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

Suresh K. Agarwal, Ahmed Hamed Salem, Alexey V. Danilov, Beibei Hu, Soham D Puvvada, Martin Gutierrez, David Chien, Lionel D. Lewis, Shekman L. Wong

Research output: Contribution to journalArticle

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Abstract

Aims: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results: Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) 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. Conclusions: Coadministration 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.

Original languageEnglish (US)
Pages (from-to)846-854
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Volume83
Issue number4
DOIs
StatePublished - 2017

Fingerprint

Ketoconazole
Non-Hodgkin's Lymphoma
Pharmacokinetics
Cytochrome P-450 CYP3A
Architectural Accessibility
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Cytochrome P-450 CYP3A Inhibitors
Confidence Intervals
B-Cell Chronic Lymphocytic Leukemia
Area Under Curve
Safety

Keywords

  • BCL-2
  • drug–drug interaction
  • ketoconazole
  • pharmacokinetics
  • venetoclax

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. / Agarwal, Suresh K.; Salem, Ahmed Hamed; Danilov, Alexey V.; Hu, Beibei; Puvvada, Soham D; Gutierrez, Martin; Chien, David; Lewis, Lionel D.; Wong, Shekman L.

In: British Journal of Clinical Pharmacology, Vol. 83, No. 4, 2017, p. 846-854.

Research output: Contribution to journalArticle

Agarwal, Suresh K. ; Salem, Ahmed Hamed ; Danilov, Alexey V. ; Hu, Beibei ; Puvvada, Soham D ; Gutierrez, Martin ; Chien, David ; Lewis, Lionel D. ; Wong, Shekman L. / Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma. In: British Journal of Clinical Pharmacology. 2017 ; Vol. 83, No. 4. pp. 846-854.
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abstract = "Aims: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results: Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) 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. Conclusions: Coadministration 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.",
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T1 - Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma

AU - Agarwal, Suresh K.

AU - Salem, Ahmed Hamed

AU - Danilov, Alexey V.

AU - Hu, Beibei

AU - Puvvada, Soham D

AU - Gutierrez, Martin

AU - Chien, David

AU - Lewis, Lionel D.

AU - Wong, Shekman L.

PY - 2017

Y1 - 2017

N2 - Aims: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results: Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) 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. Conclusions: Coadministration 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.

AB - Aims: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. Methods: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5–11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. Results: Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax) 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. Conclusions: Coadministration 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.

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