A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first‐pass hepatic extraction

Abstract

AimsPrevious studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of ar temisinin in healthy subjects. MethodsTwenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/ 500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two-compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction. ResultsArtemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half-life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non-linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first-pass extraction. ConclusionArtemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the timecourse of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

“…However, previous detailed PK studies of oral and parenteral administration of ARS have demonstrated a clear malaria effect on the relative bioavailability thought to result from reduced first pass metabolism (40,41). The decreased absorption rate with increasing parasite density was unexpected and opposite to previous observations (39,(42)(43)(44)(45)(46)(47)(48). The underlying mechanism of this effect cannot be elucidated from data collected in this study.…”

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

“…The elimination t 1/2 of ART has been reported to be between 1.4 and 4.8 h in noncompartmental (2,6,7,9,21,22,26,42,43) and compartmental (10,19,23,24,40) analyses. The present analysis supports a biexponential disposition for ART, while most previous compartmental analyses have reported a monoexponential disposition.…”

“…A number of published studies have evaluated the pharmacokinetics of ART in healthy adults (6,7,10,19,23,43) and adults with malaria (2,9,21,22,24,26,42), but only one has included children with malaria (40). In the latter Vietnamese study, 23 children aged 2 to 12 years were given 5 days of ART dosed according to body weight (approximately 10 mg) and 31 adults received 500 mg of ART daily for 5 days.…”

Reprint of “Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin”

“…with linear absorption and exponential elimination as in Saralamba et al [19], to being quite complicated, e.g. involving 9 compartments as in Gordi et al [20], and of various complexities in between, e.g. 4 compartments as in Tan et al [21].…”

“…However, when information is known about the processes and mechanisms involved, models selected in this way can be less useful than models of process [23], and of course different models must be used for different observational situations (e.g. Gordi et al [20] measure drug concentrations in saliva samples as opposed to the more common use of plasma samples, and so uses a model tailored for that situation). To be fully certain of model appropriateness, fits should be reported and validated on an individual patient basis in addition to any population levels of interest.…”