Quinine Pharmacokinetic-Pharmacodynamic Relationships in Uncomplicated Falciparum Malaria

ABSTRACTThe relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for ≥28 days. All patients received a 7-day oral quinine regimen either alone (n= 22) or in combination with rifampin (n= 8). The median fever clearance time was 58.5 h, and the mean ± standard deviation parasite clearance time was 73 ± 24 h. After recovery, six patients had recrudescences ofPlasmodium falciparummalaria and seven had delayed appearances ofP. vivaxinfection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 μg · day/ml had a relative risk of 5.3 (95% confidence interval = 1.6 to 17.7) of having a subsequent recrudescence of infection (P= 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 μg/ml and an MIC of 0.7 μg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).