Published: May 16, 2020
Chloroquine has been used for the treatment of malaria for more than 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 PKPD 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 PKPD delayed response model, where the equilibration half-lives were 32.7 h (95% CI: 27.4-40.5) for plasma data and 24.1 h (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 h-1 (95% CI: 0.196-0.230), translating to a parasite clearance half-life of 4.5 h (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 PKPD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semi-mechanistic population PKPD modelling. This PKPD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing.