Authors: Sabarinath, Sreedharan N.¹; Asthana, Omkar P.²; Puri, Sunil K.³; Srivastava, Kumkum³; Madhusudanan, Kunnath P.⁴; Gupta, Ram C.¹

Source: Clinical Pharmacokinetics, Volume 44, Number 11, 2005 , pp. 1191-1203(13)

Publisher: Adis International

Abstract:

Objective: To evaluate the pharmacokinetics of - and -diastereomers of arteether in healthy male volunteers.

Participants and methods: The study was a single-centre clinical pharmacokinetic trial in healthy male subjects. A group comprising 13 subjects aged 25–50 years received a single intramuscular 150mg individual dose of the arteether formulation containing - and -isomers in a 30 : 70 ratio. Serial blood samples collected over a period of 0–192 hours were analysed by high-performance liquid chromatography-electrospray ionisation/tandem mass spectrometry and the plasma concentrations were subjected to compartmental and noncompartmental analyses. Pharmacodynamic parameters such as area under the inhibitory curve, ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC), maximum plasma concentration to MIC (C_max/MIC) and time that plasma concentration exceeds the MIC (T>MIC) were calculated in vitro in four strains of Plasmodium falciparum to evaluate the in vivo effectiveness of the proposed dosage regimen.

Results: There were no adverse effects observed during the study. The extent of metabolism of arteether to dihydroartemisinin (DHA) was low (~5%) so as to be therapeutically nonsignificant. The pharmacokinetic profiles of the arteether diastereomers were different, and the maximum plasma concentrations of - and -isomers were reached at 4.77 ± 1.21 hours and 6.96 ± 1.62 hours, respectively, after which they showed biphasic decline with apparent terminal elimination half-lives of 13.24 ± 1.08 hours and 30.17 ± 2.44 hours, respectively. The plasma and renal clearances, as well as whole blood to plasma partition ratios of the isomers, were comparable, while the apparent volume of distribution during terminal phase of the -isomer was approximately 3-fold higher than that of the -isomer. in vitro erythrocyte culture experiments with four strains of P. falciparum showed similar MICs for both isomers of arteether. The highest observed MIC of 8 g/L was selected for estimating the pharmacokinetic and pharmacodynamic parameters, which showed excellent correlation with published data on the clinical efficacy of arteether.

Conclusion: The pharmacokinetics of arteether isomers demonstrated stereoselectivity, which was reflected mainly in the volume of distribution and the terminal elimination half-life. The - and -isomers of arteether appeared to compliment each other pharmacokinetically, with the -isomer providing comparatively rapid and higher plasma concentrations resulting in immediate reduction in percentage parasitaemia, while the -isomer, with its longer terminal elimination half-life, mean residence time and sustained plasma concentrations, maintained the activity for longer periods. The extent of metabolic conversion of arteether to DHA was minimal, so as to have any therapeutic or toxic significance.

Keywords: Antimalarials; Arteether; Malaria; Research and development

Document Type: Research article

Affiliations: 1: 1 Pharmacokinetics and Metabolism Division, Central Drug Research Institute, Lucknow, India 2: 2 Clinical and Experimental Medicine Division, Central Drug Research Institute, Lucknow, India 3: 3 Parasitology Division, Central Drug Research Institute, Lucknow, India 4: 4 Sophisticated Analytical Instrumentation Facility, Central Drug Research Institute, Lucknow, India

Publication date: 2005-01-01

Related content

• In this: publication
• By this: publisher
• In this Subject: Pharmacology
• By this author: Sabarinath, Sreedharan N. ;  Asthana, Omkar P. ;  Puri, Sunil K. ;  Srivastava, Kumkum ;  Madhusudanan, Kunnath P. ;  Gupta, Ram C.

Website © Publishing Technology. Article copyright remains with the publisher, society or author(s) as specified within the article.

• Terms and conditions
• Privacy policy
• Information for advertisers