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Pharmacology

Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing

Ali Mohamed Ali, Melissa A. Penny, Thomas A. Smith, Lesley Workman, Philip Sasi, George O. Adjei, Francesca Aweeka, Jean-René Kiechel, Vincent Jullien, Marcus J. Rijken, Rose McGready, Julia Mwesigwa, Kim Kristensen, Kasia Stepniewska, Joel Tarning, Karen I. Barnes, Paolo Denti, for the WWARN Amodiaquine PK Study Group
Ali Mohamed Ali
aSwiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
cIfakara Health Institute, Bagamoyo, Tanzania
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Melissa A. Penny
aSwiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
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Thomas A. Smith
aSwiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
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Lesley Workman
dDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
eWorldWide Antimalarial Resistance Network (WWARN) Clinical Pharmacology and Southern African Regional Hub, University of Cape Town, Cape Town, South Africa
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Philip Sasi
fMuhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania
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George O. Adjei
gCentre for Tropical Clinical Pharmacology and Therapeutics, College of Health Sciences, University of Ghana, Korle Bu, Ghana
hOffice of Research, Innovation and Development, University of Ghana, Legon, Ghana
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Francesca Aweeka
iDepartment of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, California, USA
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Jean-René Kiechel
jDrugs for Neglected Diseases Initiative, Geneva, Switzerland
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Vincent Jullien
kService de Pharmacologie, Hôpital Européen George Pompidou, Université Paris Descartes, Paris, France
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Marcus J. Rijken
lShoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
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Rose McGready
lShoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand
mCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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Julia Mwesigwa
nMedical Research Council Unit, Fajara, the Gambia
oFaculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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Kim Kristensen
pDevelopment DMPK-PKPD, Novo Nordisk, Copenhagen, Denmark
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Kasia Stepniewska
mCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
qWorldwide Antimalarial Resistance Network, University of Oxford, Oxford, United Kingdom
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Joel Tarning
mCentre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
qWorldwide Antimalarial Resistance Network, University of Oxford, Oxford, United Kingdom
rMahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
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Karen I. Barnes
dDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
eWorldWide Antimalarial Resistance Network (WWARN) Clinical Pharmacology and Southern African Regional Hub, University of Cape Town, Cape Town, South Africa
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Paolo Denti
dDivision of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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DOI: 10.1128/AAC.02193-17
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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.

FOOTNOTES

    • Received 26 October 2017.
    • Returned for modification 5 December 2017.
    • Accepted 22 June 2018.
    • Accepted manuscript posted online 23 July 2018.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02193-17.

  • Copyright © 2018 Ali et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing
Ali Mohamed Ali, Melissa A. Penny, Thomas A. Smith, Lesley Workman, Philip Sasi, George O. Adjei, Francesca Aweeka, Jean-René Kiechel, Vincent Jullien, Marcus J. Rijken, Rose McGready, Julia Mwesigwa, Kim Kristensen, Kasia Stepniewska, Joel Tarning, Karen I. Barnes, Paolo Denti, for the WWARN Amodiaquine PK Study Group
Antimicrobial Agents and Chemotherapy Sep 2018, 62 (10) e02193-17; DOI: 10.1128/AAC.02193-17

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Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing
Ali Mohamed Ali, Melissa A. Penny, Thomas A. Smith, Lesley Workman, Philip Sasi, George O. Adjei, Francesca Aweeka, Jean-René Kiechel, Vincent Jullien, Marcus J. Rijken, Rose McGready, Julia Mwesigwa, Kim Kristensen, Kasia Stepniewska, Joel Tarning, Karen I. Barnes, Paolo Denti, for the WWARN Amodiaquine PK Study Group
Antimicrobial Agents and Chemotherapy Sep 2018, 62 (10) e02193-17; DOI: 10.1128/AAC.02193-17
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KEYWORDS

NONMEM
dose optimization
malaria
pediatrics

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