Drug-drug interactions with venetoclax in acute myeloid leukemia

Abstract

Background and Aims: Venetoclax is an important treatment option, especially in patients who are unfit for acute myeloid leukemia treatment. However, because venetoclax is metabolized by CYP3A4, it can lead to many drug-drug interactions (DDIs). DDIs may make a drug less effective, cause unexpected side effects, or increase the action of a particular drug. This study aims to examine venetoclax-related DDIs in this vulnerable patient population and to illuminate possible interventions for both patients and clinicians. Methods: This observational study was performed between November 2018-December 2022 in the Department of Hematology, Erciyes University Faculty of Medicine. The study involves 60 patients and uses Lexi-interact® to determine potential DDIs (pDDIs) in all patients and uses Lexi-interact® to take into account category D and category X interactions. Results: Forty-seven (78.4%) patients experienced drug interactions. The most common drug interactions were with azole antifungals, most commonly with posaconazole in category D (31.6%). Clarithromycin and diltiazem were found in more than 20% of patients. Carbamazepine, phenytoin and cladribine were found as contraindicated (category X) drugs. Conclusion: The study shows that at least 78.4% of the patients treated with venetoclax were at risk of DDIs. Dose reduction of venetoclax is necessary when used with azole antifungals. Due to the extremely high occurrence of DDIs, pharmacists have a significant role in drug interaction management in the multidisciplinary team.

Keywords

• Acute myeloid leukemia
• Interaction
• Posaconazole
• Venetoclax

References

1. Agarwal, S.K., DiNardo, C.D., Potluri, J., Dunbar, M., Kantarjian, H.M., Humerickhouse, R.A., . . . Salem, A.H. (2017). Manage-ment of venetoclax-posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clinical Ther-apeutics, 39 (2), 359-367. doi: 10.1016/j.clinthera.2017.01.003. google scholar
2. Agarwal, S.K., Tong, B., Bueno, O.F., Menon, R.M., & Salem A.H. (2018). Effect of azithromycin on venetoclax pharmacokinet-ics in healthy volunteers: implications for dosing venetoclax with p-gp inhibitors. Advances in Therapy, 35, 2015-2023. doi: 10.1007/s12325-018-0793-y google scholar
3. Bhatnagar, S., Mukherjee, D., Salem, A.H., Miles, D., Menon, R.M., & Gibbs, J.P. (2021). Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug-drug interaction predictions using a PBPK approach. Cancer Chemotherapy and Pharmacology, 87, 465-474. doi: 10.1007/s00280-020-04179-w google scholar
4. Chiney, M.S., Menon, R.M., Bueno, O.F., Tong, B., & Salem, A.H. (2018). Clinical evaluation of p-glycoprotein inhibition by vene-toclax: a drug interaction study with digoxin. Xenobiotica, 48(9), 904-910. doi: 10.1080/00498254.2017.1381779. google scholar
5. Delafuente, J.C. (2003). Understanding and preventing drug interactions in elderly patients. Critical Reviews in Oncology/Hematology, 48(2), 133-143. doi: 10.1016/j.critrevonc.2003.04.004. google scholar
6. European Medicines Agency EPAR Product information on veneto-clax vencylxto. (2002). Erişim adresi https://www.ema.europa.eu/ en/medicines/human/EPAR/venclyxto. google scholar
7. Freise, K.J., Shebley, M., & Salem, A.H. (2017). Quantitative predic-tion of the effect of CYP3A inhibitors and inducers on venetoclax pharmacokinetics using a physiologically based pharmacokinetic model. Journal of Clinical Pharmacology, 57 (6), 796-804. doi: 10.1002/jcph.858 google scholar
8. Juliusson, G., Antunovic, P., Derolf, A., Lehmann, S., Möllgârd, L., Stockelberg, D., Tidefelt, U., . . . Höglund, M. (2009). Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish acute leukemia registry. Blood, 113, 4179-4187. doi: 10.1182/blood-2008-07-172007. google scholar

9. Kadia, T.M., Reville, P.K., Borthakur, G., Yilmaz, M., Kornblau, S., Alvarado, Y., Dinardo, C.D., . . . Kantarjian, H.M. (2021). Vene-toclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial. The Lancet Haematol-ogy, 8 (8), 552-561. doi: 10.1016/S2352-3026(21)00192-7. google scholar
10. Ma, C. (2014). Role of pharmacists in optimizing the use of anticancer drugs in the clinical setting. Pharmacy Research and Practice, 3, 11-24. doi: 10.2147/IPRP.S40428 google scholar
11. Maertens, J.A., Girmenia, C., Brüggemann, R.J., Duarte, R.F., Kib-bler, C.C., Ljungman, P., Racil, Z., . . . Cordonnier, C. (2018). European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. Jour-nal of Antimicrobial Chemotherapy, 73 (12), 3221-3230. doi: 10.1093/jac/dky286. google scholar
12. Marion, D.W. Diaphragmatic pacing. In: UpToDate, (2022). Erişim adresi http://www.lexi.com. google scholar
13. Rocque, G.B., Williams, C.P., Halilova, K.I., Borate, U., Jackson, B.E., Van Laar, E.S., Pisu, M., . . . Safford MM. (2018). Improving shared decision-making in chronic lymphocytic leukemia through multidisciplinary education. Translational Behavioral Medicine, 8 (2), 175-182. doi: 10.1093/tbm/ibx034. google scholar
14. Rausch, C.R., DiNardo, C.D., Maiti, A., Jammal, N.J., Kadia, T.M., Marx, K.R., Borthakur, G., . . . Konopleva, M.Y. (2021). Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia. Cancer, 127 (14), 2489-2499. doi: 10.1002/cncr.33508. google scholar
15. Venclexta (venetoclax) [prescribing information]. (2019). Erişim adresi https://www.accessdata.fda.gov/drugsatfda_docs/ label/2016/208573s000lbl.pdf google scholar
16. Vervloessem, T., Ivanova, H., Luyten, T., Parys, JB., . . . Bultynck, G. (2017). The selective Bcl-2 inhibitor venetoclax, a BH3 mimetic, does not dysregulate intracellular Ca2+ signaling. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1864(6), 968976. doi: 10.1016/j.bbamcr.2016.11.024. google scholar