Impact of Multiple Concomitant CYP3A Inhibitors on Venetoclax Pharmacokinetics: A PBPK and Population PK‐Informed Analysis

Abstract

Venetoclax is an approved, orally bioavailable, B-cell lymphoma type 2 (BCL-2) inhibitor that is primarily metabolized by cytochrome P450 3A (CYP3A). Polypharmacy is common in patients undergoing treatment for hematological malignancies such as acute myeloid leukemia or chronic lymphocytic leukemia, and although venetoclax exposure has been well characterized with 1 concomitant CYP3A inhibitor, complex drug-drug interactions (DDIs) involving more than 1 inhibitor have not been systematically evaluated. Here, we aimed to describe the potential impact of multiple concomitant CYP3A inhibitors on venetoclax pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) and population PK modeling. The modeling approaches were informed by clinical data in the presence of single or multiple CYP3A inhibitors, and the effects of 1 or more inhibitors were systematically considered within these modeling frameworks. The PBPK modeling approach was independently validated against clinical data involving more than 1 CYP3A inhibitor along with CYP3A substrates other than venetoclax. Both approaches indicated that combining a strong CYP3A inhibitor with another competitive CYP3A inhibitor does not seem to result in any additional increase in venetoclax exposure, beyond what would be expected with a strong inhibitor alone. This suggests that the current dose reductions recommended for venetoclax would be appropriate even when 2 or more CYP3A inhibitors are taken concomitantly. However, the results indicate that the involvement of time-dependent inhibition might lead to additional inhibitory effects over and above the effect of a single strong CYP3A inhibitor. Thus, the clinical management of such interactions must consider the underlying mechanism of the interactions.

Pooled Population Pharmacokinetic Analyses of Venetoclax in Patients Across Indications and Healthy Subjects from Phase 1, 2, and 3 Clinical Trials

“…Owing to an already large reduction (85%) in clearance caused by strong CYP3A inhibitors, additional CYP3A inhibitors are unlikely to add to the effect. Interestingly, a recent study published using a physiologically based PK approach had come to a similar conclusion that when combining 1 strong CYP3A inhibitor with additional competitive CYP3A inhibitors, no further effect can be observed beyond a single strong inhibitor alone 32 …”

“…Interestingly, a recent study published using a physiologically based PK approach had come to a similar conclusion that when combining 1 strong CYP3A inhibitor with additional competitive CYP3A inhibitors, no further effect can be observed beyond a single strong inhibitor alone. 32 The expanded and improved population PK model successfully characterized venetoclax plasma concentration across multiple patient populations and healthy volunteers. Comprehensive covariate analyses validated previously reported clinically relevant factors affecting venetoclax PK, supporting the recommendation in the prescribing information to administer venetoclax with food and reduce venetoclax dosage when coadministered with moderate and strong CYP3A inhibitors.…”

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B‐cell lymphoma‐2 inhibitor

“…31,50 This supports that the recommended dose adjustment of venetoclax when administered in combination with more than one strong CYP3A inhibitor should be identical to that prescribed for a single strong CYP3A inhibitor. 50…”

“…A common issue with patients with hematological malignancies is the need for multiple therapies to address comorbidities or side effects from cancer treatments. Using PBPK and popPK to investigate whether additional dose adjustments were needed in patients taking multiple strong CYP3A inhibitors concomitantly, it was found that venetoclax exposures were similar to that of just taking one strong CYP3A inhibitor 31,50 . This supports that the recommended dose adjustment of venetoclax when administered in combination with more than one strong CYP3A inhibitor should be identical to that prescribed for a single strong CYP3A inhibitor 50 …”

Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review

“…A summary of the included analyses is shown in Table 1. Among the six analyses included, a median (range) of 274 (73-3016) patients were used for the development of the PPK model, with five analyses 11,16,18,19,22 involving more than 200 subjects. All analyses were based on clinical trials, and three analyses did not state NCT numbers.…”