Developing an Original Pharmacokinetic-Pharmacodynamic Model for Artesunate in Severe Malaria Patients with Acute Kidney Injury in North Central Nigeria

Severe malaria complicated by acute kidney injury creates pharmacokinetic-pharmacodynamic challenges for artesunate dosing that are inadequately addressed by existing models derived from uncomplicated malaria populations. This study developed an original PK-PD model for artesunate and its active metabolite dihydroartemisinin in severe malaria patients with concurrent acute kidney injury at tertiary hospitals in Plateau and Benue States, North Central Nigeria. A prospective intensive pharmacokinetic sampling study was conducted in 50 adult patients with severe falciparum malaria stratified by AKI stage. Artesunate and DHA plasma concentrations were measured by validated LC-MS/MS. The PD endpoint was parasite clearance half-life measured by microscopy and qPCR. Population PK-PD modelling was performed using NONMEM with covariate analysis for AKI severity, baseline parasitaemia, and CYP2C9 genotype. Results demonstrated that AKI significantly reduced artesunate hydrolysis to DHA (clearance reduced by 54 percent in AKI stage 3 patients), resulting in higher artesunate and lower DHA exposure compared to non-AKI patients. Paradoxically, reduced DHA formation in severe AKI was associated with prolonged parasite clearance half-lives (4.8 versus 3.1 hours; p < 0.001). An original adaptive dosing algorithm based on the final PK-PD model and incorporating AKI staging was developed and evaluated by simulation. The study constitutes the first original PK-PD analysis of artesunate in malaria-AKI patients in Nigeria and provides a dosing optimisation framework for this high-mortality patient subgroup. Keywords: artesunate, pharmacokinetics-pharmacodynamics, severe malaria, acute kidney injury, Plateau State