JAC Advance Access published online on June 16, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn231
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Original research |
Pharmacokinetics of artesunate in the domestic pig
1 Physiopathology and Parasitical Pharmacology Research Unit, Institut de Médecine Tropicale du Service de Santé des Armées and UMR-MD3, Université de la Méditerranée, Marseille, France 2 Experimental Chirurgy and Physiology Unit, Institut de Médecine Tropicale du Service de Santé des Armées, Marseille Armées, France 3 Reanimation Department, Hôpital d'Instruction des Armées Laveran, Marseille Armées, France 4 Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier I, Montpellier, France
Received 11 January 2008; returned 18 February 2008; revised 14 May 2008; accepted 19 May 2008
* Correspondence address. Unité de Recherche en Physiopathologie et Pharmacologie Parasitaire (UR3P), Institut de Médecine Tropicale du Service de Santé des Armées, Le Pharo, BP 46, 13998 Marseille Armées, France. Tel: +33-4-91-15-01-13; Fax: +33-4-91-15-01-64; E-mail: veronique.sinou{at}club-internet.fr
Objectives: The aim was to study the pharmacokinetic profile of artesunate and its metabolite dihydroartemisinin (DHA) in a pig model.
Methods: Thirteen pigs received either intravenous (iv) or intramuscular (im) artesunate (60 mg), with the alternative preparation given 24 h later in an open crossover design. Five of them also received an additional intra-arterial (ia) artesunate dose (60 mg). The plasma concentrations of artesunate and DHA were determined by high-performance liquid chromatography with electrochemical detection. Population modelling was performed with NONMEM, using a two-compartment model.
Results: Plasma concentration–time profiles were comparable to those observed in humans, with a rapid and biphasic decline for both artesunate and DHA. Following an iv bolus, artesunate had a median maximum plasma concentration (Cmax) of 13.8 µM [interquartile range (IQR), 10.4–22.1 µM], elimination half-life (t1/2) = 18 min (IQR, 16–22 min), total plasma clearance (CL) = 5.58 L/h/kg (IQR, 3.31–5.91 L/h/kg) and volume of distribution (Vd) = 1.85 L/kg (IQR, 1.27–3.20 L/kg). The median Cmax value for DHA was 3.30 µM (IQR, 2.08–5.95 µM), t1/2 = 26 min (IQR, 23–31 min), CL/Fm = 4.37 L/h/kg (IQR, 3.29–6.87 L/h/kg) and Vd/Fm = 2.56 L/kg (IQR, 1.93–4.49 L/kg). Artesunate and DHA pharmacokinetic parameters were similar after ia administration. Following im dosing, median artesunate Cmax was 4.81 µM (IQR, 3.74–5.40 µM), t1/2 = 18 min (IQR, 16–28 min), CL = 4.37 L/h/kg (IQR, 4.13–4.68 L/h/kg) and Vd = 2.07 L/kg (IQR, 1.83–2.79 L/kg); the bioavailability was 100%. For DHA, median Cmax was 1.43 µM (IQR, 1.00–1.92 µM), t1/2 = 27 min (IQR, 25–37 min), CL/Fm = 4.68 L/h/kg (IQR, 3.35–6.73 L/h/kg) and Vd/Fm = 3.31 L/kg (IQR, 2.89–4.27 L/kg).
Conclusions: The pharmacokinetic properties of artesunate and DHA in pigs were similar to those reported in humans, suggesting that the swine model is suitable for determining the preclinical pharmacokinetics of artemisinin derivatives.
Key Words: antimalarials , swine , population pharmacokinetics , preclinical