Pharmacokinetics of Piperaquine and Safety Profile of Dihydroartemisinin-Piperaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

Abstract

There are limited data on the pharmacokinetic and safety profiles of dihydroartemisinin-piperaquine (DHA-PQ) among human immunodeficiency virus-infected (HIV-positive [HIV+]) individuals taking antiretroviral therapy (ART). In a two-step (parallel-group) pharmacokinetic trial with intensive blood sampling, we compared the area under the concentration-time curve from days 0 to 28 (AUC0-28 days) and the safety outcomes of piperaquine among malaria-uninfected HIV+ adults. In step 1, half the adult dose of DHA-PQ was administered for 3 days as an initial safety check to four groups (n = 6/group) of HIV+ adults (age ≥18 years): (i) antiretroviral-naive individuals, (ii) individuals on nevirapine-based ART, (iii) individuals on efavirenz-based ART, and (iv) individuals on ritonavir-boosted lopinavir-based ART. In step 2, a full adult treatment course of DHA-PQ was administered to a different cohort of participants in three groups: (i) antiretroviral-naive individuals, (ii) individuals on efavirenz-based ART, and (iii) individuals on nevirapine-based ART (n = 10 to 15/group). The ritonavir-boosted lopinavir-based ART group was dropped in step 2 due to the limited number of participants who were on this second-line ART and were eligible for recruitment. Piperaquine's AUC0-28 days in both steps was 43% lower among participants on efavirenz-based ART than among ART-naive participants. There were no significant differences in AUC0-28 days between the other ART groups and the ART-naive group in each of the two steps. Furthermore, no differences in treatment-emergent clinical and laboratory adverse events were observed across the groups in steps 1 and 2. Although it was well tolerated at the half and full standard adult treatment courses, the efavirenz-based antiretroviral regimen was associated with reduced piperaquine exposure, which may compromise dihydroartemisinin-piperaquine's effectiveness in programmatic settings. (The clinical trials presented in this study have been registered at the WHO's International Clinical Trials Registry Platform under ID numbers PACTR2010030001871293 and PACTR2010030001971409.).

• Authors: Clifford G Banda, Fraction Dzinjalamala, Mavuto Mukaka, Jane Mallewa, Victor Maiden, Dianne J Terlouw, David G Lalloo, Saye H Khoo, Victor Mwapasa
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 62 Issue 8 (08 2018) ISSN: 1098-6596 [Electronic] United States
• PMID: 29784846 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Banda et al.

Chemical References

• Alkynes
• Anti-Retroviral Agents
• Antimalarials
• Artemisinins
• Benzoxazines
• Cyclopropanes
• Quinolines
• artenimol
• Nevirapine
• piperaquine
• efavirenz

Topics

• Adult
• Alkynes
• Anti-Retroviral Agents (therapeutic use)
• Antimalarials (therapeutic use)
• Artemisinins (therapeutic use)
• Benzoxazines (therapeutic use)
• Cyclopropanes
• Female
• HIV Infections (drug therapy)
• Humans
• Malaria (drug therapy)
• Male
• Middle Aged
• Nevirapine (therapeutic use)
• Quinolines (therapeutic use)