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Antimicrobial Agents and Chemotherapy, September 2008, p. 3085-3091, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.01585-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

First Assessment in Humans of the Safety, Tolerability, Pharmacokinetics, and Ex Vivo Pharmacodynamic Antimalarial Activity of the New Artemisinin Derivative Artemisone{triangledown}

Johannes Nagelschmitz,1* Barbara Voith,1 Georg Wensing,1 Axel Roemer,2 Burkhard Fugmann,3 Richard K. Haynes,4 Barbara M. Kotecka,5 Karl H. Rieckmann,5 and Michael D. Edstein5

Clinical Pharmacology, Bayer Health Care AG, Wuppertal, Germany,1 A&M GmbH, Bergheim, Germany,2 Bayer Innovation GmbH, Düsseldorf, Germany,3 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,4 Australian Army Malaria Institute, Enoggera, Queensland, Australia5

Received 7 December 2007/ Returned for modification 17 February 2008/ Accepted 6 June 2008

In preclinical studies, artemisone (BAY 44-9585), a new artemisinin derivative, was shown to possess enhanced efficacy over artesunate, and it 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 for 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 (LC/MS-MS). Artemisone was well tolerated, with no serious adverse events and no clinically 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 maximum concentration of 140.2 ng/ml (range, 86.6 to 391.0), a short elimination half-life (t1/2) of 2.79 h (range, 1.56 to 4.88), a high oral clearance of 284.1 liters/h (range, 106.7 to 546.7), and a large volume of distribution of 14.50 liters/kg (range, 3.21 to 51.58). Due to artemisone's short t1/2, its pharmacokinetics were comparable after single and multiple dosing. Plasma samples taken after multiple dosing showed marked ex vivo pharmacodynamic antimalarial activities 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 those of other artemisinin's, artemisone's t1/2 is well suited for artemisinin-based combination therapy for the treatment of P. falciparum malaria.

* Corresponding author. Mailing address: Clinical Pharmacology, Pharmacodynamics (BSP-GDD-CP-Dyn), Bayer Health Care, Building 0429, Aprather Weg 18a, 42096 Wuppertal, Germany. Phone: 49-202-36-8815. Fax: 49-202-36-4115. E-mail: johannes.nagelschmitz{at}bayerhealthcare.com

{triangledown} Published ahead of print on 16 June 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3085-3091, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.01585-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dunay, I. R., Chan, W. C., Haynes, R. K., Sibley, L. D. (2009). Artemisone and Artemiside Control Acute and Reactivated Toxoplasmosis in a Murine Model. Antimicrob. Agents Chemother. 53: 4450-4456 [Abstract] [Full Text]  
  • Obaldia, N. III, Kotecka, B. M., Edstein, M. D., Haynes, R. K., Fugmann, B., Kyle, D. E., Rieckmann, K. H. (2009). Evaluation of Artemisone Combinations in Aotus Monkeys Infected with Plasmodium falciparum. Antimicrob. Agents Chemother. 53: 3592-3594 [Abstract] [Full Text]  


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