Artemisinin Pharmacokinetics and Efficacy in Uncomplicated-Malaria Patients Treated with Two Different Dosage Regimens

Abstract

The immediate efficacies of two oral dosage regimens of artemisinin were investigated in 77 male and female adult Vietnamese falciparum malaria patients randomly assigned to treatment with either 500 mg of artemisinin daily for 5 days (group A; n ‫؍‬ 40) or artemisinin at a dose of 100 mg per day for 2 days, with the dose increased to 250 mg per day for 2 consecutive days and with a final dose of 500 mg on the fifth day (group B; n ‫؍‬ 37). Parasitemia was monitored every 4 h. The average parasite clearance time was longer in group B than in group A (means ؎ standard deviations, 50 ؎ 23 and 34 ؎ 14 h, respectively; P < 0.01). Artemisinin concentrations in saliva samples obtained on days 1 and 5 were quantified by high-performance liquid chromatography. The average oral clearance, based on saliva drug concentrations in group B patients, was twofold higher than that in group A patients on day 1 (P < 0.01), with no differences in drug half-lives (P ‫؍‬ 0.40), indicating a saturable first-pass metabolism. Female patients had higher oral clearance values on day 1. Artemisinin's pharmacokinetic parameters were similar on day 5 in both groups, although a significant increase in oral clearance from day 1 to day 5 was evident. Thus, artemisinin exhibited both dose-and time-dependent pharmacokinetics. The escalating dose studied did not result in higher artemisinin concentrations toward the end of the treatment period.Artemisinin and its semisynthetic family of derivatives are the most potent antimalarials available for treatment of falciparum malaria infections (15,25,26). Artemisinin has a short elimination half-life, a rapid onset of action, no major side effects, and markedly induces of its own metabolic elimination, resulting in five-to sevenfold decreases in its concentrations over 5 to 7 days of administration in both malaria patients and healthy subjects (1, 3-5). A major drawback with artemisinin and its derivatives is the high recrudescence rates within 2 to 3 weeks after monotherapy (14,17). It has proved difficult in field studies to determine whether the relapsed malaria episodes are due to new infections or the persistence of the previous one. However, true recrudescence has been described in patients kept in vector-free environments for longer periods of time (12,13,16). There is also evidence of true recrudescence, as determined by a PCR technique with patients treated with a combination of artemether and benflumetol (10) as well as artesunate alone (18). It has been suggested that the occurrence of recrudescence may partly be due to the decreasing artemisinin concentrations toward the end of treatment (4). Thus, the time-dependent kinetics of the drug can be of importance in dosing suggestions.Reports concerning dose-response studies with the artemisinin endoperoxides are lacking. Rectal administration of artemisinin was shown to have efficacy comparable to that of oral treatment in terms of the parasite clearance time (PCT) and the fever subsidence time (FST) in patients with uncomplicated falciparum mal...

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

“…In comparisons of the AUCs of different doses in previous studies, the relative bioavailability after 4 to 7 days was between 0.13 and 0.29 (7,9,22,26,40,43). One study of African adults with malaria who received 500 mg of ART daily for 3 days and a single dose of mefloquine (42) measured ART in saliva and found that relative bioavailability was lower (0.45) only on the third day when mefloquine was given after the last dose of ART.…”

“…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.…”

“…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.…”

First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone

“…Time-dependent pharmacokinetics has been well described for artemisinin in healthy subjects and malaria patients (4,10), with a decrease in dose-normalized artemisinin concentrations over 5 days of drug administration due to autoinduction of metabolism (9,25). Declining plasma concentrations for artemether (29) and, less convincingly, for artesunate and dihydroartemisinin (14,35) have been reported following multiple doses.…”

Can the host immune system promote multiple invasions of erythrocytesin vivo? Differential effects of medication and host sex in a wild malaria-like model

“…Several factors may account for the differential efficacy of the primaquine treatment between sexes that could affect the efficacy of the drug reducing the intensity of infection. Many other reports in medical and veterinarian literature have identified host sex as a key factor affecting drug pharmacokinetics at two different levels, the absorption and the metabolism of drugs (Gordi et al 2002 ;Pinsonneault and Sadeé, 2003 ;Klein, 2004) although, in humans there are no differences in the kinetic parameters of primaquine between sexes (Elmes et al 2006). Also, other factors tightly related to sexual characteristics, such as hormone concentrations and genetic differences, may be involved in the influence of sex on drug pharmacokinetics (Pinsonneault and Sadeé, 2003).…”