Population Pharmacokinetics and Pharmacodynamic Considerations of Amodiaquine and Desethylamodiaquine in Kenyan Adults with Uncomplicated Malaria Receiving Artesunate-Amodiaquine Combination Therapy

Abstract

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 in patients of AQ and its active metabolite, desethylamodiaquine (DAQ), were not characterized to date. The pharmacokinetics of AQ and DAQ in 54 adult patients receiving the AS/AQ combination were therefore investigated 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. The mean AQ apparent clearance and distribution volume were 3,410 liters/h and 39,200 liters, respectively. The mean terminal elimination half-life of DAQ was 211 h. Body weight 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 of 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 investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.Artemisinin-based combination therapy (ACT) is currently the optimal treatment for uncomplicated malaria due to Plasmodium falciparum (8). These combinations comprise an artemisinin derivative and a slowly eliminated partner drug. The former, which is fast acting and has a short half-life, provides a rapid reduction of the parasite biomass, while the latter provides effective concentrations over a prolonged period, allowing the clearance of the residual parasites (15, 23). The high efficacy of these combinations has been documented in several trials (2,7,10,13,14,17), and thus, ACTs are now the WHO recommended treatment for uncomplicated P. falciparum malaria.Artesunate (AS) plus amodiaquine (AQ) is one of these recommended ACTs. Amodiaquine is a 4-aminoquinoline which inhibits the glutathione-mediated degradation of ferriprotoporphyrin IX (6). Despite its own efficacy, amodiaquine is considered a prodrug of its active metabolite, desethylamodiaquine (DAQ), since DAQ is eliminated much more slowly than AQ and is therefore the main agent responsible for treatment efficacy (8).The PK parameters of the drug combined with the artemisinin derivative are of interest since they determine the length of treatment efficacy, as well as the beginning and duration of the selective window, i.e., the period corresponding to concentrations that are not high enough to be efficient against a new infection but are nevertheless sufficient to select resistant parasites (15,22).The pharmacokinetics (PK) of AQ/DAQ have been investigated...

Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

“…Amodiaquine and desethylamodiaquine had terminal elimination half-lives of 16.8 h and 12.4 days, respectively, which are somewhat longer than those reported previously (5 to 10 h and 8 to 10 days) (23,38,40,60). This finding might therefore reflect longer follow-up than that in previous studies.…”

“…Multiphasic disposition has been observed previously in adults and children with malaria, and differences in compartment structure (i.e., three-versus two-compartment disposition for desethylamodiaquine) might be a result of modeling dense and sparse data in the different studies (17,23,60). The estimated amodiaquine and desethylamodiaquine population parameters are similar to those from the noncompartmental analysis and those reported in previous studies (2,17,23,40,44,48,64). Polymorphisms of CYP2C8, which is the main enzyme for amodiaquine metabolism, might contribute to interindividual variability of amodiaquine elimination and formation of desethylamodiaquine.…”

“…Three previous studies have described the pharmacokinetic properties of amodiaquine and desethylamodiaquine in nonpregnant adults and children using nonlinear mixed-effects modeling (2,17,23). A nonlinear mixed-effects approach, in contrast to results from a noncompartmental analysis, provides a mechanistic understanding of the pharmacokinetic properties of the drug with the ability to characterize potential covariate relationships with higher statistical power.…”

“…One previously published study of adult patients with falciparum malaria attempted to model amodiaquine and desethylamodiaquine simultaneously using nonlinear mixed-effects modeling (23). Jullien and colleagues suggested a supplementary unknown route of amodiaquine elimination in their model (28,45,63).…”

“…The pharmacokinetic properties of amodiaquine and desethylamodiaquine have been investigated in healthy volunteers, patients with P. falciparum malaria, and children (2,17,20,23,37,38,40,45,52,53,60,64,65). A multiphasic exponential decline has been suggested for both amodiaquine and desethylamodiaquine, with terminal elimination half-lives of approximately 10 h and 10 days, respectively (25).…”