Population pharmacokinetics and pharmacodynamic considerations of amodiaquine and desethylamodiaquine in Kenyan adults with uncomplicated malaria receiving the artesunate-amodiaquine combination therapy

by Jullien V, Ogutu B, Juma E, Carn G, Obyono C, and Kiechel JRAntimicrobial Agents and Chemotherapy, June 2010, 54(6):2611-17.

Summary: Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to Plasmodium falciparum and is now available as a fixed dose combination. Despite its widespread use, the simultaneous  pharmacokinetics of AQ and its active metabolite, desethylamodiaquine (DAQ) were not characterized to date in patients. The pharmacokinetics of AQ and DAQ were therefore investigated in 54 adult patients receiving the AS/AQ combination by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination as well as a first-order and irreversible transformation  into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. Mean AQ apparent clearance and distribution volume were 3410 L/h and 39200 L respectively. Mean terminal elimination half-life of DAQ was 211 h. Bodyweight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting in a fixed dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented the investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.

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