Mechanistic Modelling of Primaquine Pharmacokinetics, Gametocytocidal Activity, and Mosquito Infectivity.
Chotsiri P., Mahamar A., Hoglund RM., Koita F., Sanogo K., Diawara H., Dicko A., Simpson JA., Bousema T., White NJ., Brown JM., Gosling R., Chen I., Tarning J.
Clinical studies have shown that adding a single 0.25mg base/kg dose of primaquine to standard antimalarial regimens rapidly sterilises Plasmodium falciparum gametocytes. However, the mechanism of action and overall impact on malaria transmission is still unknown. Using data from 81 adult Malians with P. falciparum gametocytaemia who received the standard dihydroartemisinin-piperaquine treatment course and were randomised to receive either a single dose of primaquine between 0.0625 and 0.5 mg base/kg or placebo. We characterised the pharmacokinetic-pharmacodynamic relationships for transmission blocking activity. Both gametocyte clearance and mosquito infectivity were assessed. A mechanistically-linked pharmacokinetic-pharmacodynamic model adequately described primaquine and carboxy-primaquine pharmacokinetics, gametocyte dynamics, and mosquito infectivity at different clinical doses of primaquine. Primaquine showed a dose-dependent gametocytocidal effect that precedes clearance. A single low dose of primaquine (0.25 mg/kg) rapidly prevented P. falciparum transmissibility.