Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

Tan Beesan, Naik Himanshu, Jang In-Jin, Yu Kyung-Sang, Kirsch, Shin Chang-Sik, Craft J, Fleckenstein, Fleckenstein Lawrence

Description

The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h -1 . The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9-unit change in CLM/F in the same direction. Conclusions A novel simultaneous parent-metabolite pharmacokinetic model with good predictive power was developed to study the population pharmacokinetics of AS and DHA in healthy subjects following single- and multiple-dosing of AS with or without the presence of food. Food intake and weight were significant covariates for Ka and CLM/F, respectively.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2009
• Nombre de lectures: 6
• Langue: English

Extrait

Malaria Journal

BioMedCentral

Open Access Research Population pharmacokinetics of artesunate and dihydroartemisinin following single and multipledosing of oral artesunate in healthy subjects 1 12 21 Beesan Tan, Himanshu Naik, InJin Jang, KyungSang Yu, Lee E Kirsch, 3 41 ChangSik Shin, J Carl Craftand Lawrence Fleckenstein*

1 2 Address: Collegeof Pharmacy, University of Iowa, Iowa City, IA, USA,Department of Pharmacology and Clinical Pharmacology and 3 Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea,Shin Poong Pharmaceuticals Co., Ltd., Seoul, 4 Republic of Korea andMedicines for Malaria Venture, Geneva, Switzerland

Email: Beesan Tan  beesan[e-mail]; Himanshu Naik  [e-mail]; InJin Jang  [e-mail]; Kyung Sang Yu  [e-mail]; Lee E Kirsch  lee[e-mail]; ChangSik Shin  [e-mail]; J Carl Craft  [e-mail]; Lawrence Fleckenstein*  l[e-mail] * Corresponding author

Published: 18 December 2009Received: 24 September 2009 Accepted: 18 December 2009 Malaria Journal2009,8:304 doi:10.1186/147528758304 This article is available from: http://www.malariajournal.com/content/8/1/304 © 2009 Tan et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single or multipledosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. Methods:Data from 118 concentrationtime profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 25 mg/kg of single and multiple dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixedeffect modelling was used to obtain the pharmacokinetic and variability (inter individual and residual variability) parameter estimates. Results:A novel parentmetabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 1 3.85 h. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% interindividual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent intercompartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of highfat and high caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1.9unit change in CLM/F in the same direction.

Page 1 of 13 (page number not for citation purposes)