Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study. Issue 5 (2nd July 2020)

• Record Type: Journal Article
• Authors: Abd‐Rahman, Azrin N.; Marquart, Louise; Gobeau, Nathalie; Kümmel, Anne; Simpson, Julie A.; Chalon, Stephan; Möhrle, Jörg J.; McCarthy, James S.
• Is Part Of: Clinical pharmacology & therapeutics. Volume 108:Issue 5(2020)
• Page Start: 1055
• Page End: 1066
• Publication Date: 2020-07-02
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.1893
• Languages: English
• ISSNs: 0009-9236

Abstract

Abstract : 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.