Quantitative Prediction of the Effect of CYP3A Inhibitors and Inducers on Venetoclax Pharmacokinetics Using a Physiologically Based Pharmacokinetic Model

Abstract

The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (C R) and area under the curve from time 0 to infinity (AUC R) from these studies. The verified PBPK model was then used to simulate the effects of different CYP3A inhibitors and inducers on the venetoclax PK. Comparison of the PBPK model predicted to the observed PK parameters indicated good agreement. Verification of the PBPK model demonstrated that the ratios of the predicted:observed C R and AUC R of venetoclax were within 0.8- to 1.25-fold range for strong CYP3A inhibitors and inducers. Model simulations indicated no effect of weak CYP3A inhibitors or inducers on C or AUC , while both moderate and strong CYP3A inducers were estimated to decrease venetoclax exposure. Moderate and strong CYP3A inhibitors were estimated to increase venetoclax AUC , by 100% to 390% and 480% to 680%, respectively. The recommended venetoclax dose reductions of at least 50% and 75% when coadministered with moderate and strong CYP3A inhibitors, respectively, maintain venetoclax exposures between therapeutic and maximally administered safe doses.

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure‐response analysis

“…Venetoclax pharmacokinetics has been characterized in cancer patients and healthy volunteers . Venetoclax is CYP3A and P‐gp substrate and a weak P‐gp inhibitor . The aim of the analyses described in this report was to evaluate the venetoclax exposure‐response relationship and determine its optimal dose in combination with HMAs or LDAC.…”

Pharmacokinetics of the BCL‐2 Inhibitor Venetoclax in Healthy Chinese Subjects

“…The pharmacokinetics of venetoclax have been well characterized in healthy volunteers and cancer patients . Venetoclax peak exposures were achieved 5 to 8 hours after dosing under low‐fat conditions, and the mean terminal‐phase elimination half‐life ranged between 14.1 and 18.2 hours at different doses .…”

“…[3][4][5][6][7] The pharmacokinetics of venetoclax have been well characterized in healthy volunteers and cancer patients. [8][9][10][11][12][13][14][15] Venetoclax peak exposures were achieved 5 to 8 hours after dosing under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. 8 Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. 8 Food increases venetoclax bioavailability by 3-to 5-fold, depending on the fat content but no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax.…”

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug‐Drug Interaction for Fesoterodine When Coadministered With Mirabegron

“…As a result of the sensitivity analysis and optimization, the K I was reduced by approximately 20% to 6.6 µM using a “middle‐out” approach . The adjusted CYP2D6 K I of 6.6 µM was verified by simulating the DDI with another CYP2D6 substrate (metoprolol), and using this value in the model accurately captured the observed metoprolol DDI.…”

“…The in vitro inhibitory potential of mirabegron against CYP2D6 was optimized with desipramine and verified with metoprolol as substrates, whereas mirabegron was not predicted to cause clinical inhibition of CYP3A substrate (ie, solifenacin or midazolam) clearance. For the analysis of mirabegron coadministration with desipramine, a sensitivity analysis was conducted to optimize the in vitro‐generated K i (6.6 vs 8.2 µM) against CYP2D6 using a “middle‐out” approach, as described previously, to most accurately reflect the clinically observed DDI with desipramine. Following model optimization, application of the mirabegron model (as a CYP inhibitor) accurately predicted 3.47‐fold and 1.61‐fold higher desipramine AUC inf and C max values, respectively, following coadministration with mirabegron, consistent with observed clinical study results .…”