TY - JOUR AU - Abd-Rahman, AN AU - Marquart, L AU - Gobeau, N AU - Kummel, A AU - Simpson, JA AU - Chalon, S AU - Mohrle, JJ AU - McCarthy, JS Y2 - 2020/11/27 Y1 - 2020/07/02 SN - 0009-9236 UR - http://hdl.handle.net/11343/252451 AB - Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with blood-stage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour-1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing. LA - English PB - WILEY T1 - Population Pharmacokinetics and Pharmacodynamics of Chloroquine in aPlasmodium vivaxVolunteer Infection Study DO - 10.1002/cpt.1893 IS - Clinical Pharmacology and Therapeutics VL - 108 IS - 5 SP - 1055-1066 L1 - /bitstream/handle/11343/252451/cpt.1893.pdf?sequence=1&isAllowed=y ER -