Pharmacokinetics and Kinetic-Dynamic Modeling of an 8-Aminoquinoline CandidateAnticyanide and Antimalarial Drug (WR242511)

摘要

Malaria is a major cause of health problems in a large portion of the world. The8-aminoquinoline compound, primaquine, is one of the only compounds useful for relapses of P. vivax and P. ovale malaria. Primaquine has several toxicities which include methemoglobinemia and hemolytic anemia. The induction of methemoglobinemia is a treatment for cyanide poisoning. We studied the pharmacokinetics and pharmacodynamics (percent methemoglobin) for WR242511, an 8-aminoquinoline primaquine replacement and potential anticyanide compound. The drug's pharmacokinetics and pharmacodynamics are described for oral and intravenous dosing and two PK-PD models are shown to describe the single dose data. A significant lag occurs between the onset of appearance of drug in the plasma and the onset on methemoglobinemia. Peak drug concentrations occurred within 4 hours for oral dosing and peak effect (% methemoglobin) did not occur 72-96 hours for both the oral and intravenous routes. Elimination half life for the