Quinine pharmacokinetic-pharmacodynamic relationships in uncomplicated falciparum malaria

Abstract

The 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 > or = 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 of Plasmodium falciparum malaria and seven had delayed appearances of P. vivax infection 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 microg.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 microg/ml and an MIC of 0.7 microg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).

FIG. 1.

Sequence of events in the model.

FIG. 2.

Relationship between the AUC_0-7 for quinine and FCT and PCT in patients treated with quinine alone (closed circles) and quinine plus rifampin (open circles).

FIG. 3.

Concentrations of quinine and 3OH-Q in the plasma of patients with P. falciparum malaria with (upper graph) and without (lower graph) subsequent recrudescences. The data are shown as medians and the 95% CI of the median.

FIG. 4.

Cumulative cure rates for patients with P. falciparum malaria for whom the AUC_3-7 for quinine was ≥20 or <20 μg · day/ml.

FIG. 5.

In vivo pharmacodynamics of quinine in falciparum malaria. The mean profile of the parasite burden in successfully treated patients declines logarithmically until total eradication(s) because the concentrations in plasma remain above the MPC (approximately 3.3 μg/ml), whereas in patients with recrudescent infections, parasite killing (E) falls below maximal values after 48 h of treatment. A parasite multiplication rate of 1 per cycle results from average MICs of 0.7 μg/ml at the end of the first week, and thereafter, the parasite multiplication rate (10 per cycle) is unrestrained (11).