Background: Malaria-induced alteration of physiological parameters and pharmacokinetic properties of antimalarial drugs may be clinically relevant. Whether and how malaria alters the disposition of piperaquine (PQ) was investigated in this study.
Methods: The effect of malaria on drug metabolism-related enzymes and PQ pharmacokinetic profiles was studied in Plasmodium yoelii-infected mice in vitro/in vivo. Whether the malaria effect was clinically relevant for PQ was evaluated using a validated physiologically-based pharmacokinetic (PBPK) model with malaria-specific scalars obtained in mice.
Results: The infection led to a higher blood-to-plasma partitioning (Rbp) for PQ, which was concentration-dependent and correlated to the parasitemia. No significant change in plasma protein binding was found for PQ. Drug metabolism-related genes (CYPs/UGTs/NRs, except for CYP2a5) were downregulated in infected mice, especially at the acute phase. The plasma oral clearances (CL/F) of three probe substrates for CYP enzymes were significantly decreased (by ≥35.9%) in mice even with moderate infection. The validated PBPK model indicated that the hepatic clearance (CLH) of PQ was the determinant of its simulated CL/F, which was predicted to slightly decrease (by ≤23.6%) in severely infected mice but not in malaria patients. The result fitted well with the plasma pharmacokinetics of PQ in infected mice and literature data on malaria patients. The blood clearance of PQ was much lower than its plasma clearance due to its high Rbp.
Conclusions: The malaria-induced alteration of drug metabolism was substrate-dependent, and its impact on the disposition of PQ and maybe other long-acting aminoquinoline antimalarials was not expected to be clinically relevant.
Keywords: Malaria; PBPK modeling; clearance; drug metabolizing enzymes; piperaquine.
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