Pharmacokinetics of intramuscular artemether in patients with severe falciparum malaria with or without acute renal failure.
OBJECTIVE
The pharmacokinetics of intramuscular artemether and its major plasma metabolite-dihydroartemisinin, were investigated in patients with severe manifestations of falciparum malaria.


METHODS
Six severe falciparum malaria patients with acute renal failure (ARF) and 11 without ARF were recruited into the study. They were treated with intramuscular artemether at a loading dose of 160 mg, followed by daily doses of 80 mg for another 6 days (total dose 640 mg).


RESULTS
Patients with and without ARF showed a good initial response to treatment; the parasite and fever clearance times were 66(30-164) and 76(36-140) h [median(range)], respectively. None had reappearance of parasitaemia in their peripheral blood smear within 7 days of initiation of treatment. In comatose patients, the time to recovery of consciousness was 51.6(22-144) h. Artemether was detected in plasma as early as 1 h after a 160 mg dose, and declined to undetectable levels within 24 h in most cases. Patients with ARF had significantly higher Cmax [2.38(1.89-3.95) vs 1.56(1.05-3.38) ng ml(-1) mg(-1) dose], AUC [35.4(22-52.9) vs 25.2(13.4-52.9) ng ml(-1) h mg(-1) dose], and lower Vz/F [5.45(3.2-6.9) vs 8.6(4.2-12.3) l kg(-1)] and CL/F [7.4(5.4-13.8) vs 19.1(8.5-25.1) ml min(-1) kg(-1)] when compared with those without ARF. In addition, t1/2,z was significantly longer in ARF patients [7.0(5.5-10.0) vs 5.7(4.2-6.6) h]. The pharmacokinetics of dihydroartemisinin in the two groups of patients were comparable.


CONCLUSIONS
ARF significantly modified the pharmacokinetics of intramuscular artemether. The changes could be attributed to either improved absorption/bioavailability, a reduction of systemic clearance, or a change in plasma protein binding of the drug.
Karbwang
J
J
Clinical Pharmacology Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Na-Bangchang
K
K
Tin
T
T
Sukontason
K
K
Rimchala
W
W
Harinasuta
T
T
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077549:Artemether; D037621:Artemisinins; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012717:Sesquiterpenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol; D000077549:Artemether