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Antimicrobial Agents and Chemotherapy, December 2005, p. 5127-5128, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5127-5128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pitfalls in Estimating Piperaquine Elimination

Joel Tarning,1 Niklas Lindegårdh,2 Anna Annerberg,2 Thida Singtoroj,2 Nicholas P. J. Day,2 Michael Ashton,1 and Nicholas J. White2*

Department of Pharmacology, Göteborg University, Sahlgrenska Academy, Göteborg, Sweden,1 Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand2

Received 12 September 2005/ Accepted 12 September 2005


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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.


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TEXT
 
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 (t1/2, 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 taken at prespecified time points up to 93 days after administration. At this final time point, the plasma PQ was 3.6 ng/ml. The whole-blood PQ was detectable for 64 days (10.1 ng/ml) (Fig. 1). Our results suggest that previously published values of the PQ terminal elimination half-life are likely to be underestimates resulting from insufficient assay sensitivity and duration of sampling with oversimplified fitting of a two-compartment model. This finding is very reminiscent of studies of the related compound chloroquine where, as assay methods became more sensitive, the multiphasic nature of the elimination phase became evident and estimates of the terminal elimination half-life became progressively longer (2, 3).



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  		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.

In the present single-dose study with increasing sampling duration, the terminal phase estimates had decreasing slopes (i.e., lengthening half-lives). Plasma sampling with end points at 21, 64, and 93 days gave estimated half-lives (based on all measurements from day 10 forward) of 14, 30, and 33 days, respectively. The estimated terminal elimination half-life is as long as 80 days when based only on the last three measured concentrations. This phenomenon is likely to be a result of multiphasic elimination. Quantification of PQ in blood with a higher LLOQ was achieved over a period of 64 days and suggests a terminal half-life of 36 days, which further supports an underestimation of the half-life when sampling duration is insufficient (Fig. 2). These are preliminary observations, and further studies in a larger series will be necessary to determine whether a triphasic elimination profile is adequate to define the terminal phase of PQ.



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  		FIG. 2. Antimalarial pharmacodynamics. Elimination of piperaquine, illustrating the different estimates of the terminal elimination half-life as a function of follow-up duration and assay sensitivity. The inset illustrates potential problems with an insufficient follow-up period for drugs with multiphasic elimination kinetics and a long terminal half-life.


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ACKNOWLEDGMENTS
 
This study was part of the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme funded by the Wellcome Trust of Great Britain. This research was supported in part by the Swedish International Development Cooperation Agency (SIDA). This investigation received financial support from the Medicines for Malaria Venture.


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FOOTNOTES
 
* Corresponding author. Mailing address: Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd., Bangkok 10400, Thailand. Phone: (66)-2-354-9172. Fax: (66)-2-354-9169. E-mail: nickw{at}tropmedres.ac. Back


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Antimicrobial Agents and Chemotherapy, December 2005, p. 5127-5128, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5127-5128.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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