Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma

被引：81

作者：

Agarwal, Suresh K. ^{[1
]}

Salem, Ahmed Hamed ^{[1
,2
]}

Danilov, Alexey V. ^{[3
,4
,5
]}

Hu, Beibei ^{[1
]}

Puvvada, Soham ^{[6
]}

Gutierrez, Martin ^{[7
]}

Chien, David ^{[8
]}

Lewis, Lionel D. ^{[3
,4
]}

Wong, Shekman L. ^{[1
]}

机构：

[1] AbbVie Inc, Clin Pharmacol & Pharmacometr, Dept R4PK,Bldg AP31-3,1 North Waukegan Rd, N Chicago, IL 60064 USA

[2] Ain Shams Univ, Dept Clin Pharm, Fac Pharm, Cairo, Egypt

[3] Geisel Sch Med Dartmouth, Dept Med, Lebanon, NH USA

[4] Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH 03766 USA

[5] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[6] Univ Arizona, Ctr Canc, Tucson, AZ USA

[7] Hackensack Univ, Med Ctr, Ctr Canc, Hackensack, NJ USA

[8] AbbVie Inc, Oncol Dev, N Chicago, IL USA

来源：

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY | 2017年 / 83卷 / 04期

关键词：

BCL-2; drug-drug interaction; ketoconazole; pharmacokinetics; venetoclax; CHRONIC LYMPHOCYTIC-LEUKEMIA; CONCISE GUIDE; PHARMACOLOGY; PROTEIN;

D O I：

10.1111/bcp.13175

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

AimsTo examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. MethodsTwelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50mg dose of venetoclax orally on Day 1 and Day 8, and a 400mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96h after each venetoclax dose on Day 1 and Day 8. ResultsEleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (C-max) and area under the plasma concentration-time curve from time 0 to infinity (AUC) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively. ConclusionsCoadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.

引用

页码：846 / 854

页数：9

共 27 条

[1] Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study [J].

Agarwal, Suresh K. ;

Hu, Beibei ;

Chien, David ;

Wong, Shekman L. ;

Salem, Ahmed Hamed .

JOURNAL OF CLINICAL PHARMACOLOGY, 2016, 56 (11) :1335-1343

[2] A dual role for the anti-apoptotic Bcl-2 protein in cancer: Mitochondria versus endoplasmic reticulum [J].

Akl, Haidar ;

Vervloessem, Tamara ;

Kiviluoto, Santeri ;

Bittremieux, Mart ;

Parys, Jan B. ;

De Smedt, Humbert ;

Bultynck, Geert .

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 2014, 1843 (10) :2240-2252

[3] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Enzymes [J].

Alexander, Stephen P. H. ;

Fabbro, Doriano ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :6024-6109

[4] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Transporters [J].

Alexander, Stephen P. H. ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. ;

Edwards, D. P. ;

Farndale, R. ;

Fong, T. M. ;

Forrest, D. ;

Fowler, C. J. ;

Fuller, P. ;

Gainetdinov, R. R. ;

Gershengorn, M. A. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :6110-6202

[5] THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Overview [J].

Alexander, Stephen P. H. ;

Kelly, Eamonn ;

Marrion, Neil ;

Peters, John A. ;

Benson, Helen E. ;

Faccenda, Elena ;

Pawson, Adam J. ;

Sharman, Joanna L. ;

Southan, Christopher ;

Buneman, O. Peter ;

Catterall, William A. ;

Cidlowski, John A. ;

Davenport, Anthony P. ;

Fabbro, Doriano ;

Fan, Grace ;

McGrath, John C. ;

Spedding, Michael ;

Davies, Jamie A. ;

Aldrich, R. ;

Attali, B. ;

Back, M. ;

Barnes, N. M. ;

Bathgate, R. ;

Beart, P. M. ;

Becirovic, E. ;

Biel, M. ;

Birdsall, N. J. ;

Boison, D. ;

Brauner-Osborne, H. ;

Broeer, S. ;

Bryant, C. ;

Burnstock, G. ;

Burris, T. ;

Cain, D. ;

Calo, G. ;

Chan, S. L. ;

Chandy, K. G. ;

Chiang, N. ;

Christakos, S. ;

Christopoulos, A. ;

Chun, J. J. ;

Chung, J. -J. ;

Clapham, D. E. ;

Connor, M. A. ;

Coons, L. ;

Cox, H. M. ;

Dautzenberg, F. M. ;

Dent, G. ;

Douglas, S. D. ;

Dubocovich, M. L. .

BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5729-5743

[6] The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199 [J].

Choo, Edna F. ;

Boggs, Jason ;

Zhu, Chunqiang ;

Lubach, Joseph W. ;

Catron, Nathaniel D. ;

Jenkins, Gary ;

Souers, Andrew J. ;

Voorman, Richard .

DRUG METABOLISM AND DISPOSITION, 2014, 42 (02) :207-212

[7]

Davids MS, 2016, J CLIN ONCO IN PRESS

[8] A Dose-Escalation Study of Venetoclax (ABT-199/GDC-0199) in Combination with Bendamustine and Rituximab in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma [J].

de Vos, Sven ;

Swinnen, Lode ;

Kozloff, Mark ;

Wang, Ding ;

Reid, Erin ;

Nastoupil, Loretta ;

Fowler, Nathan ;

Cordero, Jaclyn ;

D'Amico, Diane ;

Diehl, Susan ;

Dunbar, Martin ;

Zhu, Ming ;

Wong, Shekman ;

Enschede, Sari Heitner ;

Chien, David ;

Humerickhouse, Rod A. ;

Flowers, Christopher .

BLOOD, 2015, 126 (23)

[9] Molecular Profiling and Relationship with Clinical Response in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Potent Inhibitor of Mutant IDH1, in Addition to Data from the Completed Dose Escalation Portion of the Phase 1 Study [J].

DiNardo, Courtney ;

de Botton, Stephane ;

Pollyea, Daniel A. ;

Stein, Eytan M. ;

Fathi, Amir T. ;

Roboz, Gail J. ;

Collins, Robert ;

Swords, Ronan T. ;

Flinn, Ian W. ;

Altman, Jessica K. ;

Tallman, Martin S. ;

Kantarjian, Hagop M. ;

Derti, Adnan ;

Goldwasser, Meredith ;

Prahl, Malia ;

Wu, Bin ;

Yen, Katherine ;

Agresta, Sam ;

Stone, Richard M. .

BLOOD, 2015, 126 (23)

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

Freise, Kevin J. ;

Jones, Aksana K. ;

Menon, Rajeev M. ;

Verdugo, Maria E. ;

Humerickhouse, Rod A. ;

Awni, Walid M. ;

Salem, Ahmed Hamed .

HEMATOLOGICAL ONCOLOGY, 2017, 35 (04) :679-684

← 1 2 3 →