Piperaquine Ppharmacokinetic and pharmacodynamic profiles in healthy volunteers of Papua New Guinea after administration of three-monthly doses of dihydroartemisinin-piperaquine

Millat-Mart&#237;nez, P; Salman, S; Moore, BR; Baro, B; Page-Sharp, M; Batty, KT; Robinson, LJ; Pomat, W; Karunajeewa, H; Laman, M; Manning, L; Mitj&#224;, O; Bassat, Q

Author(s): Millat-Martínez, P; Salman, S; Moore, BR; Baro, B; Page-Sharp, M; Batty, KT; Robinson, LJ; Pomat, W; Karunajeewa, H; Laman, M; Manning, L; Mitjà, O; Bassat, Q;
Details: Publication Year 2022-08-16,Volume 66,Issue #8,Page e0018522
Journal Title: Antimicrobial Agents and Chemotherapy
Abstract: Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.
Publisher: ASM
Keywords: Adult; *Antimalarials/pharmacology; *Artemisinins/adverse effects/pharmacokinetics; Female; Healthy Volunteers; Humans; *Long QT Syndrome/chemically induced/drug therapy; Longitudinal Studies; *Malaria, Falciparum/drug therapy; Male; Papua New Guinea; Piperazines; *Quinolines/pharmacology; QT interval; cardiac safety; malaria; pharmacokinetics; piperaquine
Research Division(s): Population Health And Immunity
PubMed ID: 35862743
Publisher's Version: https://doi.org/10.1128/aac.00185-22
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2022-08-30 09:11:29

Last Modified: 2022-08-30 09:19:18