A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans.
OBJECTIVE
Alvespimycin, a new generation of heat shock protein 90 (Hsp90) inhibitor in clinical trial, is a promising therapeutic agent for cancer. Pharmacokinetic models of alvespimycin would help in the understanding of drug disposition, predicting drug exposure and interpreting dose-response relationship. In the present study we aimed to develop a physiologically based pharmacokinetic (PBPK) model of alvespimycin in mice and evaluate the utility of the model for predicting alvespimycin disposition in other species.


METHODS
A literature search was performed to collect pharmacokinetic data for alvespimycin. A PBPK model was initially constructed to demonstrate the disposition of alvespimycin in mice, and then extrapolated to rats and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters.


RESULTS
A PBPK model, employing a permeability-limited model structure and saturable tissue binding, was built in mice. It successfully characterized the time course of the disposition of alvespimycin in mice. After extrapolation to rats, the model simulated the alvespimycin concentration-time profiles in rat tissues with acceptable accuracies. Likewise, a reasonable match was found between the observed and simulated human plasma pharmacokinetics of alvespimycin.


CONCLUSIONS
The PBPK model described here is beneficial to the understanding and prediction of the effects of alvespimycin in different species. It also provides a good basis for further development, which necessitates additional studies, especially those needed to clarify the in-depth mechanism of alvespimycin elimination. A refined PBPK model would benefit the understanding of dose-response relationships and optimization of dosing regimens.
Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
Zhe-Yi
ZY
Hu
Jingtao
J
Lu
Yuansheng
Y
Zhao
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D016227:Benzoquinones / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D008954:Models, Biological; D051381:Rats; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Hsp90 inhibitor; PBPK modelling; alvespimycin; drug disposition; interspecies scaling