Skip to main content

Advertisement

SpringerLink
Log in

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

  • Research Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

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 26 h. 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013;88:803–16.

    Article  CAS  PubMed  Google Scholar 

  2. Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995;333:1052–7. Erratum in: N Engl J Med. 333;1515.

    Article  CAS  PubMed  Google Scholar 

  3. Jaglowski S, Jones JA. Choosing first-line therapy for chronic lymphocytic leukemia. Expert Rev Anticancer Ther. 2011;11:1379–90.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Zwiebel JA, Cheson BD. Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol. 1998;25:42–59.

    CAS  PubMed  Google Scholar 

  5. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187–205.

    Article  CAS  PubMed  Google Scholar 

  6. Kitada S, Pedersen IM, Schimmer AD, Reed JC. Dysregulation of apoptosis genes in hematopoietic malignancies. Oncogene. 2002;21:3459–74.

    Article  CAS  PubMed  Google Scholar 

  7. Zaja F, Di Loreto C, Amoroso V, Salmaso F, Russo D, Silvestri F, et al. BCL-2 immunohistochemical evaluation in B-cell chronic lymphocytic leukemia and hairy cell leukemia before treatment with fludarabine and 2-chloro-deoxy-adenosine. Leuk Lymphoma. 1998;28:567–72.

    Article  CAS  PubMed  Google Scholar 

  8. Tomek M, Akiyama T, Dass CR. Role of Bcl-2 in tumour cell survival and implications for pharmacotherapy. J Pharm Pharmacol. 2012;64:1695–702.

    Article  CAS  PubMed  Google Scholar 

  9. Owen C, Assouline S, Kuruvilla J, Uchida C, Bellingham C, Sehn L. Novel therapies for chronic lymphocytic leukemia: a Canadian perspective. Clin Lymphoma Myeloma Leuk. 2015;15:627–34.

    Article  PubMed  Google Scholar 

  10. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.

    Article  CAS  PubMed  Google Scholar 

  11. Ackler S, Oleksijew A, Chen J, Chyla BJ, Clarin J, Foster K, et al. Clearance of systemic hematologic tumors by venetoclax (Abt-199) and navitoclax. Pharmacol Res Perspect. 2015;3, e00178.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311–22.

    Article  CAS  PubMed  Google Scholar 

  13. Gerecitano JF, Roberts AW, Seymour JF, Wierda WG, Kahl BS, Pagel JM, et al. A phase 1 study of venetoclax (ABT-199/GDC-0199) monotherapy in patients with relapsed/refractory non-Hodgkin lymphoma. Blood. 2015;126:254.

    Google Scholar 

  14. Ma S, Brander DM, Seymour JF, Kipps TJ, Barrientos JC, Davids MS, et al. Deep and durable responses following venetoclax (ABT-199/GDC-0199) combined with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: results from a phase 1b study. Blood. 2015;126:830.

    Google Scholar 

  15. Konopleva M, Pollyea D, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase 2 study of venetoclax monotherapy in patients with acute myelogenous leukaemia. Cancer Discov. 2016, submitted.

  16. Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, et al. Safety and efficacy of venetoclax (ABT-199/GDC-0199) in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma: phase 1b results. Blood. 2015;126:3038.

    Article  Google Scholar 

  17. DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, et al. A Phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Blood. 2015;126:327.

    Article  Google Scholar 

  18. Boeckmann AJ, Sheiner LB, Beal SL. NONMEM users guide part V. 2013. https://nonmem.iconplc.com/nonmem730/Latest_User…/guides/V.pdf. Accessed 22 Feb 2016.

  19. United States Food and Drug Administration. Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling. 2010. http://www.fda.gov/downloads/Drugs/…/Guidances/UCM204959.pdf. Accessed 22 Feb 2015.

  20. Ramalingam SS, Kummar S, Sarantopoulos J, Shibata S, LoRusso P, Yerk M, et al. Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. J Clin Oncol. 2010;28:4507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ferri FF. Ferri’s best test: a practical guide to laboratory medicine and diagnostic imaging. 3rd ed. Philadelphia: Saunders, an imprint of Elsevier Inc.; 2015.

    Google Scholar 

  22. Vogel HG, Maas J, Gebauer A. Drug discovery and evaluation: methods in clinical pharmacology. Berlin: Springer; 2011.

    Book  Google Scholar 

  23. University of Washington. Drug interaction database program. https://www.druginteractioninfo.org/. Accessed 22 Feb 2016.

  24. United States Food and Drug Administration. Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed 22 Feb 2015.

  25. University of California, San Francisco. UCSF-FDA transportal. http://dbts.ucsf.edu/fdatransportal/index/. Accessed 22 Feb 2016.

  26. Indiana University Department of Medicine. P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/main-table/. Accessed 22 Feb 2016.

  27. Pharmacology Weekly. Online drug therapy tables. https://archive.is/ULoJ4. Accessed 22 Feb 2016.

  28. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158:693–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.

    Article  CAS  PubMed  Google Scholar 

  30. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13:143–51.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Yanez JA, Remsberg CM, Sayre CL, Forrest ML, Neal M. Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development: challenges and opportunities during drug development. Ther Deliv. 2011;2:643–72.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Duffull SB, Wright DFB, Winter HR. Interpreting population pharmacokinetic-pharmacodynamic analyses—a clinical viewpoint. Br J Clin Pharmacol. 2011;71:807–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Joerger M. Covariate pharmacokinetic model building in oncology and its potential clinical relevance. AAPS J. 2012;14:119–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ludden TM. Nonlinear pharmacokinetics. Clin Pharmacokinet. 1991;20:429–46.

    Article  CAS  PubMed  Google Scholar 

  35. Lee PID, Amidon GL. Pharmacokinetic analysis: a practical approach. Lancaster: Technomic Publishing Company, Inc.; 1996.

    Google Scholar 

  36. Salem AH, Agarwal S, Dunbar M, Nuthalapati S, Chien D, Freise KJ, et al. Effect of low and high fat meals on the pharmacokinetics of venetoclax, a selective first-in-class BCL-2 inhibitor. J Clin Pharmacol. 2016. doi:10.1002/jcph.741.

    Google Scholar 

  37. Agarwal SK, Hu B, Chien D, Wong SL, Salem AH. 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 Clin Pharmacol. 2016. doi:10.1002/jcph.730.

    Google Scholar 

  38. Agarwal S, Salem AH, Danilov AV, Hu B, Puvvada S, Gutierrez M., et al. Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a Bcl-2 inhibitor, in patients with Non-Hodgkin lymphoma. Br J Clin Pharmacol. 2016, submitted.

  39. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol. 1992;44:275–83.

    Article  CAS  PubMed  Google Scholar 

  40. Gorski JC, Vannaprasaht S, Hamman MA, Ambrosius WT, Bruce MA, Haehner-Daniels B, et al. The effect of age, sex, and rifampin administration on intestinal and hepatic cytochrome P450 3A activity. Clin Pharmacol Ther. 2003;74:275–87.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was sponsored by AbbVie and Genentech/Roche. AbbVie and Genentech contributed to the study design, research, and interpretation of data and the writing, reviewing, and approving of the publication. Venetoclax is being developed in collaboration between AbbVie and Genentech.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA

    Aksana K. Jones, Kevin J. Freise, Suresh K. Agarwal, Shekman L. Wong & Ahmed Hamed Salem

  2. Oncology Development, AbbVie Inc., 1 N. Waukegan Road, North Chicago, Illinois, 60064, USA

    Rod A. Humerickhouse

  3. Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt

    Ahmed Hamed Salem

Authors
  1. Aksana K. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin J. Freise
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh K. Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rod A. Humerickhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shekman L. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmed Hamed Salem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmed Hamed Salem.

Ethics declarations

Conflict of Interest

All authors are AbbVie employees and may hold AbbVie stocks or options.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jones, A.K., Freise, K.J., Agarwal, S.K. et al. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis. AAPS J 18, 1192–1202 (2016). https://doi.org/10.1208/s12248-016-9927-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12248-016-9927-9

KEY WORDS

Search

Navigation