Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061, Ludwigshafen, Germany
Pharmacotherapeutic group: other antineoplastic agents
ATC code: L01XX52
Venetoclax is a potent, selective inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. Overexpression of BCL-2 has been demonstrated in CLL cells where it mediates tumour cell survival and has been associated with resistance to chemotherapeutics. Venetoclax binds directly to the BH3-binding groove of BCL-2, displacing BH3 motif-containing pro-apoptotic proteins like BIM, to initiate mitochondrial outer membrane permeabilization (MOMP), caspase activation, and programmed cell death. In non-clinical studies, venetoclax has demonstrated cytotoxic activity in tumour cells that overexpress BCL-2.
The effect of multiple doses of venetoclax up to 1200 mg once daily on the QTc interval was evaluated in an open-label, single-arm study in 176 patients. Venetoclax had no effect on QTc interval and there was no relationship between venetoclax exposure and change in QTc interval.
Venetoclax in combination with obinutuzumab for the treatment of patients with previously untreated CLL – study BO25323 (CLL14)
A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of venetoclax + obinutuzumab versus obinutuzumab + chlorambucil in patients with previously untreated CLL and comorbidities (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance [CrCl] <70 ml/min). Patients in the study were assessed for risk of TLS and received prophylaxis accordingly prior to obinutuzumab administration. All patients received obinutuzumab at 100 mg on Cycle 1 Day 1, followed by 900 mg which could have been administered on Day 1 or Day 2, then 1000 mg doses on Days 8 and 15 of Cycle 1, and on Day 1 of each subsequent cycle, for a total of 6 cycles. On Day 22 of Cycle 1, patients in the venetoclax + obinutuzumab arm began the 5-week venetoclax dose-titration schedule, continuing through Cycle 2 Day 28. Upon completion of the dose-titration schedule, patients continued venetoclax 400 mg once daily from Cycle 3 Day 1 until the last day of Cycle 12. Each cycle was 28 days. Patients randomised to the obinutuzumab + chlorambucil arm received 0.5 mg/kg oral chlorambucil on Day 1 and Day 15 of Cycles 1-12. Patients continued to be followed for disease progression and overall survival after completing therapy.
Baseline demographic and disease characteristics were similar between the study arms. The median age was 72 years (range: 41 to 89 years), 89% were white, and 67% were male; 36% and 43% were Binet stage B and C, respectively. The median CIRS score was 8.0 (range: 0 to 28) and 58% of patients had CrCl <70 ml/min. A 17p deletion was detected in 8% of patients, TP53 mutations in 10%, 11q deletion in 19%, and unmutated IgVH in 57%. The median follow-up at the time of the primary analysis was 28 months (range: 0 to 36 months).
At baseline, the median lymphocyte count was 55 × 109 cells/l in both study arms. On Cycle 1 Day 15, the median count had decreased to 1.03 × 109 cells/l (range: 0.2 to 43.4 × 109 cells/l) in the obinutuzumab + chlorambucil arm and 1.27 × 109 cells/l (range: 0.2 to 83.7 × 109 cells/l) in the venetoclax + obinutuzumab arm.
Progression-free survival (PFS) was assessed by investigators and by an Independent Review Committee (IRC) using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).
Efficacy results for investigator-assessed PFS at the time of the primary analysis (data cut-off date 17 August 2018) are shown in Table 5.
Table 5. Investigator-assessed progression-free survival in patients with previously untreated CLL in CLL14 (primary analysis):
| Venetoclax + obinutuzumab (N=216) | Obinutuzumab + chlorambucil (N=216) | |
|---|---|---|
| Number of events (%) | 30 (14) | 77 (36) |
| Median, months (95% CI) | NR | NR |
| Hazard ratio (95% CI) | 0.35 (0.23, 0.53) | |
| P-valuea | <0,0001 | |
| 12-month PFS estimate (95% CI) | 94.6 (91.5, 97.7) | 92.2 (88.4, 95.8) |
| 24-month PFS estimate (95% CI) | 88.2 (83.7, 95.1) | 64.1 (57.4, 70.8) |
CI = confidence interval; NR = not reached
a Stratified P-value
At an updated efficacy analysis (data cut-off date 23 August 2019 and median follow-up of 40 months), the median PFS had not been reached in the venetoclax + obinutuzumab arm and was 35.6 months [95% CI: 33.7,40.7] in the obinutuzumab + chlorambucil arm with a HR of 0.31 [95% CI: 0.22, 0.44]. The 36-month PFS estimate in the venetoclax + obinutuzumab arm was 81.9% [95% CI: 76.5, 87.3] and in the obinutuzumab + chlorambucil arm was 49.5% [95% CI: 42.4, 56.6]. The updated Kaplan-Meier curve for PFS is shown in Figure 1.
Figure 1. Kaplan-Meier curve of investigator-assessed progression-free survival (ITT population) in CLL14 with 40 months follow-up:
Table 6. Additional efficacy results in CLL14 (primary analysis):
| Endpoint | Venetoclax + obinutuzumab (N=216) | Obinutuzumab + chlorambucil (N=216) |
|---|---|---|
| IRC-assessed PFS | ||
| Number of events (%) | 29 (13) | 79 (37) |
| Median, months | NR | NR |
| Hazard ratio(95% CI) | 0.33 (0.22, 0.51) | |
| P-valuea | <0.0001 | |
| 12-month PFS estimate (95% CI) | 94.6 (91.5, 97.7) | 91.1 (87.3, 95.1) |
| 24-month PFS estimate (95% CI) | 88.6 (84.2, 93) | 63.7 (57, 70.4) |
| Response rate | ||
| ORRb, % (95% CI) | 85 (79.2, 89.2) | 71 (64.8, 77.2) |
| CR+CRib, (%) | 50 | 23 |
| MRD negativity ratec at end of treatment | ||
| Peripheral blood, % (95% CI) | 76 (69.17, 81.05) | 35 (28.83, 41.95) |
| P-value | <0.0001 | |
| Bone marrowd, % (95% CI) | 57 (50.05, 63.64) | 17 (12.36, 22.83) |
| P-value | <0.0001 | |
CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = independent review committee; MRD = minimal residual disease; NR = not reached; ORR = overall response rate (CR + CRi + PR).
a Stratified P-value.
b P-values based on Cochran-Mantel-Haenszel test; P=0.0007 for ORR; P<0.0001 for CR+CRi.
c Minimal residual disease was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cut-off for a negative status was <1 CLL cell per 104 leukocytes.
d Per protocol, MRD in bone marrow was to be assessed only in responding patients (CR/CRi and PR).
The PFS benefit with venetoclax + obinutuzumab versus obinutuzumab + chlorambucil treatment was observed across the following subgroups: sex; age; Binet stage at screening; estimated CrCL; del(17p)/TP53 mutation; IgVH mutational status.
A randomised (1:1), multicenter, open-label phase 3 study evaluated the efficacy and safety of Venclyxto + rituximab versus BR in patients with previously treated CLL. Patients in the Venclyxto + rituximab arm completed the Venclyxto 5-week dose-titration schedule and then received 400 mg once daily for 24 months from Cycle 1 Day 1 of rituximab in the absence of disease progression or unacceptable toxicity. Rituximab was initiated after the 5-week dose-titration schedule at 375 mg/m 2 for Cycle 1 and 500 mg/m 2 for Cycles 2- 6. Each cycle was 28 days. Patients randomised to BR received bendamustine at 70 mg/m 2 on Days 1 and 2 for 6 cycles and rituximab as described above.
Median age was 65 years (range: 22 to 85); 74% were male, and 97% were white. Median time since diagnosis was 6.7 years (range: 0.3 to 29.5). Median prior lines of therapy was 1 (range: 1 to 5); and included alkylating agents (94%), anti-CD20 antibodies (77%), B-cell receptor pathway inhibitors (2%) and prior purine analogs (81%, including 55% FCR). At baseline, 46.6% of patients had one or more nodes ≥5 cm, and 67.6% had ALC ≥25 × 109/l. A 17p deletion was detected in 26.9% of patients, TP53 mutations in 26.3%, 11q deletion in 36.5%, and unmutated IgVH gene in 68.3%. Median follow-up time for primary analysis was 23.8 months (range: 0.0 to 37.4 months).
Progression-free survival (PFS) was assessed by investigators using the International Workshop for Chronic Lymphocytic Leukaemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008).
Efficacy results for PFS at the time of pre-specified primary analysis (data cut-off date 8 May 2017) are shown in Table 7.
Table 7. Investigator-assessed progression-free survival in patients with previously treated CLL in MURANO:
| Venetoclax + rituximab N=194 | Bendamustine + rituximab N=195 | |
|---|---|---|
| Number of events (%) | 32 (16.5) | 114 (58.5) |
| Disease progression | 21 | 98 |
| Death events | 11 | 16 |
| Median, months (95% CI) | NR | 17,0 (15.5, 21.6) |
| Hazard ratio (95% CI) | 0.17 (0.11, 0.25) | |
| P-valuea | <0,0001 | |
| 12-month PFS estimate (95% CI) | 92.7 (89.1, 96.4) | 72.5 (65.9, 79.1) |
| 24-month PFS estimate (95% CI) | 84.9 (79.1, 90.6) | 36.3 (28.5, 44.0) |
CI = confidence interval; NR = not reached
a Stratified P-value.
At an updated efficacy analysis with all patients off treatment (data cut-off date 8 May 2018 and median follow-up of 36 months) the 36-month PFS estimate in the venetoclax + rituximab arm was 71.4% [95% CI: 64.8, 78.1] and in the bendamustine + rituximab arm was 15.2% [95% CI: 9.1, 21]. Kaplan-Meier curves of investigator-assessed PFS from the updated efficacy analysis are shown in Figure 2.
In total, 130 patients in the venetoclax + rituximab arm completed 2 years of venetoclax treatment without progression. Of the 130 patients, 92 patients completed the 6-month post treatment follow-up visit. The estimated PFS rate at 6 months post treatment was 92%.
Figure 2. Kaplan-Meier curves of investigator-assessed progression-free survival (intent-to-treat population) in MURANO (data cut-off date 8 May 2018):
Efficacy results for the pre-specified primary analysis (data cut-off date 8 May 2017) were also assessed by an Independent Review Committee (IRC) demonstrating a statistically significant 81% reduction in the risk of progression or death for patients treated with venetoclax + rituximab (hazard ratio: 0.19 [95% CI: 0.13, 0.28]; P<0.0001). Additional efficacy results for the pre-specified primary analysis are shown in Table 8 and Figure 3 and Figure 4.
Table 8. Additional efficacy results in MURANO:
| Investigator assessed | IRC assessed | |||
|---|---|---|---|---|
| Endpoint | Venetoclax + rituximab N=194 | Bendamustine + rituximab N=195 | Venetoclax + rituximab N=194 | Bendamustine + rituximab N=195 |
| Response rate | ||||
| ORR, % (95% CI) | 93.3 (88.8, 96.4) | 67.7 (60.6, 74.2) | 92.3 (87.6, 95.6) | 72.3 (65.5, 78.5) |
| CR+CRi, (%) | 26.8 | 8.2 | 8.2 | 3.6 |
| nPR, (%) | 3.1 | 6.2 | 1.5 | 0.5 |
| PR, (%) | 63.4 | 53.3 | 82.5a | 68.2a |
| MRD negativity rate at end of combination treatmentb | ||||
| Peripheral blood, % (95% CI)c | 62.4 (55.2, 69.2) | 13.3 (8.9, 18.9) | NA | NA |
| Bone marrow, % (95% CI)d | 15.5 (10.7, 21.3) | 1.0 (0.1, 3.7) | NA | NA |
| Overall Survivale | ||||
| Number of events (%) | 15 (7,7) | 27 (13,8) | ||
| Hazard ratio (95% CI) | 0,48 (0,25, 0,90) | |||
| Time to next anti-leukaemic therapy | ||||
| Number of events (%) | 23 (11.9) | 83 (42.6) | NA | NA |
| Median, months (95% CI) | NR | 26.4 | NA | NA |
| Hazard ratio | 0.19 (0.12, 0.31) | NA | ||
CR = complete remission; CRi = complete remission with incomplete marrow recovery; IRC = independent review committee; MRD = minimal residual disease; nPR = nodular partial remission; NA = not available; NR = not reached; ORR = overall response rate (CR + CRi + nPR + PR); PR = partial remission.
a The discrepancy between IRC- and investigator-assessed CR rate was due to interpretation of residual adenopathy on CT scans. Eighteen patients in the venetoclax + rituximab arm and 3 patients in the bendamustine + rituximab arm had negative bone marrow and lymph nodes <2 cm.
b Minimal residual disease was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry. The cut-off for a negative status was one CLL cell per 10 4 leukocytes.
c Of those with MRD assay results available in peripheral blood, 72.5% (121/167) in the venetoclax + rituximab arm and 20% (26/128) in the bendamustine + rituximab arm were found to be MRD negative.
d Of those with MRD assay results available in bone marrow, 76.9% (30/39) in the venetoclax + rituximab arm and 6.7% (2/30) in the bendamustine + rituximab arm were found to be MRD negative.
e Overall survival data are not yet mature.
Median DOR was not reached with median follow-up of approximately 23.8 months.
Figure 3. Kaplan-Meier curves of overall survival (intent-to-treat population) in MURANO:
The observed PFS benefit of venetoclax + rituximab compared with bendamustine + rituximab was consistently observed across all subgroups of patients evaluated, including age (<65, ≥65 years and <75, ≥75 years), prior lines of therapy (1, >1), bulky disease (<5 cm, ≥5 cm), 17p deletion, 11q deletion, TP53 mutation, IgVH mutation, and refractory versus relapse to most recent therapy (Figure 4).
Figure 4. Forest plot of Investigator-Assessed PFS in Subgroups from MURANO:
The safety and efficacy of venetoclax in 107 patients with previously treated CLL with 17p deletion were evaluated in a single arm, open-label, multi-center study (M13-982). Patients followed a 4- to 5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed. The median age was 67 years (range: 37 to 85 years); 65% were male, and 97% were white. The median time since diagnosis was 6.8 years (range: 0.1 to 32 years; N=106). The median number of prior anti-CLL treatments was 2 (range: 1 to 10 treatments); 49.5% with a prior nucleoside analogue, 38% with prior rituximab, and 94% with a prior alkylator (including 33% with prior bendamustine). At baseline, 53% of patients had one or more nodes ≥5 cm, and 51% had ALC ≥25 × 109/l. Of the patients, 37% (34/91) were fludarabine refractory, 81% (30/37) harboured the unmutated IgVH gene, and 72% (60/83) had TP53 mutation. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months).
The primary efficacy endpoint was overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using the IWCLL updated NCI-WG guidelines (2008). Efficacy results are shown in Table 9. Efficacy data are presented for 107 patients with data cutoff date 30 April 2015. An additional 51 patients were enrolled in a safety expansion cohort. Investigator-assessed efficacy results are presented for 158 patients with a later data cutoff date 10 June 2016. The median time on treatment for 158 patients was 17 months (range: 0 to 34 months).
Table 9. Efficacy results in patients with previously treated CLL with 17p deletion (study M13-982):
| Endpoint | IRC assessment (N=107)a | Investigator assessment (N=158)b |
|---|---|---|
| Data cutoff date | 30 April 2015 | 10 June 2016 |
| ORR, % (95% CI) | 79 (70.5, 86.6) | 77 (69.9, 83.5) |
| CR + CRi, % | 7 | 18 |
| nPR, % | 3 | 6 |
| PR, % | 69 | 53 |
| DOR, months, median (95% CI) | NR | 27.5 (26.5, NR) |
| PFS, % (95% CI) | ||
| 12-month estimate | 72 (61.8, 79.8) | 77 (69.1, 82.6) |
| 24-month estimate | NA | 52 (43, 61) |
| PFS, months, median (95% CI) | NR | 27.2 (21.9, NR) |
| TTR, months, median (range) | 0.8 (0.1-8.1) | 1.0 (0.5-4.4) |
a One patient did not harbour the 17p deletion.
b Includes 51 additional patients from the safety expansion cohort.
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery, DOR = duration of response; IRC = independent review committee; nPR = nodular PR; NA = not available; NR = not reached; ORR = overall response rate; PFS = progression-free survival, PR = partial remission; TTR = time to first response.
Minimal residual disease (MRD) was evaluated using flow cytometry in 93 of 158 patients who achieved complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) with limited remaining disease with venetoclax treatment. MRD negativity was defined as a result below 0.0001 (<1 CLL cell per 10 4 leukocytes in the sample). Twenty-seven percent (42/158) of patients were MRD negative in the peripheral blood, including 16 patients who were also MRD negative in the bone marrow.
The efficacy and safety of venetoclax in patients with CLL who had been previously treated with and failed ibrutinib or idelalisib therapy were evaluated in an open-label, multi-center, non-randomised, phase 2 study (M14-032). Patients received venetoclax via a recommended dose-titration schedule. Patients continued to receive venetoclax 400 mg once daily until disease progression or unacceptable toxicity was observed.
At the time of data cut-off (26 July 2017), 127 patients were enrolled and treated with venetoclax. Of these, 91 patients had received prior ibrutinib therapy (Arm A) and 36 had received prior idelalisib therapy (Arm B). The median age was 66 years (range: 28 to 85 years), 70% were male, and 92% were white. The median time since diagnosis was 8.3 years (range: 0.3 to 18.5 years; N=96). Chromosomal aberrations were 11q deletion (34%, 43/127), 17p deletion (40%, 50/126), TP53 mutation (38%, 26/68) and unmutated IgVH (78%, 72/92). At baseline, 41% of patients had one or more nodes ≥5 cm and 31% had ALC ≥25 × 109/l. The median number of prior oncology treatments was 4 (range: 1 to 15) in ibrutinib-treated patients and 3 (range: 1 to 11) in idelalisib-treated patients. Overall, 65% of patients received prior nucleoside analogue, 86% rituximab, 39% other monoclonal antibodies, and 72% alkylating agent (including 41% with bendamustine). At the time of evaluation, median duration of treatment with venetoclax was 14.3 months (range: 0.1 to 31.4 months).
The primary efficacy endpoint was ORR according to IWCLL updated NCI-WG guidelines. Response assessments were performed at 8 weeks, 24 weeks, and every 12 weeks thereafter.
Table 10. Efficacy results as assessed by investigator in patients who have failed a B-cell receptor pathway inhibitor (study M14-032):
| Arm A (ibrutinib failures) (N=91) | Arm B (idelalisib failures) (N=36) | Total (N=127) | |
|---|---|---|---|
| ORR, % (95% CI) | 65 (54.1, 74.6) | 67 (49.0, 81.4) | 65 (56.4, 73.6) |
| CR + CRi, % | 10 | 11 | 10 |
| nPR, % | 3 | 0 | 2 |
| PR, % | 52 | 56 | 53 |
| PFS, % (95% CI) | |||
| 12-month estimate | 75 (64.7, 83.2) | 80 (63.1, 90.1) | 77 (68.1, 83.4) |
| 24-month estimate | 51 (36.3, 63.9) | 61 (39.6, 77.4) | 54 (41.8, 64.6) |
| PFS, months, median (95% CI) | 25 (19.2, NR) | NR (16.4, NR) | 25 (19.6, NR) |
| OS, % (95% CI) 12-month estimate | 91 (82.8, 95.4) | 94.2 (78.6, 98.5) | 92 (85.6, 95.6) |
| TTR, months, median (range) | 2.5 (1.6-14.9) | 2.5 (1.6-8.1) | 2.5 (1.6-14.9) |
| 17p deletion and/or TP53 mutation status ORR, % (95% CI) | |||
| Yes | (n=28) 61 (45.4, 74.9) | (n=7) 58 (27.7, 84.8) | (n=35) 60 (46.6, 73.0) |
| No | (n=31) 69 (53.4, 81.8) | (n=17) 71 (48.9, 87.4) | (n=48) 70 (57.3, 80.1) |
CI = confidence interval; CR = complete remission; CRi = complete remission with incomplete marrow recovery, nPR = nodular PR; NR = not reached, ORR = overall response rate;. OS = overall survival; PFS = progression-free survival, PR = partial remission, TTR = time to first response.
The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 70% (Arm A: 70%; Arm B: 69%). One patient (ibrutinib failure) achieved complete remission with incomplete marrow recovery. The ORR for patients with 17p deletion and/or TP53 mutation was 72% (33/46) (95% CI: 56.5, 84.0) in Arm A and 67% (8/12) (95% CI: 34.9, 90.1) in Arm B. For patients without 17p deletion and/or TP53 mutation, the ORR was 69% (31/45) (95% CI: 53.4, 81.8) in Arm A and 71% (17/24) (95% CI: 48.9, 87.4) in Arm B.
Median OS and DOR were not reached with median follow-up of approximately 14.3 months for Arm A and 14.7 months for Arm B.
Twenty-five percent (32/127) of patients were MRD negative in the peripheral blood, including 8 patients who were also MRD negative in bone marrow.
Of the 194 patients with previously treated CLL who received venetoclax in combination with rituximab, 50% were 65 years or older.
Of the 107 patients who were evaluated for efficacy from M13-982 study, 57% were 65 years or older. Of the 127 patients who were evaluated for efficacy from M14-032 study, 58% were 65 years or older.
Of the 352 patients evaluated for safety from 3 open-label monotherapy trials, 57% were 65 years or older. There were no clinically meaningful differences in safety or efficacy observed between older and younger patients in the combination and monotherapy studies.
Following multiple oral administrations, maximum plasma concentration of venetoclax was reached 5-8 hours after dose. Venetoclax steady state AUC increased proportionally over the dose range of 150-800 mg. Under low-fat meal conditions, venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 μg/ml and AUC 24 was 32.8 ± 16.9 μg•h/ml at the 400 mg once daily dose.
Administration with a low-fat meal increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal increased venetoclax exposure by 5.1- to 5.3-fold compared to fasting conditions. It is recommended that venetoclax should be administered with a meal (see section 4.2).
Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 μM (0.87-26 μg/ml). The mean blood-to-plasma ratio was 0.57. The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients.
In vitro studies demonstrated that venetoclax is predominantly metabolised by cytochrome P450 CYP3A4. M27 was identified as a major metabolite in plasma with an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro.
Co administration with CYP and UGT substrates: In vitro studies indicated that venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6 or CYP3A4 at clinically relevant concentrations. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9 and UGT1A1 in vitro, but it is not predicted to cause clinically relevant inhibition. Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9 and UGT2B7.
Co administration with transporter substrates/inhibitors: Venetoclax is a P-gp and BCRP substrate as well as a P-gp and BCRP inhibitor and a weak OATP1B1 inhibitor in vitro (see section 4.5). Venetoclax is not expected to inhibit OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1 or MATE2K at clinically relevant concentrations.
The population estimate for the terminal phase elimination half-life of venetoclax was approximately 26 hours. Venetoclax shows minimal accumulation with accumulation ratio of 1.30-1.44. After a single oral administration of 200 mg radiolabeled [14C]-venetoclax to healthy subjects, >99.9% of the dose was recovered in faeces and <0.1% of the dose was excreted in urine within 9 days. Unchanged venetoclax accounted for 20.8% of the administered radioactive dose excreted in faeces. The pharmacokinetics of venetoclax do not change over time.
Based on a population pharmacokinetic analysis that included 219 subjects with mild renal impairment (CrCl ≥60 and <90 ml/min), 86 subjects with moderate renal impairment (CrCl ≥30 and <60 ml/min) and 217 subjects with normal renal function (CrCl ≥90 ml/min), venetoclax exposures in subjects with mild or moderate renal impairment are similar to those with normal renal function. The pharmacokinetics of venetoclax has not been studied in subjects with severe renal impairment (CrCl <30 ml/min) or patients on dialysis (see section 4.2).
Based on a population pharmacokinetic analysis that included 74 subjects with mild hepatic impairment, 7 subjects with moderate hepatic impairment and 442 subjects with normal hepatic function, venetoclax exposures are similar in subjects with mild and moderate hepatic impairment and normal hepatic function. Mild hepatic impairment was defined as normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin >1.0 to 1.5 times ULN, moderate hepatic impairment as total bilirubin >1.5 to 3.0 times ULN, and severe hepatic impairment as total bilirubin >3.0 ULN.
In a dedicated hepatic impairment study, venetoclax Cmax and AUC in subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=6) hepatic impairment were similar to subjects with normal hepatic function, after receiving a 50 mg single dose of venetoclax. In subjects with severe (Child-Pugh C; n=5) hepatic impairment, the mean venetoclax Cmax was similar to subjects with normal hepatic function but venetoclax AUCinf was on average 2.7-fold higher (range: no change to 5-fold higher) than venetoclax AUCinf in the subjects with normal hepatic function (see section 4.2).
Based on population pharmacokinetic analyses, age, sex, and weight do not have an effect on venetoclax clearance.
Toxicities observed in animal studies with venetoclax included dose-dependent reductions in lymphocytes and red blood cell mass. Both effects were reversible after cessation of dosing with venetoclax, with recovery of lymphocytes occurring 18 weeks post treatment. Both B- and T-cells were affected, but the most significant decreases occurred with B-cells.
Venetoclax also caused single cell necrosis in various tissues, including the gallbladder and exocrine pancreas, with no evidence of disruption of tissue integrity or organ dysfunction; these findings were minimal to mild in magnitude.
After approximately 3 months of daily dosing in dogs, venetoclax caused progressive white discoloration of the hair coat, due to loss of melanin pigment in the hair.
Venetoclax and the M27 major human metabolite were not carcinogenic in a 6-month transgenic (Tg.rasH2) mouse carcinogenicity study at oral doses up to 400 mg/kg/day of venetoclax and at a single dose level of 250 mg/kg/day of M27. Exposure margins (AUC), relative to the clinical AUC at 400 mg/day, were approximately 2-fold for venetoclax and 5.8-fold for M27.
Venetoclax was not genotoxic in bacterial mutagenicity assay, in vitro chromosome aberration assay and in vivo mouse micronucleus assay. The M27 metabolite was negative for genotoxicity in the bacterial mutagenicity and chromosomal aberration assays.
No effects on fertility were observed in fertility and early embryonic development studies in male and female mice. Testicular toxicity (germ cell loss) was observed in general toxicity studies in dogs at exposures of 0.5 to 18 times the human AUC exposure at a dose of 400 mg. Reversibility of this finding has not been demonstrated.
In embryo-foetal development studies in mice, venetoclax was associated with increased post-implantation loss and decreased foetal body weight at exposures of 1.1 times the human AUC exposure at a dose of 400 mg. The major human metabolite M27 was associated with post-implantation loss and resorptions at exposures approximately 9-times the human M27-AUC exposure at a 400 mg dose of venetoclax. In rabbits, venetoclax produced maternal toxicity, but no foetal toxicity at exposures of 0.1 times the human AUC exposure at a 400 mg dose.
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