contrary to these findings,malnutrition has been reported to reduce the proteinbinding capacity of RMP, thereby increasing the renalclearance and decreasing the drug levels in adults [24].The study of Graham et al. showed that PZA but notEMB levels were lower in malnourished children,though not significant [11]. The authors observed asignificant association between stunting and RMPexposure in children treated for TB in south India [9].Further, this study showed that children with stunting

and underweight had significantly lower peak concen-tration and exposure of RMP and PZA compared tonormal children.

c) HIV infection: While the available anti-TB drugs areefficacious and have resulted in high cure rates in HIV-uninfected populations, studies have shown that HIV-infected people with TB have high mortality andrecurrence rates [47, 48]. The efficacy of intermittentshort course regimens in HIV-infected adults andchildren and the ideal dose of anti-TB drugs whenused thrice-weekly, especially in the setting of HIVhave not been well studied. In a recent systematicreview, the use of daily regimens, RMP throughout thetreatment period and duration of >6 months wereassociated with better outcomes in HIV-infected TBpatients [49]. Recent reports from high HIV prevalencecountries have documented poorer treatment outcomesin children with TB, HIV being the most important riskfactor [15, 50]. While HIV could influence outcome indifferent ways, inability to achieve and sustain thera-peutic levels of anti-TB drugs (possibly due tomalabsorption) could be a major factor in causingpoor treatment outcomes and emergence of drugresistance. We have found evidence of malabsorption anddecreased bioavailability of anti-TB drugs in patients withadvanced HIV disease and TB [51].

The impact of HIV infection on blood levels of anti-TB drugs has not been adequately studied in children(Table 4). In the study of Graham et al. conducted with27 Malawian children with TB, 18 of whom were HIVco-infected, PZA and EMB concentrations were notsignificantly lower in HIV infected children compared tothe uninfected [11]. Schaaf et al. described low RMPserum concentrations in a large proportion of children

Table 3 Pharmacokinetics of anti-TB drugs in normally nourished and malnourished children

Nutritional status RMP INH PZA EMB Ref.

Cmax(μg/ml)

AUC(μg/ml.h)

Cmax(μg/ml)

AUC(μg/ml.h)

Cmax(μg/ml)

AUC(μg/ml.h)

Cmax(μg/ml)

Normal 44.3 (17.1) 496 (407) 1.0 (0.9) [11]Undernutrition 33.7 (23.2) 312 (261) 1.9 (1.2)

Marasmus 35.4 (16.8) 337 (337) 2.8

Stunted 5.6 (1.1)* 26.8 (7.4)* 5.7 (2.1) 22.9 (9.6) 35.7 (6.2)* 198.2 (31.4)* [9]Normal 7.5 (2.3) 35.6 (10.9) 7.0 (2.8) 27.8 (12.9) 41.9 (6.2) 237.1 (33.9)

Underweight 6.2 (1.2) 29.7 (7.2) 5.8 (2.0) 23.3 (8.9) 37.2 (6.2)* 208.3 (39.6)*

Normal 7.4 (2.5) 35.0 (11.9) 7.0 (2.9) 28.1 (13.4) 41.9 (6.5) 236.9 (32.5)

Wasted 7.7 (2.2) 37.8 (13.8) 8.1 (3.8) 31.3 (16.4) 42.8 (7.9) 236.0 (49.8)

Normal 6.8 (2.4) 31.6 (10.3) 6.1 (2.5) 24.9 (11.3) 39.5 (6.9) 224.3 (36.2)

Above values are Mean (SD)

AUC values for RMP, INH & PZA: 0–24 h (11), 0–8 h (9)

*denotes <0.05 vs. Normal group

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with TB who received standard RMP dosages, irrespec-tive of HIV status [8]. Hence, while the impact of HIVand associated immune suppression in influencingtreatment outcomes is well described, whether druglevels play a role in this pathway needs further study. Ingeneral, intermittent dosing of anti-TB drugs is notrecommended in patients with HIV co-infection. How-ever, the RNTCP uses fully intermittent regimens inadults and children with TB, regardless of HIV status.

d) Genetic factors: The association between blood levelsof INH and acetylator (N-acetyl transferase, theenzyme that metabolizes INH in the liver) status is awell known phenomenon (Table 5). The study ofMcllleron et al. in children showed dose in mg/kgbody weight and NAT2 genotypes to be dominantdeterminants of INH concentrations. The influence ofNAT2 genotype on the pharmacokinetics of INH wasevident from the finding that any dose reduction below6 mg/kg body weight would tend to disadvantage fastacetylators, but slow acetylators would require only a3 mg/kg dose to achieve a satisfactory exposure to INH[6]. It has, therefore been suggested that the dosage ofINH should be tailored based on age and possiblyNAT2 genotype [16]. Studies done in adult HIV-TB co-infected patients showed that the blood levels of INHwere more affected in rapid than slow acetylators ofINH [51]. The impact of drug transporter polymor-phisms on RMP exposure has also been reported[17, 18]. However, most of these studies have been

done in adult populations; similar studies in childrenare required.

Research Needs Drug concentrations are among the mostimportant determinants of clinical response to a drugaccounting for both toxicity and efficacy. Available datafrom different settings suggest that age, nutritional status,HIV infection and gene polymorphisms could significantlyinfluence the pharmacokinetics of anti-TB medications. Afew studies have also reported on the impact of bodyweight, sex and drug-food interactions on the pharmacoki-netics of certain anti-TB drugs [21–23]. However, thesestudies have not correlated drug concentrations with TBtreatment outcomes. More pharmacokinetic studies that areadequately powered to examine the relationship betweendrug pharmacokinetics and response to anti-TB treatmentare required in children, especially in the younger agegroup. Since drug metabolism is likely to be different inchildren, pharmacokinetic studies to examine potentialdrug-drug and drug-food interactions are also required.Although childhood MDR TB is uncommon, it is importantto undertake pharmacokinetic studies of second-line anti-TB medications in children to get a better understanding ofthe pharmacokinetic profile of these drugs. The interplaybetween malnutrition and anti-TB drug pharmacokineticsneeds to be studied further. Inadequate exposure totherapeutic agents in this vulnerable population may leadto poor treatment outcomes. In the case of HIV infection,

Drug HIV status Cmax(μg/ml)

AUC(μg/ml.h)

Reference #

RMP HIV infected 4.9 (2.0) 14.9 (7.4) [8]HIV uninfected 6.9 (5.9) 18.1 (12.5)

PZA HIV infected 34.0 (18.1) 411 (382) [11]HIV uninfected 41.9 (22.9) 322 (240)

EMB HIV infected 1.8 (1.3) 18.7 (11.5)

HIV uninfected 1.8 (1.1) 23.8 (13.8)

Table 4 Pharmacokinetics ofanti-TB drugs in HIV-infectedand uninfected children

Above values are Mean (SD)

AUC values for RMP 0–6 h,PZA 0–24 h, EMB 0-∞

Table 5 Pharmacokinetics of INH according to N-Acetyl transferase 2 genotype

Dose PK variable NAT2 genotype Reference #

Slow Intermediate Fast

10 mg/kg AUC (2–5 h) μg/ml.h 18.4 (4.7)a * 8.2 (3.4)a 5.4 (3.1)a [4]

4–6 mg/kg Cmax μg/ml 4.1 (2.7–5.7)b * 2.6 (1.6–5.2)b 1.5 (1.2–4.1)b [6]AUC (0–6 h) μg/ml.h 10.6 (8.7–16.1)b * 6.4 (4.2–13.3)b 2.3 (1.8–6.1)b

10 mg/kg Cmax μg/ml 7.3 (2.8)a * Not available 5.4 (2.1)a [9]AUC (0–8 h) μg/ml.h 31.1 (12.1)a * Not available 17.3 (6.1)a

aMean±SDbMedian (IQR)

*denotes p<0.05 vs. other group/s

440 Indian J Pediatr (April 2011) 78(4):435–442

dosage selection based upon age alone may be relativelyinaccurate. Variability in body weight among children ofthe same age can lead to dosage errors. Additionally, HIVinfected children tend to weigh less than their non-infectedcounterparts of the same age range. Hence, dosagescalculated on the basis of body surface area would be moreaccurate, because many physiological parameters such asblood volume, extra cellular water volume and glomerularfiltration rate correlate closely with body surface area.

Contributions GR was involved in collection of data. GR and HKcompiled the data and designed the main text of the article and tables.GR drafted the manuscript and SS provided valuable suggestions andcritical inputs.

Work Done at Department of Biochemistry &Clinical Pharmacology,Tuberculosis Research Centre (Indian Council of Medical Research),Chennai, India.

Conflict of Interest None.

Role of Funding Source None.

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