Journal article
A Physiologically Based Pharmacokinetic Model of Mitoxantrone in Mice and Scale-up to Humans: a Semi-Mechanistic Model Incorporating DNA and Protein Binding
The AAPS journal, Vol.14(2), pp.352-364
06/2012
DOI: 10.1208/s12248-012-9344-7
PMCID: PMC3326165
PMID: 22451016
Abstract
We conducted a pharmacokinetic (PK) study of mitoxantrone (Novantrone®), a clinically well-established anticancer agent, in mice and developed a mechanism-based PBPK (physiologically based pharmacokinetic) model to describe its disposition. Mitoxantrone concentrations in plasma and six organs (lung, heart, liver, kidney, spleen, and brain) were determined after a 5 mg/kg i.v. dose. We evaluated three different PBPK models in order to characterize our experimental data: model 1 containing Kp values, model 2 incorporating a deep binding compartment, and model 3 incorporating binding of mitoxantrone to DNA and protein. Among the three models, only model 3 with DNA and protein binding captured all the experimental data well. The estimated binding affinity for DNA (
K
DNA
) and protein (
K
macro
) were 0.0013 and 1.44 μM, respectively. Predicted plasma and tissue AUC values differed from observed values by <19 %, except for heart (60 %). Model 3 was further used to simulate plasma mitoxantrone concentrations in humans for a 12-mg/m
2
dose, using human physiological parameters. The simulated results generally agreed with the observed time course of mitoxantrone plasma concentrations in patients after a standard dose of 12 mg/m
2
. In summary, we reported for the first time a mechanism-based PBPK model of mitoxantrone incorporating macromolecule binding which may have clinical applicability in optimizing clinical therapy. Since mitoxantrone is a substrate of the efflux transporters ABCG2 and ABCB1, the incorporation of efflux transporters may also be necessary to characterize the data obtained in low-dose studies.
Details
- Title: Subtitle
- A Physiologically Based Pharmacokinetic Model of Mitoxantrone in Mice and Scale-up to Humans: a Semi-Mechanistic Model Incorporating DNA and Protein Binding
- Creators
- Guohua An - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200 USAMarilyn E Morris - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200 USA
- Resource Type
- Journal article
- Publication Details
- The AAPS journal, Vol.14(2), pp.352-364
- Publisher
- Springer US; Boston
- DOI
- 10.1208/s12248-012-9344-7
- PMID
- 22451016
- PMCID
- PMC3326165
- ISSN
- 1550-7416
- eISSN
- 1550-7416
- Language
- English
- Date published
- 06/2012
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984065313902771
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