Venetoclax exposure‐efficacy and exposure‐safety relationships in patients with treatment‐naïve acute myeloid leukemia who are ineligible for intensive chemotherapy

Abstract

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC.The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients.For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax Deanna Brackman and Doerthe Eckert have contributed equally.

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

“…This work also expanded on a previously developed popPK model to describe the effects of multiple CYP3A inhibitors on venetoclax apparent clearance. 6 Consistent with the PBPK model predictions and literature data, analysis using popPK detected that any combination of multiple CYP3A inhibitors including at least 1 strong CYP3A inhibitor would not exert different effects than that of 1 strong CYP3A inhibitor on venetoclax apparent clearance. As this approach included a legacy model as an informative prior, 5 the estimates for the use of a single CYP3A inhibitor are largely informed by the estimate of the legacy model.…”

“…A previously developed popPK model describing venetoclax PK in patients with AML was used to test the effects of using multiple CYP3A inhibitors. 6 Briefly, this was a 2-compartment model, with first-order absorption and elimination processes, that accounted for the effects of any moderate or strong CYP3A inhibitors, regardless of how many were taken concomitantly, on venetoclax apparent clearance (CL/F). Subjects on multiple CYP3A inhibitors were assigned to the highest strength of the CYP3A inhibitors used.…”

“…A total of 4571 plasma venetoclax concentrations from 771 patients across 5 clinical studies of venetoclax in AML were available for analyses. 6 From this, a total of 791 concentrations from 224 patients were taken during coadministration with moderate and/or strong CYP3A inhibitors, of which 87 concentrations were available from 41 patients during coadministration of more than 1 CYP3A inhibitor (moderate or strong). In this analysis, the use of multiple CYP3A inhibitors (grouped by number and strength) were tested in the popPK model as separate covariates and compared with the legacy model.…”

“…1,2 The pharmacokinetics (PK) of venetoclax have been well described using noncompartmental analyses and population PK (popPK) modeling. [3][4][5][6] Venetoclax is primarily metabolized by cytochrome P450 3A (CYP3A), with biliary elimination accounting for approximately 10% of elimination. 7 Coadministration of multiple doses of rifampin, a strong CYP3A inducer, decreased the area under the plasma concentration-time curve (AUC) for venetoclax by 71%.…”

“…In particular, popPK analyses with venetoclax have been used to provide label recommendations for the use of venetoclax with gastric acid-reducing agents in patients with renal impairment and in patients of specific races. 5,6 The PBPK modeling utilizes mechanistic in vitro, preclinical, and clinical PK data to provide quantitative PK estimates, and has been used regularly to predict the impact of untested DDI scenarios. The impact of strong CYP3A inhibitors and moderate CYP3A inhibitors/inducers on venetoclax PK has been investigated with PBPK modeling 12 and has been successfully utilized to support appropriate dose adjustments of venetoclax for other strong and moderate CYP3A inhibitors.…”