Population pharmacokinetics of fosmidomycin and clindamycin in combination with artesunate for uncomplicated Plasmodium falciparum malaria in Gabonese children and adults.

BACKGROUND: The increasing prevalence of artemisinin resistance in Plasmodium falciparum malaria highlights the urgent need for new, effective treatment strategies. The combination of fosmidomycin and clindamycin has shown promise, but further investigation is required, particularly regarding its pharmacokinetics. This study aimed to develop population pharmacokinetic models for fosmidomycin and clindamycin administered alongside artesunate, to evaluate the adequacy of weight-based dosing in children and adults with uncomplicated malaria and to identify relevant covariates influencing drug disposition.

METHODS: This analysis was conducted within an open-label, randomized clinical trial in Lambaréné, Gabon. Forty patients aged 3-57 years with uncomplicated P. falciparum malaria received an oral combination of artesunate (2 mg/kg), fosmidomycin (30 mg/kg), and clindamycin (10 mg/kg) administered every 12 h for three days. Plasma samples were collected at various time points and analyzed via LC-MS/MS. Population pharmacokinetic models for fosmidomycin and clindamycin were developed using non-linear mixed-effects modeling to characterize drug exposure and identify significant covariates.

RESULTS: Pharmacokinetic data were best described by one-compartment models with first-order absorption for both drugs. Allometric scaling based on body weight was a significant covariate influencing clearance and volume of distribution for both fosmidomycin and clindamycin. Notably, body temperature was identified as a significant covariate affecting fosmidomycin clearance. Dosing based on body weight resulted in consistent exposure (AUCτ) of fosmidomycin across all age groups. However, clindamycin exposure was substantially lower in children under 12 years of age compared to older patients.

CONCLUSION: We successfully developed robust population pharmacokinetic models for both fosmidomycin and clindamycin. These models confirmed that body weight is a key determinant of drug disposition for both agents, and that body temperature influences fosmidomycin clearance. While the current fosmidomycin dosing appears adequate across age groups, the standard 10 mg/kg dose of clindamycin results in lower exposure in young children compared to adolescence and adults. Dose simulation suggests that increasing clindamycin to 12 mg/kg in children under 35 kg would provide equal drug exposure in all age groups.