Published Ahead of Print 4 August 2014. 10.1128/AAC.02538-14. 2014, 58(10):6068. DOI: Antimicrob. Agents Chemother. S. M. D. K. Ganga Senarathna and Kevin T. Batty Application to Pediatric Dosing Antimalarial Drugs and Potential Interspecies Allometric Scaling of http://aac.asm.org/content/58/10/6068 Updated information and services can be found at: These include: REFERENCES http://aac.asm.org/content/58/10/6068#ref-list-1 at: This article cites 151 articles, 38 of which can be accessed free CONTENT ALERTS more» articles cite this article), Receive: RSS Feeds, eTOCs, free email alerts (when new http://journals.asm.org/site/misc/reprints.xhtml Information about commercial reprint orders: http://journals.asm.org/site/subscriptions/ To subscribe to to another ASM Journal go to: on September 15, 2014 by Curtin University Library http://aac.asm.org/ Downloaded from on September 15, 2014 by Curtin University Library http://aac.asm.org/ Downloaded from
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Published Ahead of Print 4 August 2014. 10.1128/AAC.02538-14.
2014, 58(10):6068. DOI:Antimicrob. Agents Chemother. S. M. D. K. Ganga Senarathna and Kevin T. Batty Application to Pediatric DosingAntimalarial Drugs and Potential Interspecies Allometric Scaling of
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This article cites 151 articles, 38 of which can be accessed free
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Interspecies Allometric Scaling of Antimalarial Drugs and PotentialApplication to Pediatric Dosing
S. M. D. K. Ganga Senarathna,a,b Kevin T. Battya,b
School of Pharmacy, Faculty of Health Sciences, Curtin University, Bentley, Western Australia, Australiaa; Curtin Health Innovation Research Institute, Curtin University,Bentley, Western Australia, Australiab
Pharmacopeial recommendations for administration of antimalarial drugs are the same weight-based (mg/kg of body weight)doses for children and adults. However, linear calculations are known to underestimate pediatric doses; therefore, interspeciesallometric scaling data may have a role in predicting doses in children. We investigated the allometric scaling relationships ofantimalarial drugs using data from pharmacokinetic studies in mammalian species. Simple allometry (Y � a � Wb) was utilizedand compared to maximum life span potential (MLP) correction. All drugs showed a strong correlation with clearance (CL) inhealthy controls. Insufficient data from malaria-infected species other than humans were available for allometric scaling. Theallometric exponents (b) for CL of artesunate, dihydroartemisinin (from intravenous artesunate), artemether, artemisinin, clin-damycin, piperaquine, mefloquine, and quinine were 0.71, 0.85, 0.66, 0.83, 0.62, 0.96, 0.52, and 0.40, respectively. Clearance wassignificantly lower in malaria infection than in healthy (adult) humans for quinine (0.07 versus 0.17 liter/h/kg; P � 0.0002) anddihydroartemisinin (0.81 versus 1.11 liters/h/kg; P � 0.04; power � 0.6). Interpolation of simple allometry provided better esti-mates of CL for children than MLP correction, which generally underestimated CL values. Pediatric dose calculations based onsimple allometric exponents were 10 to 70% higher than pharmacopeial (mg/kg) recommendations. Interpolation of interspeciesallometric scaling could provide better estimates than linear scaling of adult to pediatric doses of antimalarial drugs; however,the use of a fixed exponent for CL was not supported in the present study. The variability in allometric exponents for antimalar-ial drugs also has implications for scaling of fixed-dose combinations.
The World Health Organization and standard pharmacopeialsources recommend that antimalarial drugs be administered
at the same weight-based (mg/kg of body weight) or linear dosefor children and adults (1). However, this linear method of dosagecalculation is known to underestimate the optimum pediatricdose of many drugs (2–5). Recent clinical reports indicate thathigher doses of sulfadoxine-pyrimethamine (6, 7), chloroquine(6, 8, 9), quinine (10), piperaquine (11–14), and artesunate (15,16) are required for effective antimalarial therapy in children.
Allometric scaling is a well-established technique for relatingphysiological or pharmacokinetic parameters to body weight (17–22), and allometric relationships have been demonstrated for awide range of drugs, including antimicrobial agents (23–27). Theconventional applications of interspecies allometric scaling in-clude prediction of human doses by extrapolation from preclini-cal animal studies and dose estimates for other mammalian spe-cies in veterinary medicine (18, 23, 26, 28). Increasing interest hasbeen shown in the application of interspecies allometric scalingdata to predict pharmacokinetic parameters or drug doses in chil-dren (27, 29, 30). Despite a paucity of reports on antimalarialdrugs (31, 32), interpolation of allometric scaling of chloroquinesupports recommendations from clinical studies for higher chlo-roquine doses in children (8, 9, 33).
The rationale for using scaling techniques to estimate pharma-cokinetic parameters in children is that relatively few pediatricpharmacokinetic investigations are conducted, compared to adultstudies, and sparse sampling is normally required because thereare practical and ethical limitations to obtaining rich pharmaco-kinetic data sets from pediatric subjects (34). One alternative toconventional interspecies scaling is fixed-exponent scaling fromhuman adult pharmacokinetic data (2–5, 34–37). The principle ofscaling with a fixed exponent (e.g., 2/3 or 3/4) may provide some
consistency and practical advantages; however, the validity of a uni-versal exponent in pharmacokinetics is subject to conflicting evi-dence and debate (3, 5, 27, 34–40). Regardless of the scaling methodthat is used, caution is required for recommendations for very youngchildren, due to immature clearance mechanisms, and for diseasestates for which there are limited data available or evidence that clear-ance may be altered in compromised patients (30, 35, 36).
We sought to investigate the allometric scaling relationships ofantimalarial drugs using data from pharmacokinetic studies ofhealthy and malaria-infected mammalian species. Our hypothesiswas that linear scaling (i.e., exponent of 1.0) would not apply andthat interpolation of interspecies allometric scaling would be suit-able for estimating pediatric doses of antimalarial drugs.
MATERIALS AND METHODSData collection. A comprehensive literature search was conducted viaPubMed, OvidSP, Google Scholar, and citation records, using relevant keywords, including the specific antimalarial drugs and mammalian species.The initial target list of antimalarial drugs was determined from WHOtreatment guidelines (1): artemisinin, artesunate, artemether, dihydroar-temisinin, mefloquine, amodiaquine, piperaquine, chloroquine, quinine,primaquine, lumefantrine, sulfadoxine-pyrimethamine, atovaquone,proguanil, tetracycline, doxycycline, and clindamycin. Exclusions com-prised fixed-dose combinations where data for individual drugs were not
Received 12 February 2014 Returned for modification 6 May 2014Accepted 25 July 2014
readily available (sulfadoxine-pyrimethamine, artemether-lumefantrine,atovaquone-proguanil), drugs for which pharmacokinetic data wereavailable from fewer than three mammalian species (amodiaquine andlumefantrine), and drugs that are contraindicated in children (tetracy-cline and doxycycline). Chloroquine (33) and doxycycline (41) had beenstudied previously and were excluded.
The pharmacokinetic studies were screened for suitability of the data,with a focus on uniformity of biological matrix (especially for quinolineswith high blood-plasma ratio), period over which blood and plasma sam-ples were collected for the pharmacokinetic study (preferably �3 half-lives), route of administration, and use of validated analytical methods.Although pharmacokinetic parameters from studies with intravenous (orparenteral) drug administration are preferred for allometric scaling, otherroutes of administration were more appropriate for some antimalarials, suchas those which are available only as oral formulations. The final list of drugs(and routes of administration) was as follows: artemisinin (intravenous [IV],intraperitoneal, and oral), artesunate (IV) and the active artemisinin metab-olite dihydroartemisinin (from IV artesunate), artemether (IV and intramus-cular), mefloquine (oral), piperaquine (oral), quinine (IV), and clindamycin(IV).
Pharmacokinetic parameters. Clearance (CL), volume of distribu-tion during terminal phase (Vz), and half-life (t1/2) data were collated ordetermined from the available data using model-independent equations(CL � k � V; Vz � CL/k). Comprehensive pharmacokinetic data (e.g.,mean residence time [MRT] and steady-state volume of distribution[Vss]) were reported in a limited range of studies and therefore were notincluded in the present analysis. In studies where different doses wereadministered to the same subjects and there was no evidence of dose-dependent variability, the mean value of the pharmacokinetic parameterwas used. However, if separate groups were given different doses within astudy, the data were treated independently except when the results werereported as group data. In human studies where body weight was notreported, 60 kg was used for Asian and African subjects, whereas 70 kg wasused for Caucasian subjects, based on standard references and other re-ports used in the present study. The body weight of animals was notprovided in some nonhuman studies; hence, published standard bodyweights of the respective species were used for the allometric scaling (17,25, 28, 42).
Allometric scaling. Simple allometry was the principal method of in-terspecies scaling, using the equation
Y � a � Wb (1)
where Y is the pharmacokinetic parameter (e.g., CL or Vz), W is the bodyweight of the species, a is the coefficient, and b is the allometric exponent(19, 24, 38).
The pharmacokinetic parameter data were plotted against bodyweight on a log-log scale (SigmaPlot version 12.5; Systat Software, Inc.,Chicago, IL) to determine the allometric coefficient and exponent by re-gression analysis.
Data from healthy control subjects were used for the allometric scal-ing, as there were insufficient pharmacokinetic studies in malaria-infectednonhuman species for each antimalarial drug that was investigated. How-ever, pharmacokinetic parameters from human (adults) studies of ma-laria infection were compared to the healthy-control data, as a guide to theapplication of allometric interpolation to decisions on pediatric doses.
Maximum life span potential (MLP) correction. Several alternativemethods of scaling and use of correction factors have been proposed andreviewed (17–19, 26, 43, 44), although the physiological relevance andapplication of some methods were not applicable in the present study. Themost relevant and best-studied method for our consideration was MLPcorrection, which is an integral feature of the “rule of exponents” ap-proach (26, 44). According to the rule of exponents, simple allometry isthe best predictor for exponents in the range from 0.50 to 0.70, whereasCL � MLP provides the best prediction method when the range is 0.71 to0.99 (44). As the CL exponent from simple allometry was �1 for all anti-malarial drugs, we compared MLP correction to simple allometry.
The maximum life span potential (MLP) was calculated from theequation (17)
MLP � 10.839 � BW0.636 � B�0.225 (2)
where BW is brain weight in grams and B is body weight in grams (thecoefficient 10.839 is replaced with 185.5 if the brain and body weights arein kg [44]). Brain and body weight data for mammalian species are wellestablished (17, 42, 45).
The CL � MLP data were plotted against body weight on a log-logscale (SigmaPlot) to determine the coefficient and exponent by regressionanalysis. Clearance exponents from simple allometry and MLP correctionwere used to determine interpolated CL for children and compared toavailable clinical study data.
Pediatric doses. A standard allometric model for pediatric dosing is touse one of the following equations:
where dosechild is the total dose for a child at the specified weight(weightchild), doseadult is the standard total dose for an adult at the speci-fied weight (weightadult), and CLchild and CLadult are the total CL of thedrug.
The exponent derived by allometric scaling (equation 1) was appliedin the present study (equation 3) to compare calculated doses to pharma-copeial or reference doses for arbitrary weights of 15 kg and 25 kg (chil-dren approximately 4 and 8 years of age, respectively). Dose estimates forchildren less than 2 years were not considered, due to the known physio-logical and pharmacokinetic differences between very young infants andadults (35, 36).
Statistical analyses. Data analysis and representation were performedwith SigmaPlot version 12.5 (Systat Software, Inc., Chicago, IL). Data aremeans � standard deviations (SD) unless otherwise indicated. The 95%confidence interval (CI) was determined for the allometric exponent[95% CI � mean � (1.96 � standard error)]. The Student t test was usedfor two-sample comparison as appropriate, with significance at a P valueof �0.05.
RESULTSSimple allometry. Simple allometric scaling data for CL and Vz
are shown in Tables 1 and 2 respectively. A strong correlation wasfound for both CL and Vz for all antimalarials except Vz for theprodrug artesunate (Tables 1 and 2). Artemether (Fig. 1) is nor-mally administered by intramuscular injection, but the inclusionof IV data from a rodent and rabbit study did not significantly alterthe allometric parameters. Artemisinin was given parenterally inthe studies of mice and rats, but as oral administration was used inhuman studies, CL data were corrected for oral bioavailability tofacilitate scaling (Table 1). Due to the mixed sources of data, ar-temisinin was excluded from subsequent analyses.
The 95% CI for CL of piperaquine, mefloquine, and quininedid not encompass 2/3 or 3/4, hence the application of these fixedexponents could not be supported by the present data (Table 1,Fig. 1). Linear dosing of piperaquine could be supported, based onthe 95% CI for CL in the present analysis (Table 1).
The 95% CI for Vz encompassed unity for three of the sevendrugs: artemether, piperaquine, and quinine (Table 2). Volume ofdistribution is normally used in calculations of loading dose andin pharmacokinetic modeling; therefore, no further analysis of Vz
was undertaken for the purposes of the present study.Control versus malaria. In the absence of pharmacokinetic
data from malaria-infected nonhuman species for each antimalar-ial drug, a direct comparison of pharmacokinetic parameters fromhuman (adult) healthy controls and malaria-infected patients was
performed (Table 3). Artesunate could be excluded on the basisthat dose predictions according to the active metabolite dihydro-artemisinin may be more appropriate. Apart from quinine anddihydroartemisinin, which showed significantly lower CL in ma-laria infection than in healthy controls, the P values were �0.1 andthe power of the analyses were �30% for the other antimalarialdrugs. Despite limited data, it was also apparent that CL of quininein malaria infected children is likely to be significantly lower thanCL in healthy controls (Table 3). The power of the analysis fordihydroartemisinin CL was �80%; hence, a type I error cannot beexcluded in the present study.
MLP correction. The MLPs for mice, rats, rabbits, dogs, pigs,human adults, 15-kg children, and 25-kg children were 2.7, 4.8,8.7, 20, 16, 93, 109, and 106 years, respectively. The effect of MLPcorrection is therefore to multiply CL 3- to 5-fold in rodents, 16-to 20-fold in dogs, pigs, sheep, and cows (17), 35-fold in horses,93-fold in adult humans, and �100-fold in human children. Theresult was that scaling extended over four orders of magnitude(Fig. 2). Compared to simple allometry (Table 1), the r2 for MLP-corrected scaling of CL for dihydroartemisinin (0.99), mefloquine(0.96), and quinine (0.98) improved, but the r2 for artemether(0.98), clindamycin (0.96), and piperaquine (0.99) was similar orslightly lower.
The effect of MLP correction on interpolated prediction of CLin children, compared to simple allometry, is shown in Table 4.Results for interpolation of simple allometry for artemether andquinine are illustrated in Fig. 1, with interpolation at 10 kg and 15
kg, respectively, to facilitate comparison with clinical study data(Table 4). Dihydroartemisinin scaling by both simple allometryand MLP correction is provided in Fig. 2. Predictions based onsimple allometry were close to the results from clinical studies ofdihydroartemisinin and artemether, albeit in children with ma-laria infection (Table 4). In contrast, simple allometry showed anoverestimation of CL for mefloquine and quinine. It was observedthat MLP correction routinely underestimated CL (Table 4).
Pediatric doses. Pediatric dose calculations were based onpharmacopoeial (mg/kg) recommendations (1) and were 10 to70% higher, according to allometric predictions (Table 5). Meflo-quine and quinine had the lowest exponent, which led to predic-tions 1.6- to 2.5-fold higher than reference doses.
Although quinine CL is significantly lower in malaria infectionthan in healthy controls and data presented in Table 3 suggest thatquinine CL is lower in malaria-infected children than in adults(contrary to allometric principles), the allometric exponent forquinine CL (Table 1) was used in the present analysis. Cautiousinterpretation of the result for quinine is therefore required. How-ever, increased doses for dihydroartemisinin (as IV artesunate),clindamycin, and mefloquine appear to be warranted (a piper-aquine dose increase would likely not be clinically relevant orpractical).
DISCUSSION
The present study has demonstrated that interpolation of inter-species allometric scaling could be a useful strategy to include in
TABLE 1 Simple allometric scaling data for clearance (CL) of antimalarial drugs in healthy mammals
development and refinement of pediatric doses for antimalarialdrugs. We found strong allometric relationships for seven drugs(dihydroartemisinin, artemether, artemisinin, clindamycin, pip-eraquine, mefloquine, and quinine) and showed that linear scal-ing of clearance is not applicable, although the 95% confidenceintervals spanned unity for dihydroartemisinin and piperaquine(Table 1). In contrast, linear scaling of the volume of distributionappeared to be valid for some drugs, notably artemether and pip-eraquine (Table 2).
Allometric scaling is founded on sound theoretical principlesand evidence of a power law relationship between biological pa-
rameters and body weight; however, there are conflicting reportson the application of fixed exponents and correction factors (20,35, 36, 38–40, 46, 47). Historical research on basal metabolic rateestablished a 2/3 power scaling of body mass and is supported bythe concept of scaling surface area to volume of 3-dimensionalobjects (20, 39). The “1/4 power law” is based on seminal studiesthat scaled the metabolic rate of animals using an exponent of 3/4and is reported to be consistent with structure and function ob-servations in biology (20, 21, 38, 39). This power law has beentranslated to the use of an exponent of 3/4 for drug clearance, 1/4for elimination half-life, and 1 for volume of distribution (21, 22,35, 36, 38, 39). It has recently been argued that the small numericaldifference between 2/3 and 3/4 powers is of little clinical relevancein pharmacokinetics (36).
The physiological origins of interspecies relationships providesome context for the limitations of allometric scaling in pharma-cokinetics, which have been the subject of detailed review (39,48–50). One limitation of scaling pharmacokinetic parametersthat we encountered was a small range of mammalian species andlow number of subjects in each study (typically 6 to 16 in humanstudies and 6 to 8 in other species). We were able to obtain datafrom only two or three nonhuman species, a finding that is con-sistent with similar previous investigations (24, 31, 33). However,some pharmacokinetic studies, especially veterinary reports, werecompiled with data from at least 8 species (17, 19, 23, 51), andinterspecies scaling of physiological parameters, such as basalmetabolic rate, comprises data from over 20 species (21). A largerrange of animal studies would therefore enhance the quality ofallometric scaling data in future studies.
Further limitations may occur if there are species differences inthe pharmacokinetic properties of drugs that lead to unpredict-able and weak allometric scaling outcomes (39, 49, 50). Highlyprotein-bound drugs (�98% in humans), such as mefloquine(52) and piperaquine (53), may have inconsistent scaling if bind-ing is substantially lower in other species. Bioavailability and renalor hepatic clearance mechanisms also may have species differenceswhich could be relevant for antimalarial drugs that are subject tohepatic metabolism and commonly administered as oral formu-lations. However, there is generally a paucity of relevant data toaddress these potential limitations in the scaling of pharmacoki-netic parameters (49, 50).
Notwithstanding the limitations of interspecies scaling and thepower law relationship debate, allometric scaling data indicatethat fixed exponents of 2/3 or 3/4 may not be universally applica-ble in pharmacokinetics (24, 28, 29, 31, 33, 38, 44, 47). Our anal-yses showed that the 95% CI encompassed both 2/3 and 3/4 for CLof artemether and artemisinin, whereas the upper limit of the 95%CIs for mefloquine, quinine, and chloroquine (0.63, based on re-analysis of a previous study [33]) were all �0.65 (Table 1). Incontrast, the allometric exponents for dihydroartemisinin andpiperaquine CL were 0.85 and 0.96, respectively, and the 95% CIof the exponent spanned unity. Hence, the use of a fixed exponentfor CL of antimalarial drugs is not supported by the present study.
The influence of allometric exponents on interpolated dosepredictions can be substantial and varies according to bodyweight. For example, if the recommended adult dose of a drug is10 mg/kg (for a 70-kg adult), arbitrary exponents of 0.6 and 0.75would lead to predicted doses of 18.5 mg/kg and 14.7 mg/kg, re-spectively, for a 15-kg child and of 15.1 mg/kg and 12.9 mg/kg,respectively, for a 25-kg child. The differential between adult and
FIG 1 Simple allometric scaling relationship with 95% confidence interval(---) for CL of artemether and quinine. Artemether scaling (top) compriseddata from 5 studies (Œ). The scaled estimate of CL for a 10-kg child (o) was 1.5liters/h/kg. By comparison, the mean adult CL is 0.88 liter/h/kg (Table 3), theestimated CL based on a fixed exponent of 3/4 is 1.4 liters/h/kg, and the CLfrom one clinical study in children (9.5 kg) was 1.5 liters/h/kg (150). Quininescaling (bottom) comprised data from 12 studies (�). The scaled estimate ofCL for a 15-kg child (Œ) was 0.37 liter/h/kg. By comparison, the mean adult CLis 0.17 liter/h/kg (Table 3), the estimated CL based on a fixed exponent of 3/4is 0.25 liter/h/kg, and the CL from one clinical study in children (15 kg) was0.24 liter/h/kg (118).
child doses will decrease for children with higher body weights andwill also decrease as the exponent approaches unity. The potentialeffect of these inverse relationships on dose predictions demon-strates the importance of high-quality data for allometric scaling.
It was evident from our detailed literature search that an exten-sive range of interspecies scaling for antimalarial drugs was pre-cluded by several factors. In particular, the target list of antimalar-ials was limited by a paucity of data for individual drugs withinsome common, fixed-dose combinations, and we could not ob-tain pharmacokinetic data from a minimum of three mammalianspecies for amodiaquine and lumefantrine. Studies with intrave-nous (or parenteral) drug administration would have been opti-mal, but inclusion of other routes of administration was necessaryfor artemisinin, artemether, mefloquine, and piperaquine. An im-portant issue was the small body of pharmacokinetic research inmalaria-infected nonhuman species for the antimalarial drugs,and this limitation was addressed by comparing drug clearancefrom studies in malaria-infected human adults with that reportedfor healthy controls (Table 3). Consistent with previous reports,only quinine was shown conclusively to have significantly differ-ent clearance in malaria infection (54). Our data indicate thatdihydroartemisinin clearance was higher in healthy controls thanpatients with malaria infection (Table 3); however, the power ofthe analysis was inconclusive. The apparent clearance (CL/F) ofpiperaquine and mefloquine could be higher in malaria infectionthan in healthy controls (Table 3) and may be a function of alteredbioavailability, as has been reported for dihydroartemisinin (55).
Our investigation of the relevance of correction factors for al-lometric scaling was to ascertain if the more sophisticated ap-proaches to interpolation of interspecies scaling would be benefi-cial for antimalarial drugs. Some of the techniques require rawconcentration-time data (17, 18, 43), which were not available inmost reports, and we therefore confined our analysis to maximumlife span potential (MLP). This correction method has been incor-porated in the rule of exponents, whereby simple allometry is usedfor exponents in the range from 0.50 to 0.77 and scaling CL �MLP against body weight is recommended when the exponentfrom simple allometry is in the range from 0.71 to 0.99 (44).
Our study showed that MLP correction led to substantiallylower interpolated CL estimates, compared to simple allometry
TABLE 3 Clearance of antimalarial drugs in malaria-infected patients compared to healthy adults
DrugRoute ofadministrationa
CL (liters/h/kg) (no.of groupsb) Healthy vs. malaria
140–145Quinine (children) IV 0.24 (1) 0.064 � 0.014 (5) NAd NA 118, 146, 147a IV, intravenous; IM, intramuscular.b Data are means � SD. Some studies comprised several groups.c Piperaquine studies included piperaquine alone and piperaquine-dihydroartemisinin data for healthy volunteers, but only piperaquine-dihydroartemisinin data for patients withmalaria. Our data and a previous report (148) indicate that there is no significant difference in piperaquine clearance when administered alone or in combination withdihydroartemisinin.d NA, not applicable.
FIG 2 Allometric scaling relationship for clearance of dihydroartemisinin.(Top) Simple allometric scaling of data from 7 studies (Œ). The scaled estimateof CL for a 15-kg child (o) was 2.2 liters/h/kg. By comparison, the mean adultCL is 1.1 liters/h/kg (Table 3), the estimated CL based on a fixed exponent of3/4 is 1.6 liters/h/kg, and the CL from one clinical study in children (13 kg) was2.2 liters/h/kg (149). (Bottom) CL � MLP correction (y axis) for the same 7studies (�). The scaled estimate of CL for a 15-kg child (Œ) is 0.53 liter/h/kg.
Senarathna and Batty
6072 aac.asm.org Antimicrobial Agents and Chemotherapy
and data from clinical reports, except for one group of childrentreated with mefloquine (Table 4). We conclude that the applica-tion of MLP correction for antimalarial drugs is not supported bythe present study. By comparison, simple allometry overestimatedthe CL/F of mefloquine in children with uncomplicated falcipa-rum malaria, which could lead to excessive dose predictions, andtherefore, this requires more detailed, contemporary clinical in-vestigations. Conversely, interpolation from simple allometryprovided good estimates of CL for dihydroartemisinin and arte-mether (Table 4). The piperaquine data appear to be conflicting;however, there were several clinical differences between the twopopulations and no conclusive explanation for the findings (56,57). Two recent reports of piperaquine pharmacokinetics showedlower CL/F values, suggesting that the rule of exponents may be
applicable to piperaquine, but as noted in Table 4, these data couldnot be included in the present study due to the use of pooledresults from different partner drugs (12) and use of capillary bloodanalysis to determine the pharmacokinetic parameters (13).
Quinine predictions are problematic, due to the difference inCL (and Vz) between healthy subjects and patients with malaria,and the reported lower CL in children than adults (Table 3).Therefore, cautious interpretation of allometric scaling results arerequired for quinine, due to the complex and multifactorial effectsof malaria infection on the pharmacokinetic properties of thisdrug.
The final component of our study was to translate the allomet-ric scaling results to dose estimates (Table 5). The recommenda-tions for dihydroartemisinin (as IV artesunate) and clindamycin
TABLE 4 Antimalarial drug clearance from clinical studies in children compared to interpolated CL from simple allometry and MLP correction
Drug
Allometric exponenta
Interpolated CL(liters/h/kg)a Clinical studyb
Simpleallometry
MLPcorrection
Simpleallometry
MLPcorrection CL (liters/h/kg) Wt (kg) Reference
Dihydroartemisinin 0.85 1.31 2.21 0.48 2.16 13 149Artemether 0.66 1.18 1.52 0.35 1.5 9.5 150Piperaquine 0.96 1.46 1.40 0.50 1.85c 16 56Piperaquine 0.96 1.46 1.39 0.57 0.85c 19.1 57Mefloquine 0.52 1.0 0.068 0.023 0.046d 9.5e 151Mefloquine 0.52 1.0 0.068 0.023 0.048d 9.5e 152Mefloquine 0.52 1.0 0.045 0.024 0.026d 23 153Quininef 0.40 0.93 0.37 0.13 0.24 15.4 118a Allometry was conducted in healthy controls; CL/F was determined for piperaquine and mefloquine.b Data from studies in malaria-infected children; CL/F was determined for piperaquine and mefloquine.c Piperaquine CL/F was determined from studies of piperaquine-dihydroartemisinin in malaria-infected children. There is no significant difference in piperaquine clearance whenpiperaquine is administered alone or in combination with dihydroartemisinin (148). One recent study reported a CL/F of 0.57 liter/h/kg; however, the data were pooled from aprevious study of piperaquine-dihydroartemisinin (57) and an investigation of piperaquine-artemisinin (12). A report of a piperaquine CL/F of 0.42 liter/h/kg from capillary bloodsamples could not be compared directly to investigations using venous plasma samples for determination of piperaquine pharmacokinetic parameters (13).d Mefloquine CL/F was determined from studies of mefloquine-sulfadoxine-pyrimethamine in malaria-infected children. Mefloquine clearance may be lower when mefloquine isadministered in combination with sulfadoxine and pyrimethamine (101).e Malaria-infected children were all �2 years of age in these studies; the mean age was 1.6 years.f All quinine data are from studies in healthy controls.
TABLE 5 Allometric interpolation of antimalarial doses in comparison to current pharmacopeial recommendations
DrugRoute ofadministration Standard regimena
Dose (mg) for:
15-kg child 25-kg child
Referenceb Allometryc Referenceb Allometryc
Dihydroartemisinin(as IVartesunate)
IV Dose at 0, 12, 24 h, then once/day(2.4 mg/kg/dose)
35 45 60 70
Artemetherd Oral Twice/day for 3 days 40 30 60 40Clindamycin Oral Twice/day for 7 days (10 mg/kg/dose) 150 260 250 360Piperaquine Oral Once/day for 3 days (18 mg/kg/day) 270 290 450 470Mefloquine Oral 2/3 total dose day 1; 1/3 total dose
day 2 (25-mg/kg total dose)375 790 625 1,025
Quinine IV Three times per day for 5–7 days (10mg/kg/dose)
150 370 250 460
a As reported by the World Health Organization (1) and confirmed by reference to the British National Formulary.b Based on mg/kg doses and practical recommendations.c Based on reference doses and equation 3, where adult dose was according to a 70-kg body weight and the allometric exponent was from Table 1. Doses were mostly rounded to a10-mg increment rather than the nearest practical dose.d Current artemether dose recommendation is for body weight range (1, 2, 3, and 4 20-mg tablets for patients weighing 5 to 14 kg, 15 to 24 kg, 25 to 34 kg, and �34 kg,respectively). The adult (70 kg) dose is therefore the same as that for a child of 34 kg (80 mg), which equates to 1.1 mg/kg for adults and 2.3 mg/kg for the 34-kg child. Hence,current practical dose recommendations are higher (mg/kg) for children and vary within the weight ranges.
would be modest increases that can be achieved in the clinicalsetting, whereas the small predicted increase in piperaquine dosewould not be practical. It is notable that recent clinical studieshave recommended higher doses for piperaquine (11, 13, 14) andartesunate in children (15). Indeed, the doses proposed in thelatter study closely match the allometric predictions of 3 mg/kg(15-kg child) and 2.8 mg/kg (25-kg child), based on scaling fordihydroartemisinin in the present study.
The recommended mefloquine doses were 1.6- to 2-foldhigher than reference doses for adults (mg/kg), which could beviewed as excessive and to the best of our knowledge have not beenproposed in any clinical studies. However, recent allometric scal-ing of chloroquine indicated that pediatric doses 1.6-fold higherthan those for adults (mg/kg) were potentially appropriate, andthese doses were exceeded by clinical studies where 2-fold-higherdoses were used in children (8, 9, 33). Complementary data areavailable for quinine, notwithstanding our cautious interpreta-tion of the allometric scaling. Indeed, our results from simpleallometry of quinine suggest that 18 to 24 mg/kg could be moreappropriate than 10 mg/kg (Table 5), and a recent study supportsearlier recommendations in adults that 20 mg/kg quinine shouldbe used as a loading dose in children (10).
An important consideration from our allometric exponentdata is that disproportionate dose increases appear to apply toantimalarial drugs, and the implications for rational pediatric dos-ing of combination regimens are therefore significant. For exam-ple, an adult dose of a dihydroartemisinin-piperaquine (120/960mg; approximately 2/16 mg/kg for a 60-kg patient) oral fixed-dosecombination is reduced by linear calculations to 30/240 mg for a15-kg child. However, based on our allometric interpolation, thiswould result in an appropriate scaled dose of piperaquine and adihydroartemisinin dose that is 20% lower than optimum. Allo-metric scaling of fixed-dose combinations will be valid only if thesame exponent applies to both drugs (or a default-to-fixed-expo-nent scaling is used); however, our data indicate this is unlikely tobe appropriate for artemisinin-based combination therapies, dueto mismatch of the allometric exponents (Table 1).
We conclude that interpolation of interspecies allometric scal-ing is plausible for estimation of pediatric doses of antimalarialdrugs and would be valuable in designing clinical pharmacoki-netic or efficacy studies. The limitations of allometric scaling arewell documented; however, the ongoing use of linear scaling ofadult to pediatric doses (mg/kg) is recognized as flawed (36) andshould be the subject of further investigation in antimalarial che-motherapy.
ACKNOWLEDGMENTS
We gratefully acknowledge the statistical advice of Richard Parsons, Fac-ulty of Health Sciences, and the supervisory support of Andrew Crowe,School of Pharmacy, Curtin University. S.M.D.K.G.S. was the recipient ofa Curtin University Strategic International Research Scholarship.
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