The effect of sickle cell genotype on the pharmacokinetic properties of artemether-lumefantrine in Tanzanian children

Sri Riyati Sugiarto; George M Bwire; Brioni R Moore; Madhu Page-Sharp; Laurens Manning; Kevin T Batty; Omary M S Minzi; Billy Ngasala; Timothy M E Davis; Julie Makani; Sam Salman

doi:10.1016/j.ijpddr.2022.05.002

The effect of sickle cell genotype on the pharmacokinetic properties of artemether-lumefantrine in Tanzanian children

Int J Parasitol Drugs Drug Resist. 2022 Aug:19:31-39. doi: 10.1016/j.ijpddr.2022.05.002. Epub 2022 May 20.

Authors

Affiliations

¹ Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
² Department of Clinical Pharmacy and Pharmacology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
³ Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Curtin Medical School, Curtin University, Bentley, Western Australia, Australia; Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley, Western Australia, Australia.
⁴ Curtin Medical School, Curtin University, Bentley, Western Australia, Australia.
⁵ Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia; Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
⁶ Curtin Medical School, Curtin University, Bentley, Western Australia, Australia; Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley, Western Australia, Australia.
⁷ Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
⁸ Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia. Electronic address: tim.davis@uwa.edu.au.
⁹ Muhimbili Sickle Cell Centre, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
¹⁰ Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia; Clinical Pharmacology and Toxicology, PathWest, Nedlands, Western Australia, Australia.

Abstract

Since there are inconsistent data relating to the effect of haemoglobinopathies on disposition of artemisinin antimalarial combination therapy, and none in sickle cell trait (SCT) or sickle cell disease (SCD), the aim of this study was to characterize the pharmacokinetic properties of artemether-lumefantrine (ARM-LUM) in children with SCD/SCT. Thirty-eight Tanzanian children aged 5-10 years with normal (haemoglobin AA; n = 12), heterozygous (haemoglobin AS; n = 14) or homozygous (haemoglobin SS; n = 12) sickle genotypes received six ARM-LUM doses (1.7 mg/kg plus 10 mg/kg, respectively) over 3 days. Sparse venous and mixed-capillary dried blood spot (DBS) samples were taken over 42 days. Plasma and DBS ARM and LUM, and their active metabolites dihydroartemisinin (DHA) and desbutyl-lumefantrine (DBL), were assayed using validated liquid chromatography-mass spectrometry. Multi-compartmental pharmacokinetic models were developed using a population approach. Plasma but not DBS concentrations of ARM/DHA were assessable. The majority (85%) of the 15 measurable values were within 95% prediction intervals from a published population pharmacokinetic ARM/DHA model in Papua New Guinean children of similar age without SCD/SCT who had uncomplicated malaria, and there was no clear sickle genotype clustering. Plasma (n = 38) and corrected DBS (n = 222) LUM concentrations were analysed using a two-compartment model. The median [inter-quartile range] LUM AUC_0-∞ was 607,296 [426,480-860,773] μg.h/L, within the range in published studies involving different populations, age-groups and malaria status. DBS and plasma DBL concentrations correlated poorly and were not modelled. These data support use of the conventional ARM-LUM treatment regimen for uncomplicated malaria in children with SCT/SCD.

Keywords: Artemether; Children; Desbutyl-lumefantrine; Dihydroartemisinin; Lumefantrine; Population pharmacokinetics; Sickle cell disease; Sickle cell trait; Tanzania.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anemia, Sickle Cell* / drug therapy
Anemia, Sickle Cell* / genetics
Antimalarials* / pharmacokinetics
Antimalarials* / therapeutic use
Artemether / therapeutic use
Artemether, Lumefantrine Drug Combination / therapeutic use
Child
Ethanolamines / therapeutic use
Fluorenes / therapeutic use
Genotype
Humans
Lumefantrine
Malaria* / drug therapy
Malaria, Falciparum* / drug therapy
Tanzania

Substances

Antimalarials
Artemether, Lumefantrine Drug Combination
Ethanolamines
Fluorenes
Artemether
Lumefantrine