Trinh Ngoc Hai

Artemisinin kinetics and dynamics during oral and rectal treatment of uncomplicated malaria

To compare parasite clearance times after oral and rectal administration of artemisinin in adults with uncomplicated malaria and to relate pharmacodynamics with artemisinin kinetics and to disclose any pharmacokinetic changes during treatment.

Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9

Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple‐dose artemisinin administration on S‐mephenytoin N‐demethylation in healthy subjects.

Artemisinin induces omeprazole metabolism in human beings.

This study investigated whether time‐dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo.

Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects

The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy‐five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1–5). A six‐drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days −6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four‐hour plasma concentrations of parent drugs and corresponding metabolites and 7‐hydroxycoumarin urine concentrations were quantified by liquid chromatography‐tandem mass spectrometry. The 1‐hydroxymidazolam/midazolam 4‐h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66‐fold (98.75% CI: 2.10–3.36)], artemether [1.54 (1.14–2.09)] and dihydroartemisinin [1.25 (1.06–1.47)] compared with day −6. The S‐4′‐hydroxymephenytoin/S‐mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47–1.94)] and arteether [1.33 (1.15–1.55)] compared with day −6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18–0.39)], arteether [0.70 (0.55–0.89)] and dihydroartemisinin [0.73 (0.59–0.90)] compared with day −6. The α‐hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day −6 in the artemisinin [0.82 (0.70–0.96)] and dihydroartemisinin [0.83 (0.71–0.96)] groups, respectively. In the artemisinin‐treated subjects this decrease was followed by a 1.34‐fold (1.14–1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.

Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses

Eight healthy male, Vietnamese subjects were administered 1×250, 2×250 and 4×250 mg artemisinin capsules in a cross‐over design with randomized sequence with a 7‐day washout period between administrations. The inter‐individual variability in artemisinin pharmacokinetics was large with parameter coefficients of variation (CV) typically between 50–70%. The parameter with the smallest variability was the elimination half‐life (CV≈30–40%). Analysis of variance indicated also a large intra‐subject variability (CV≤24%) for the dose‐normalized area under the plasma concentration–time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre‐systemic extraction. Artemisinin half‐life could not predict the extent ofin vivo exposure to the drug, there being no correlation between half‐life and oral clearance. Artemisinin oral plasma clearance was about 400 L h−1 exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half‐lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time‐dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time‐points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature.

Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19

Abstract— The purpose of the study was to determine the enantiomer pharmacokinetics of omeprazole and 5‐hydroxy‐omeprazole before and after administration of the antimalarial artemisinin to confirm artemisinins ability to induce CYP2C19. Nine healthy male Vietnamese subjects were given a single 20 mg dose of omeprazole orally 1 week before (day ‐ 7) artemisinin administration. Artemisinin was then given orally (500 mg) for 7 days (days 1–7). On days 1 and 7, a single 20 mg dose of omeprazole was coadministered with artemisinin. After a washout period of 6 days, a single 20 mg dose of omeprazole was again administered together with a single 500 mg of artemisinin (day 14). Stereoselective pharmacokinetics of omeprazole and 5‐hydroxyomeprazole was determined on days of omeprazole administration. Seven days of artemisinin administration significantly decreased the AUC of both omeprazole enantiomers (day 7), compared with day 1 (P < 0.001). All values were normalized after the washout period. Artemisinin increased the AUC ratio of R‐5‐hydroxyomeprazole/R‐omeprazole significantly (P < 0.01) on day 7. The AUC ratio of omeprazole sulphone/S‐omeprazole did not differ between study days. Artemisinin decreased the AUC of S‐omeprazole to the same extent as that of R‐omeprazole in extensive CYP2C19 metabolizers, suggesting that artemisinin induces a different enzyme in addition to CYP2C19. These results support and strengthen earlier findings that artemisinin induces CYP2C19 as well as at least one enzyme other than CYP3A4.

The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers

The combination piperaquine and dihydroartemisinin is emerging as first line treatment of uncomplicated falciparum malaria in Southeast Asia. The aim of this study was to determine the influence of a standard Vietnamese meal on the single-dose pharmacokinetics of piperaquine when administered in combination with dihydroartemisinin, and to gain extended data on the terminal half-life of piperaquine in healthy Vietnamese volunteers. Subjects were randomly assigned to take a single oral dose of piperaquine phosphate (640 mg)+dihydroartemisinin (80 mg) together with a standardized Vietnamese meal (n=16) or to remain fasting for 4h following drug intake (n=16). Frequent blood sampling was conducted during 36 h, followed by weekly samples for 7 weeks. The pharmacokinetic parameters of piperaquine were determined by noncompartmental analysis. The median (80% central range) AUC(0-last) was 11.5 (6.9-17.3)h mg/L in fed and 13.9 (2.8-19.3)h mg/L in fasting subjects, indicating a considerable variability in exposure in both groups. The estimated overall oral clearance was 0.27 (0.12-1.49)L/(h kg), the volume of distribution during the terminal elimination phase was 230 (102-419)L/kg and estimated terminal half-life was 18 (5-93) days. This study did not demonstrate a significant impact of a standardized Vietnamese meal on the oral absorption of piperaquine.