Pitfalls in Estimating Piperaquine Elimination

Abstract

By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs.The bisquinoline piperaquine (PQ) has been used as an antimalarial for decades in China, replacing chloroquine as the first-line treatment for Plasmodium falciparum malaria from 1978 until the emergence of resistance in the 1990s. PQ has undergone a renaissance in recent years as a component of artemisinin-based combination therapy (1,8). Despite this extensive use, published preclinical and pharmacokinetic data on PQ are scarce; to date, only one pharmacokinetic study has been published (4). In that study, only three of the 38 adult patients studied had detectable plasma piperaquine concentrations at the last sampling point (35 days), suggesting a long terminal half-life (t 1/2 , 23 days). The terminal elimination phase is critical for the duration of the posttreatment prophylactic effect and also for the propensity to select for resistance.We recently developed a highly sensitive high-throughput assay (lower limit of quantification [LLOQ], 2.5 ng/ml) that allows quantification of PQ in plasma for much longer than in previous studies (LLOQ, 5 ng/ml) (6) and used it in a preliminary assessment of PQ elimination. PQ in whole blood was measured as described previously (LLOQ, 10 ng/ml) (5, 7). A healthy Caucasian male volunteer received a single oral dose of three dihydroartemisinin (DHA)-PQ (Artekin) tablets, each containing 320 mg of PQ phosphate and 40 mg of DHA, together with a fatty meal to facilitate absorption. Blood was FIG. 1. PQ concentration-time profile for plasma and blood from a healthy Caucasian male volunteer after a single oral dose of DHA-PQ (three tablets, each containing 320 mg of PQ phosphate and 40 mg of DHA) together with a fatty meal.

Characterization of Human Urinary Metabolites of the Antimalarial Piperaquine

“…6 and suggests a terminal elimination half-life of 53 days. Assuming that the metabolite formation limits the elimination (i.e., formation rate limiting kinetics), this would support recent findings that the previously reported elimination half-life of PQ might be underestimated (Tarning et al, 2005). Further studies in larger series are needed to investigate the pharmacological and pharmacokinetic properties of this metabolite.…”

“…Only M1 and M2 were detected in the analyzed serum/plasma samples; therefore, these are the most clinically relevant metabolites. Blood and plasma were collected for up to 93 days and urine for 123 days, and PQ pharmacokinetics was evaluated as previously reported (Tarning et al, 2005(Tarning et al, , 2006. Reanalyzed urine contained substantial amounts of M1 and M2.…”

Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

“…One study in healthy adults found that, although a three-compartment model represented the postadministration profile better, there were insufficient data to support its use over a two-compartment model (38). The mean elimination t 1/2 , a parameter influenced by the duration of sampling (45), was 512 h, a value within the previously reported range of 224 to 667 h (1,14,25,28,31,34,38,44). Since there was substantial variability in the absorption phase of the plasma PQ concentration profile, a transit compartment model was tested and proved better than simpler absorption models that used lag time, as has been found in studies of other drugs (39).…”

Efficacy and safety of dihydroartemisinin-piperaquine

“…Piperaquine (PIP), a bisquinoline antimalarial (1,3-bis [1-(7-chloro-4 quinolyl)-4 piperazinyl]-propane), has a similar mode of action to other quinoline antimalarials: interference with haem detoxification (Davis et al, 2005). It has pharmacokinetic properties similar to chloroquine with a very large apparent volume of distribution and a very long terminal elimination half-life Tarning et al, 2005). Piperaquine has been used extensively only in China, where it replaced chloroquine as first-line treatment in 1978.…”