Dose‐finding and efficacy study for i.m. artemotil (beta‐arteether) and comparison with i.m. artemether in acute uncomplicated P. falciparum malaria

Abstract

Aims The antimalarial efficacy/pharmacodynamics and pharmacokinetics of intramuscular (i.m.) artemotil in Thai patients with acute uncomplicated falciparum malaria were studied to determine effective dose regimens and to compare these with the standard dose regimen of artemether. Methods In part I of the study three different artemotil dose regimens were explored in three groups of 6-9 patients for dose finding: 3.2 mg kg x1 on day 0 and 1.6 mg kg x1 on days 1-4 (treatment A), 1.6 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment B), 3.2 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment C). In part II of the study, artemotil treatments A and C were compared in three groups of 20-22 patients with standard i.m. artemether treatment: 3.2 mg kg x1 on day 0 and 0.8 mg kg x1 on days 1-4 (treatment R).Results Full parasite clearance was achieved in all patients in Part I, but parasite clearance time (PCT) and fever clearance time (FCT) tended to be longer in treatment B. Also the incidence of recrudescence before day 28 (RI) tended to be higher for treatment B. In part II, the mean PCT for each of the two artemotil treatments (52 and 55 h, respectively) was significantly longer than for artemether (43 h). The 95% CI for the difference A vs R was 0, 16 h (P=0.0408) and for difference C vs R it was 2, 19 h (P=0.0140). FCT was similar for the three treatments. The incidence of RI ranged from 5 out of 19 for treatment C to 3 out of 20 for treatment R. Plasma concentrationtime profiles of artemotil indicated an irregular and variable rate of absorption after i.m. injection. A late onset of parasite clearance was associated with delayed absorption and/or very low initial artemotil plasma concentrations. Pharmacokineticpharmacodynamic evaluations supported a relationship between the rate of parasite clearance and exposure to artemotil during approximately the first 2 days of treatment, and suggested that artemotil has a slower rate of absorption than artemether. Safety assessment, including neurological and audiometric examinations showed no clinically relevant findings. Adverse events before and during treatment included headache, dizziness, nausea, vomiting and abdominal pain. These are characteristic of acute malaria infections and resolved during treatment. Conclusions The optimum dose regimen for artemotil in this study was identical to the standard dose regimen of artemether. The findings that artemotil is more slowly absorbed from the i.m. injection site than artemether, and that early systemic availability may be insufficient for an immediate onset of parasite clearance contributed to the decision to choose a higher loading dose of artemotil (divided over two injection sites) and to omit the fifth dose in later studies. With this optimized dosing schedule, the more pronounced depot characteristics of i.m. artemotil can be an advantage, since it may allow shorter hospitalization.

Artemether Bioavailability after Oral or IntramuscularAdministration in Uncomplicated FalciparumMalaria

“…The rate of absorption of the injected drug from the oil depot may be influenced by the oil itself. Recent studies comparing artemether and arteether absorption indicated even slower absorption of arteether injected in sesame seed oil (8). Use of alternative oils to dissolve these lipophilic drugs may accelerate absorption.…”

“…Precise oral dosing was provided by taking the powder from 40-mg artemether capsules (Kunming Pharmaceutical Factory), weighing it, and replacing the weight-adjusted amount back in the capsule. Blood samples were taken through an indwelling forearm vein catheter at 0, 15, 30, 45, 60, 90, and 120 min and then 3,4,6,8,12,18, and 24 h following drug administration. A second dose of artemether (2 mg/kg) was then given at 24 h by the alternative route.…”

Pharmacokinetic and Pharmacodynamic Profiles of Rapid-Acting Artemisinins in the Antimalarial Therapy

“…The rates of recrudescence, fever, and parasite clearances are traditional parameters for the efficacy of the antimalarial drugs in humans. These parameters exhibit the therapeutic potential of intramuscular arteether (AE) with sesame oil (Artemotil), which has much less efficacy [3,4] compared to that of intramuscular artemether (AM) [5][6][7][8][9][10][11][12][13], oral and intravenous artesunate (AS) [2,14], and the oral dihydroartemisinin (DHA) [15][16][17][18] or even than that of intramuscular / -arteether formulated with peanut oil [19][20][21][22] in India. It is clear that the efficacy and recrudescence in humans are dissimilar along those clinical trials with different artemisinin drugs by the monotherapy.…”

Artemisinin derivatives versus quinine for cerebral malaria in African children: a systematic review

“…3 The recommended treatment for cerebral malaria is quinine by slow intravenous infusion. 4 However, quinine has several drawbacks, including a short half-life, painful local reactions after intramuscular and intravenous administration 5 and neurotoxicity. 5,6 Permanent blindness with standard doses of quinine has been well documented.…”

“…4 However, quinine has several drawbacks, including a short half-life, painful local reactions after intramuscular and intravenous administration 5 and neurotoxicity. 5,6 Permanent blindness with standard doses of quinine has been well documented. 6 Furthermore, decreasing sensitivity to quinine has been reported in south-eastern Asia and the Amazon region, 7 as well as in parts of Africa.…”