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  -