Semi-mechanistic time-to-event modelling in malaria
Joel Tarning (1,2), Praiya Thana (1), Palang Chotsiri (1), Issaka Zongo (3), Nicholas Day (1,2), FranÁois Nosten (1,2), Nicholas J White (1,2).
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK, (3) Institut de Recherche en Sciences de la Santť, Bobo-Dioulasso, Burkina Faso.
Objectives: Dihydroartemisinin-piperaquine is a promising antimalarial treatment of P. vivax and P. falciparum malaria. Falciparum malaria causes the majority of deaths but vivax malaria causes substantial morbidity with frequent relapses due to the reactivation of latent parasites in the liver. The objective of these studies was to evaluate the PK/PD of piperaquine in patients with vivax and falciparum malaria.
Methods: Study 1) 250 patients with P. vivax malaria in Thailand received a standard 3-day regimen of dihydroartemisinin-piperaquine. Plasma samples were collected in 116 patients at 6 random time points and at the time of recurrent malaria. Study 2) Sparse piperaquine plasma sampling in 183 children (age between 2.33-58.1 months) were obtained after monthly dihydroartemisinin-piperaquine prophylactic treatment of falciparum malaria in Burkina Faso. In both studies, PK/PD properties of piperaquine were evaluated with nonlinear mixed-effects modelling. Recurrent malaria were modelled with a time-to-event approach for both falciparum and vivax malaria.
Results: Piperaquine population pharmacokinetics were described by a 3-compartment disposition model with transit-absorption for both children and adults, supported by prior information in the sparse data in children. Study 1) The biology of relapsing vivax malaria was accommodated by a constant baseline hazard with the addition of multiple surge functions that increased the hazard of relapse with an estimated 123% in fixed 3 week intervals. Study 2) Parasite density at the time of malaria detection was used for extrapolation of the likely time interval of falciparum malaria acquisition in children. The protective effect of piperaquine was implemented as an inhibitory EMAX function. Dose-optimization using the final PK/PD model suggested that small children had lower exposure to piperaquine after a standard body weight-normalised dose. A prospective dose increase predicted a 34% decreased malaria incidence in small children.
Conclusions: PK/PD modelling conducted here demonstrated that both the biology of relapsing vivax malaria and the acquisition of new falciparum infections were successfully described by a time-to-event approach. The results suggest that a large proportion of the first vivax relapses were suppressed completely by residual piperaquine concentrations, and that small children are under-dosed in preventive treatment of new falciparum infections.