Population pharmacokinetics of the antimalarial Amodiaquine.: A pooled analysis to optimize dosing

WWARN Amodiaquine PK Study Group

doi:10.1128/AAC.02193-17

Population pharmacokinetics of the antimalarial Amodiaquine. A pooled analysis to optimize dosing

WWARN Amodiaquine PK Study Group

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Abstract

Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

Original language	English
Article number	e02193-17
Journal	Antimicrobial Agents and Chemotherapy
Volume	62
Issue number	10
Number of pages	18
ISSN	0066-4804
DOIs	https://doi.org/10.1128/AAC.02193-17
Publication status	Published - Oct 2018

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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize DosingFinal published version, 1.71 MBLicence: CC BY

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@article{13223955efeb4501801d0f02ecd74232,

title = "Population pharmacokinetics of the antimalarial Amodiaquine.: A pooled analysis to optimize dosing",

abstract = "Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.",

author = "Ali, {Ali Mohamed} and Penny, {Melissa A} and Smith, {Thomas A} and Lesley Workman and Philip Sasi and Adjei, {George O} and Francesca Aweeka and Jean-Ren{\'e} Kiechel and Vincent Jullien and Rijken, {Marcus J} and Rose McGready and Julia Mwesigwa and Kim Kristensen and Kasia Stepniewska and Joel Tarning and Barnes, {Karen I} and Paolo Denti and J{\o}rgen Kurtzhals and Michael Alifrangis and {WWARN Amodiaquine PK Study Group}",

year = "2018",

month = oct,

doi = "10.1128/AAC.02193-17",

language = "English",

volume = "62",

journal = "Antimicrobial Agents and Chemotherapy",

issn = "0066-4804",

publisher = "American Society for Microbiology",

number = "10",

}

TY - JOUR

T1 - Population pharmacokinetics of the antimalarial Amodiaquine.

T2 - A pooled analysis to optimize dosing

AU - Ali, Ali Mohamed

AU - Penny, Melissa A

AU - Smith, Thomas A

AU - Workman, Lesley

AU - Sasi, Philip

AU - Adjei, George O

AU - Aweeka, Francesca

AU - Kiechel, Jean-René

AU - Jullien, Vincent

AU - Rijken, Marcus J

AU - McGready, Rose

AU - Mwesigwa, Julia

AU - Kristensen, Kim

AU - Stepniewska, Kasia

AU - Tarning, Joel

AU - Barnes, Karen I

AU - Denti, Paolo

AU - Kurtzhals, Jørgen

AU - Alifrangis, Michael

AU - WWARN Amodiaquine PK Study Group

PY - 2018/10

Y1 - 2018/10

N2 - Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

AB - Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

U2 - 10.1128/AAC.02193-17

DO - 10.1128/AAC.02193-17

M3 - Journal article

C2 - 30038039

SN - 0066-4804

VL - 62

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 10

M1 - e02193-17

ER -

Population pharmacokinetics of the antimalarial Amodiaquine. A pooled analysis to optimize dosing

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