Clinical pharmacokinetics of artemether and lumefantrine (Riamet (R))

This paper reports the clinical pharmacokinetics of artemether and lumefant rine in healthy volunteers and in malaria patients. These two drugs are the active components of the fixed-dose oral combination tablet co-artemether (Riamet(R)), used for the treatment of Plasmodium falciparum malaria. Artemether has a fast absorption rate followed by rapid clearance from plas ma [terminal elimination half-life (t1/2 beta) 2 to 3 hours]. Its major met abolite dihydroartemisinin (DHA) is formed rapidly and has a similar cleara nce pattern to artemether. Lumefantrine is slowly absorbed (2 hours lag tim e) followed by a slow clearance from plasma (t1/2 beta up to 10 days). Food intake significantly increases the bioavailability of both artemether (>2- fold) and lumefantrine (approximately 16-fold). Artemether and lumefantrine are predominantly metabolised by the cytochrome P450 3A4 (CYP3A4) isoenzyme. The intersubject variability for artemether, DHA and lumefantrine is high in both healthy volunteers and patients. CYP3A4 substrates/inhibitors such as the antimalarial mefloquine can be coa dministered with co-artemether without clinically relevant risk of drug-dru g interaction. Similarly, potential for a significant medical hazard in the management of Fl falciparum malaria with co-artemether following co-admini stration in close temporal relationship with quinine (a CYP3A4 substrate) i s unlikely. The wide therapeutic index of artemether and lumefantrine and t he short duration of administration of co-artemether suggest that the risk for any tolerability problems from drug accumulation is minimal.