Details

Autor(en) / Beteiligte

• Abd‐Rahman, Azrin N.
• Marquart, Louise
• Gobeau, Nathalie
• Kümmel, Anne
• Simpson, Julie A.
• Chalon, Stephan
• Möhrle, Jörg J.
• McCarthy, James S.

Titel

Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

Ist Teil von

• Clinical pharmacology and therapeutics, 2020-11, Vol.108 (5), p.1055-1066

Ort / Verlag

United States: John Wiley and Sons Inc

Erscheinungsjahr

2020

Quelle

Wiley Online Library

Beschreibungen/Notizen

• 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.