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

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  • 1 Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland; ARTECEF BV, Maarssen, The Netherlands; Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

Pharmacokinetic data were obtained to evaluate the therapeutic potential of Artemotil (β-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 α/β-arteether dissolved in peanut oil used in Indian patients.

Author Notes

Reprint requests: Qigui Li, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500.
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