{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T14:54:20Z","timestamp":1785596060946,"version":"3.56.0"},"reference-count":24,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Venetoclax is an approved, orally bioavailable, B\u2010cell lymphoma type\u00a02 (BCL\u20102) inhibitor that is primarily metabolized by cytochrome\u00a0P450\u00a03A (CYP3A). Polypharmacy is common in patients undergoing treatment for hematological malignancies such as acute myeloid leukemia or chronic lymphocytic leukemia, and although venetoclax exposure has been well characterized with 1 concomitant CYP3A inhibitor, complex drug\u2013drug interactions (DDIs) involving more than 1 inhibitor have not been systematically evaluated. Here, we aimed to describe the potential impact of multiple concomitant CYP3A inhibitors on venetoclax pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) and population PK modeling. The modeling approaches were informed by clinical data in the presence of single or multiple CYP3A inhibitors, and the effects of 1 or more inhibitors were systematically considered within these modeling frameworks. The PBPK modeling approach was independently validated against clinical data involving more than 1 CYP3A inhibitor along with CYP3A substrates other than venetoclax. Both approaches indicated that combining a strong CYP3A inhibitor with another competitive CYP3A inhibitor does not seem to result in any additional increase in venetoclax exposure, beyond what would be expected with a strong inhibitor alone. This suggests that the current dose reductions recommended for venetoclax would be appropriate even when 2 or more CYP3A inhibitors are taken concomitantly. However, the results indicate that the involvement of time\u2010dependent inhibition might lead to additional inhibitory effects over and above the effect of a single strong CYP3A inhibitor. Thus, the clinical management of such interactions must consider the underlying mechanism of the interactions.<\/jats:p>","DOI":"10.1002\/jcph.2140","type":"journal-article","created":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T07:08:02Z","timestamp":1661238482000},"page":"119-125","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Impact of Multiple Concomitant CYP3A Inhibitors on Venetoclax Pharmacokinetics: A PBPK and Population PK\u2010Informed Analysis"],"prefix":"10.1002","volume":"63","author":[{"given":"Dwaipayan","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna J.","family":"Brackman","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Suleiman","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuhong","family":"Zha","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev M.","family":"Menon","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9261-1583","authenticated-orcid":false,"given":"Ahmed Hamed","family":"Salem","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology AbbVie Inc.  North Chicago Illinois USA"},{"name":"Clinical Pharmacy Ain Shams University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"AbbVie Inc.VENCLEXTA (venetoclax) [package insert]. U.S. Food and Drug Administration website.https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/208573s026lbl.pdf. Revised October 2021. Accessed March 25 2022."},{"key":"e_1_2_10_3_1","unstructured":"Vencylxto (venetoclax)[Summary of Product Characteristics] North Chicago USA. AbbVie Inc.https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/venclyxto\u2010epar\u2010product\u2010information_en.pdf. Updated December 2016. 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