Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically‐based pharmacokinetic modeling

Abstract

The aim of the study was to develop a physiologically‐based pharmacokinetic (PBPK) model to describe and predict whole‐body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion‐limited or permeability‐limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.

Plasma Pharmacokinetics and Tissue Distribution of Doxorubicin in Rats following Treatment with Astragali Radix

“…Here, we determined the concentrations of DOX in rat plasma and six tissues following a single intravenous dose of 5 mg/kg. Consistent with previous studies [12,26], our data show that the intravenous bolus injection of DOX produces high plasma concentrations, which fall quickly due to a rapid and extensive distribution into tissues (Figure 3). More importantly, we found that short-term (≤10 d) administration of AR, whether a single-dose co-treatment or multiple-dose pre-treatment, was ineffective at changing the plasma pharmacokinetics of DOX (Table 3).…”

“…DOX administered as a conventional injection is widely distributed in the plasma and tissues but can hardly cross the blood-brain barrier [12]. There are three main metabolic routes of DOX in mammals: one-electron reduction, two-electron reduction, and deglycosylation [13].…”

Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies

“…The time from drug exposure to the epithelial effects varies for different species, doses, administration routes and type of chemotherapeutics, and partly follows species-specific differences in crypt turnover. For instance, after an intravenous dose of DOX, the concentration in the intestine is about 100 times higher than in plasma in animals and humans ( Luo et al, 2017 ; Lee et al, 2020 ). Although the DOX concentrations in the intestines might be similar as in the liver, kidney, and heart, they cause greater damage to the IECs because these cells have a rapid and extensive proliferation ( Figure 3 ) ( Luo et al, 2017 ).…”

Exploring the Pharmacokinetic Mysteries of the Liver: Application of Series Compartment Models of Hepatic Elimination

“…in vitro-to-in vivo extrapolation, IVIVE). On the other hand, physiologically-based PK (PBPK) modeling allows for characterizing dynamic changes in hepatic concentrations in pre-clinical species and scaling-up to humans (Lee et al, 2020) where the CL int and tissue-toplasma partition coefficient (K p ) are needed. Both IVIVE and PBPK modeling require a structural liver model (Rane et al, 1977;Houston, 1994;Hallifax et al, 2010;Miller et al, 2019).…”