Application of Physiologically Based Pharmacokinetic Modeling in Understanding Bosutinib Drug-Drug Interactions: Importance of Intestinal P-Glycoprotein

Abstract

Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supraproportional at the lower doses (50-200 mg) and approximately dose-proportional at the higher doses (200-600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability. These findings led us to investigate the factors influencing the underlying pharmacokinetic mechanisms of bosutinib with physiologically based pharmacokinetic (PBPK) models. Our primary objectives were to: 1) refine the previously developed bosutinib PBPK model on the basis of the latest oral bioavailability data and 2) verify the refined PBPK model with P-glycoprotein kinetics on the basis of the bosutinib drug-drug interaction (DDI) results with ketoconazole and rifampin. Additionally, the verified PBPK model was applied to predict bosutinib DDIs with dual CYP3A/P-glycoprotein inhibitors. The results indicated that 1) the refined PBPK model adequately described the observed plasma concentration-time profiles of bosutinib and 2) the verified PBPK model reasonably predicted the effects of ketoconazole and rifampin on bosutinib exposures by accounting for intestinal P-glycoprotein inhibition/induction. These results suggested that bosutinib DDI mechanism could involve not only CYP3A4-mediated metabolism but also P-glycoprotein-mediated efflux on absorption. In summary, P-glycoprotein kinetics could constitute an element in the PBPK models critical to understanding the pharmacokinetic mechanism of dual CYP3A/P-glycoprotein substrates, such as bosutinib, that exhibit nonlinear pharmacokinetics owing largely to a saturation of intestinal P-glycoprotein-mediated efflux.

Physiologically‐Based Pharmacokinetic Modeling Approach to Predict Rifampin‐Mediated Intestinal P‐Glycoprotein Induction

“…9 On the other hand, multiple-dose administrations of rifampin increase Pgp and CYP3A expression levels by a similar degree, resulting in decreases in systemic exposures of some Pgp and/or CYP3A substrates. 6,10,11 Rifampin-mediated CYP3A induction has been characterized well for DDI prediction. 12,13 In contrast, there has been an increasing need for quantitively predicting rifampin-mediated DDIs with Pgp substrates.…”

“…For example, amiodarone and felodipine are potent Pgp inhibitors but weak CYP3A inhibitors, whereas itraconazole and ketoconazole are potent inhibitors of both Pgp and CYP3A . On the other hand, multiple‐dose administrations of rifampin increase Pgp and CYP3A expression levels by a similar degree, resulting in decreases in systemic exposures of some Pgp and/or CYP3A substrates . Rifampin‐mediated CYP3A induction has been characterized well for DDI prediction .…”

The Regional-Specific Relative and Absolute Expression of Gut Transporters in Adult Caucasians: A Meta-Analysis

“…The capacity to scale transporter activity data obtained in relevant in vitro cell monolayers within PBPK models that describe regionspecific intestinal transporter expression levels based on relative expression approaches has been demonstrated for intestinal efflux transporters such as P-glycoprotein (P-gp) (Neuhoff et al, 2013;Yamazaki et al, 2018). However, by building on the incorporation of absolute transporter abundance scaling of hepatic transporter activity (i.e., the ISEF-T approach), our aim was to perform an extensive metaanalysis of the expanding human intestinal transporter absolute abundance quantification literature in order to facilitate the development of an ISEF-T approach to scale transporter activity data in and along the gut.…”

The Critical Role of Passive Permeability in Designing Successful Drugs

“…Bosutinib is an example that demonstrates the impact of P-gp efflux on oral absorption. [41] Bosutinib is an orally available tyrosine kinase inhibitor (TKI) for the treatment of leukemia (Figure 4). It is a substrate for both CYP3A and P-gp.…”

“…They may play a role in limiting oral absorption of their substrates, especially when doses are low, or compounds have poor solubility where the transporters are not saturated. Bosutinib is an example that demonstrates the impact of P‐gp efflux on oral absorption . Bosutinib is an orally available tyrosine kinase inhibitor (TKI) for the treatment of leukemia (Figure ).…”