Kevin J. Freise

Effect of Low‐ and High‐Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First‐in‐Class BCL‐2 Inhibitor

Venetoclax is a selective, first‐in‐class, B‐cell lymphoma‐2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film‐coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open‐label, single‐dose, crossover studies. In the bioequivalence study, 15 subjects received a single dose of venetoclax 50 mg under nonfasting conditions, in each of 2 periods; one period used the uncoated tablet, and the other used the film‐coated tablet. In the food effect study, 24 subjects received a single dose of venetoclax film‐coated 100‐mg tablet under fasting conditions, after a low‐fat breakfast or after a high‐fat breakfast in different periods. The venetoclax film‐coated tablet was bioequivalent to the uncoated tablet, which indicates that the film coating does not affect bioavailability. The median Tmax of venetoclax was delayed by about 2 hours when administered with food. Compared with fasting conditions, Cmax and AUC increased by approximately 3.4‐fold following a low‐fat breakfast. High‐fat meals increased Cmax and AUC by approximately 50% relative to low‐fat meals. The mean terminal half‐life was comparable between the high‐fat meal and fasting conditions (19.1 versus 16.1 hours). Based on these results and the venetoclax exposure–response profile, venetoclax should be administered with food and without specific recommendations for fat content to ensure adequate and consistent bioavailability.

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM

The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable small-molecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities (diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better (≥VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ≥VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507.

Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis

Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26xa0h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30–1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

BackgroundVenetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.ObjectiveThe objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).MethodsA total of 272 and 338 patients from four clinical studies were pooled for the exposure–efficacy and exposure–safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection).ResultsHigher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8xa0% (95xa0% confidence interval 81.5–88.0xa0%) at a venetoclax dosage of 400xa0mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events.ConclusionsThe exposure–response analyses indicated that a venetoclax dosage regimen of 400xa0mg daily results in a high (>80xa0%) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers

Background and ObjectiveVenetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics.MethodsSubjects received a single oral dose of 5xa0mg warfarin on day 1 of both periods 1 and 2, separated by axa014xa0days washout. On day 1 of period 2, subjects concomitantly received a single 400xa0mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9xa0days.ResultsModest increases of 18 to 28% were observed in the maximum observed plasma concentration (Cmax) and area under the curve from time zero to infinity (AUC∞) of both R- and S-warfarin.ConclusionsDue to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.

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

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 (CmaxR) 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 CmaxR 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 Cmax 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.

Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure–response analysis

PurposeVenetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.MethodsThe study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (nxa0=xa0105) or non-Hodgkin’s lymphoma (nxa0=xa071) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8xa0h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200xa0mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements.ResultsThe mean and upper bound of the 2-sided 90xa0% confidence interval (CI) QTc change from baseline were <5 and <10xa0ms, respectively, at all time points and doses (<400, 400, and >400xa0mg). Three subjects had single QTc values >500xa0ms and/or ΔQTcxa0>xa060xa0ms. The effect of venetoclax concentration on both ΔQTc and QTc was not statistically significant (Pxa0>xa00.05). At the mean maximum concentrations achieved with therapeutic (400xa0mg) and supra-therapeutic (1200xa0mg) venetoclax doses, the estimated drug effects on QTc were 0.137 (90xa0% CI [−1.01 to 1.28]) and 0.263 (90xa0% CI [–1.92 to 2.45])xa0ms, respectively.ConclusionVenetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy.

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression‐free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time‐variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration‐dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7‐2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8‐5.6). The analysis demonstrates a concentration‐dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

Response Rates as Predictors of Overall Survival: A Meta-Analysis of Acute Myeloid Leukemia Trials.

Background: Response rates such as overall response rate (ORR), complete response (CR) and complete response with incomplete blood recovery (CRi) can be evaluated in a much shorter period of time than overall survival (OS), potentially accelerating decision making during drug development. The objective of this work was to evaluate the relationship between ORR, CR, CRi or better (CRi+CR) rates and median OS to determine whether response rates could be used as predictors of median OS in acute myeloid leukemia (AML). Methods: A review of published literature was conducted to identify relevant AML clinical trials. Weighted linear regression was performed with various linearizing transformations of response rates and median OS. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively. Results: Twenty trials involving 26 cohorts were included in the meta-analysis. Azactidine treatment was a significant predictor with longer OS compared to decitabine or low dose cytarabine for a given response rate (P < 0.005). Linear regression analysis indicated that the correlation of both CRi or better rates and CR rates with median OS was higher than that of ORR with median OS. The final model showed a strong correlation between CRi or better rates and median OS (R2=0.66). Conclusion: Significant correlation between CRi or better rates and median OS in AML highlights the potential for CRi or better rate, in addition to CR rate, to serve as surrogate markers for median OS.

Exposure-response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma.

Abstract Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800–1200u2009mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.