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Antimicrob. Agents Chemother. doi:10.1128/AAC.01585-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

First-Time-In-Humans Safety, Tolerability, Pharmacokinetics and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative, Artemisone

Clinical Pharmacology, Bayer HealthCare AG, Wuppertal, Germany; A&M GmbH, Bergheim, Germany; Bayer Innovation GmbH, Düsseldorf, Germany; Department of Chemistry, Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Kowloon, Hong Kong; and Australian Army Malaria Institute, Enoggera, Queensland, Australia

^* To whom correspondence should be addressed. Email: johannes.nagelschmitz{at}bayerhealthcare.com.

	Abstract

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, has been shown to possess enhanced efficacy over artesunate and does not possess the neurotoxicity characteristic of the current artemisinins. In a phase I program with double-blind, randomized, placebo-controlled, single- and multiple-ascending oral dose studies we evaluated the safety, tolerability, pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of artemisone. Single-doses (10, 20, 30, 40 and 80 mg), and multiple-doses (40 and 80 mg daily x 3 days) of artemisone were administered orally to healthy subjects. Plasma concentrations of artemisone and its metabolites were measured by liquid chromatography/tandem mass spectrometry. Artemisone was well tolerated, with no serious adverse events and no clinical relevant changes in laboratory and vital parameters. The pharmacokinetics of artemisone over the 10 to 80 mg range demonstrated dose linearity. After the single 80 mg dose, artemisone had a geometric mean (range) maximum concentration of 140.2 ng/ml (80.6 - 391.0), a short elimination half-life (t) of 2.79 h (1.56 - 4.88), a high oral clearance (CL/F) of 284.1 liters/h (106.7 - 546.7) and a large volume of distribution (V/F) of 14.50 liters/kg (3.21 - 51.58). Due to artemisone's short t, its pharmacokinetics was comparable after single- and multiple-dosing. Plasma samples taken after multiple-dosing showed marked ex vivo pharmacodynamic antimalarial activity against two multidrug-resistant Plasmodium falciparum lines. Artemisone equivalent concentrations measured by bioassay revealed higher activity than artemisone measured by LC/MS/MS, confirming the presence of active metabolites. Comparable to other artemisinin's, artemisone's t is well suited for artemisinin-based combination therapy for the treatment of falciparum malaria.