Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

IMPAACT P1079 protocol team

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Methods: Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158–266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3–12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Results: Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5–12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0- 120hr:123% (p<0.001); Cday7:116% (p<0.001), Cmax: 95% (p<0.001)]. Conclusions: Nevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4–12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.

Original languageEnglish (US)
Article numbere0186589
JournalPLoS One
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2017

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Nevirapine
antimalarials
Pharmacokinetics
Antimalarials
pharmacokinetics
dihydroartemisinin
therapeutics
malaria
artemisinin
HIV
Malaria
Control Groups
Therapeutics
Area Under Curve
lumefantrine
artemether
Sub-Saharan Africa
dosage
cytochrome P-450
Implosive Therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children. / IMPAACT P1079 protocol team.

In: PLoS One, Vol. 12, No. 10, e0186589, 01.10.2017.

Research output: Contribution to journalArticle

@article{18f1c3926be7484cb8028c24dfa88f8b,
title = "Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children",
abstract = "Background: The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Methods: Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158–266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3–12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Results: Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5–12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46{\%}, p = 0.08) and dihydroartemisinin (-22{\%}, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50{\%} (p = 0.07) for artemether and 36{\%} (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0- 120hr:123{\%} (p<0.001); Cday7:116{\%} (p<0.001), Cmax: 95{\%} (p<0.001)]. Conclusions: Nevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4–12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.",
author = "{IMPAACT P1079 protocol team} and Liusheng Huang and Vincent Carey and Lindsey, {Jane C.} and Florence Marzan and David Gingrich and Bobbie Graham and Linda Barlow-Mosha and Ssemambo, {Phionah K.} and Portia Kamthunzi and Sharon Nachman and Sunil Parikh and Aweeka, {Francesca T.} and Paul Sato and Siberry, {George K.} and Hudgens, {Kimberly R.} and Vincent, {Carol A.} and Mona Farhad and Lynette Purdue and Deborah Persaud and Haak, {Maureen M.} and Pahwa, {Savita G} and Tim Cressey and Charlotte Hobbs and Travis Behm and Werner Schimana and Omolara Aderin-boye and Teopista Nakyanzi",
year = "2017",
month = "10",
day = "1",
doi = "10.1371/journal.pone.0186589",
language = "English (US)",
volume = "12",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "10",

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TY - JOUR

T1 - Concomitant nevirapine impacts pharmacokinetic exposure to the antimalarial artemether-lumefantrine in African children

AU - IMPAACT P1079 protocol team

AU - Huang, Liusheng

AU - Carey, Vincent

AU - Lindsey, Jane C.

AU - Marzan, Florence

AU - Gingrich, David

AU - Graham, Bobbie

AU - Barlow-Mosha, Linda

AU - Ssemambo, Phionah K.

AU - Kamthunzi, Portia

AU - Nachman, Sharon

AU - Parikh, Sunil

AU - Aweeka, Francesca T.

AU - Sato, Paul

AU - Siberry, George K.

AU - Hudgens, Kimberly R.

AU - Vincent, Carol A.

AU - Farhad, Mona

AU - Purdue, Lynette

AU - Persaud, Deborah

AU - Haak, Maureen M.

AU - Pahwa, Savita G

AU - Cressey, Tim

AU - Hobbs, Charlotte

AU - Behm, Travis

AU - Schimana, Werner

AU - Aderin-boye, Omolara

AU - Nakyanzi, Teopista

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Background: The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Methods: Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158–266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3–12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Results: Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5–12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0- 120hr:123% (p<0.001); Cday7:116% (p<0.001), Cmax: 95% (p<0.001)]. Conclusions: Nevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4–12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.

AB - Background: The antiretroviral drug nevirapine and the antimalarial artemisinin-based combination therapy artemether-lumefantrine are commonly co-administered to treat malaria in the context of HIV. Nevirapine is a known inhibitor of cytochrome P450 3A4, which metabolizes artemether and lumefantrine. To address the concern that the antiretroviral nevirapine impacts the antimalarial artemether-lumefantrine pharmacokinetics, a prospective non-randomized controlled study in children presenting with uncomplicated malaria and HIV in sub-Saharan Africa was carried out. Methods: Participants received artemether-lumefantrine (20/120 mg weight-based BID) for 3 days during nevirapine-based antiretroviral therapy (ART) co-administration (158–266 mg/m2 QD). HIV positive participants who were not yet on ART drugs were also enrolled as the control group. The target enrollment was children aged 3–12 years (n = 24 in each group). Intensive pharmacokinetics after the last artemether-lumefantrine dose was assessed for artemether, its active metabolite dihydroartemisinin, and lumefantrine. Pharmacokinetic parameters (area under the plasma concentration vs. time curve (AUC), maximum concentration and day 7 lumefantrine concentrations) were estimated using non-compartmental methods and compared to controls. Results: Nineteen children (16 on nevirapine and three not on ART) enrolled. Fifteen of the 16 (aged 4 to 11 years) on nevirapine-based ART were included in the pharmacokinetic analysis. Due to evolving WHO HIV treatment guidelines, insufficient children were enrolled in the control group (n = 3), so the pharmacokinetic data were compared to a historical control group of 20 HIV-uninfected children 5–12 years of age who also presented with malaria and underwent identical study procedures. Decreases of pharmacokinetic exposure [as estimated by AUC (AUC0-8hr)] were marginally significant for artemether (by -46%, p = 0.08) and dihydroartemisinin (-22%, p = 0.06) in the children on nevirapine-based ART, compared to when artemether-lumefantrine was administered alone. Similarly, peak concentration was decreased by 50% (p = 0.07) for artemether and 36% (p = 0.01) for dihydroartemisinin. In contrast, exposure to lumefantrine increased significantly in the context of nevirapine [AUC0- 120hr:123% (p<0.001); Cday7:116% (p<0.001), Cmax: 95% (p<0.001)]. Conclusions: Nevirapine-based ART increases the exposure to lumefantrine in pre-pubescent children with a trend toward diminished artemether and dihydroartemisinin exposure. These findings contrast with other studies indicating NVP reduces or results in no change in exposure of antimalarial drugs, and may be specific to this age group (4–12 years). Considering the excellent safety profile of artemether-lumefantrine, the increase in lumefantrine is not of concern. However, the reduction in artemisinin exposure may warrant further study, and suggests that dosage adjustment of artemether-lumefantrine with nevirapine-based ART in children is likely warranted.

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