PHARMACOKINETIC INVESTIGATION ON THE THERAPEUTIC POTENTIAL OF ARTEMOTIL (Β-Arteether) IN THAI PATIENTS WITH SEVERE PLASMODIUM FALCIPARUM MALARIA

Abstract

Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (beta-arteether) in 56 Thai patients with severe Plasmodium falciparum malaria. Intramuscular administration was given at 1) a low dose of 3.2 mg/kg on day 0 and 1.6 mg/kg/day on days 1-4 and 2) a high dose of 4.8 mg/kg on day 0 at 0 hours, 1.6 mg/kg at 6 hours, and 1.6 mg/kg/day on days 1-4. Cmax values of 63.7 ng/mL at 6.1 hours and 140.8 ng/mL at 5.7 hours were reached in low-dose and high-dose patients, respectively. Drug concentrations decreased slowly with half-lives of 12.5-22.4 hours on day 0 and 31.6-40.7 hours on day 4 for both dosage regimens. Although the maintaining dosage on the last day was much lower than the loading dose on day 0, the area under the curve (AUC) and Cmax on day 4 were significantly increased (2.85-4.55 fold), suggesting drug accumulation in the blood. Dihydroartemisinin (DHA), an active metabolite of Artemotil, was detected in most patients. The mean ratios of DHA and Artemotil were 0.16-0.19 in both dosage regimens for the entire study period. Similar to previous reports, all patients showed a slow response to treatment with mean values of 77.2 hours for the fever clearance time (FCT) and 75.8 hours for the parasite clearance time (PCT) (low dose) and 70.1 hours for the FCT and 64.4 hours for the PCT (high dose). Interestingly, a very rapid response to the treatment was exhibited in patient 151, with an FCT of 4 hours and a PCT of 36 hours, with different pharmacokinetic data from others on day 0. The patient had a very high Cmax (2,407 ng/mL) and AUC (12,259 ng.hr/mL) values without an intramuscular absorption phase on the first day. These values were approximately 21.9 (Cmax) and 2.6 (AUC) times higher than in other patients; this patient may have been to be injected through a vessel at first dosing. In conclusion, the patients treated with the high dosage regimen had higher AUC values and higher antimalarial efficiency (cure rate = 48%) than the low-dose subjects (cure rate = 23%). Despite the high accumulation and longer exposure time (9-11 days) when compared with other artemisinin agents, due to the slow prolonged absorption of Artemotil from injection sites, the two dosage regimens did not show a better therapeutic effects than other artemisinin drugs, including alpha/beta-arteether dissolved in peanut oil used in Indian patients.

Pharmacokinetic (PK) and Pharmacodynamic Profiles of Artemisinin Derivatives Influence Drug Neurotoxicity in Animals

“…These studies also show that the ART drug half-life is due to the accumulation of ART drugs in the plasma following multiple doses of AE and AM administered intramuscularly and AL administered orally. In accordance with the published literatures and our research experience, ARTs (QHS, AS, AM, and DHA) elicit auto-induction of a drug metabolism pathway during multiple oral treatments in malaria patients and healthy subjects (van Agtmael et al, 1999;Ashton et al, 1996 and1998;Khanh et al, 1999: Li et al, 2004Park et al, 1998). The C max and AUC values of these patients were markedly reduced from one-third to one-seventh on the last dose day compared with the first dosing day.…”

“…The intramuscular administration of AM and AE was associated with slow absorption because the drugs were dissolved in sesame oil or peanut oil that, when injected, formed a depot from which the drug was slowly released (Kager et al, 1994: Li et al, 2004. The slow elimination of AE was recently demonstrated in a rat study, which also found significant accumulation of AE in the plasma from injection sites (Li et al, 1999b).…”

Efficacy of Novel Oral Formulations of α/β Arteether against Multidrug-Resistant Malaria in Mice

“…3 days) [14,[19][20][21] . ␤ AE formulated in sesame oil by the WHO [31,32] for higher-dose injections (total dose: 576-768 mg, i.m., in 5 days) has been reported to produce much lower cure rates [33,34] . AE ( ␣ / ␤ ) has been claimed to exhibit synergistic action [35,36] .…”

A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu

“…The data from animal models will be useful for further researches. For example, the antimalarial activity of artemisinins against P. berghei in mice is comparable to the therapeutic effect in clinic, i.e., artemether (ED 90 1.02 mg/kg) and arteether (ED 90 1.95 mg/kg) on P. berghei in mice [183] matching with artemether oil injection (80 mg in 1 mL-ampoule) and arteether oil injection (150 mg in 2 mL-ampoule) in clinic [336,337]. Hence, the animal model for screening antimalarial effect should be considered reliable.…”