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Antimicrobial Agents and Chemotherapy, July 2002, p. 2219-2228, Vol. 46, No. 7
0066-4804/02/$04.00+0 DOI: 10.1128/AAC.46.7.2219-2228.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans
Mahboubeh Hosseini-Yeganeh and Andrew J. McLachlan*Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia
Received 8 August 2001/ Returned for modification 26 February 2002/ Accepted 27 March 2002
The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (Vss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the Vss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.
* Corresponding author. Mailing address: Faculty of Pharmacy, University of Sydney, NSW 2006, Australia. Phone: (612) 9351 4452. Fax: (612) 9351 4391. E-mail: andrewm{at}pharm.usyd.edu.au.
Antimicrobial Agents and Chemotherapy, July 2002, p. 2219-2228, Vol. 46, No. 7
0066-4804/02/$04.00+0 DOI: 10.1128/AAC.46.7.2219-2228.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
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