Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment

Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment

Yan Li,1 Jamie N Connarn,1 Jian Chen,2 Zeen Tong,2 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development, Celgene Corporation, Summit, NJ, USA Background: Enasidenib (IDHIFA®, AG-221) is a first-in-...

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Autores principales: Li Y, Connarn JN, Chen J, Tong Z, Palmisano M, Zhou S
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2019
Materias:
Enasidenib
modeling and simulation
CYP3A induction
4β-hydroxycholesterol
Therapeutics. Pharmacology
RM1-950
Acceso en línea:https://doaj.org/article/89d8c3d7c95e4600bcda76ac235acd0c
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spelling oai:doaj.org-article:89d8c3d7c95e4600bcda76ac235acd0c2021-12-02T01:58:14ZModeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment1179-1438https://doaj.org/article/89d8c3d7c95e4600bcda76ac235acd0c2019-02-01T00:00:00Zhttps://www.dovepress.com/modeling-and-simulation-of-the-endogenous-cyp3a-induction-marker-4beta-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438Yan Li,1 Jamie N Connarn,1 Jian Chen,2 Zeen Tong,2 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development, Celgene Corporation, Summit, NJ, USA Background: Enasidenib (IDHIFA®, AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation. Methods: Blood samples for PK and PD assessment were collected. A semi-mechanistic non-linear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity. Results: The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (Emax=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC50 =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC50 value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation. Conclusion: CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway. Keywords: enasidenib, modeling and simulation, CYP3A induction, 4β-hydroxycholesterolLi YConnarn JNChen JTong ZPalmisano MZhou SDove Medical PressarticleEnasidenibmodeling and simulationCYP3A induction4β-hydroxycholesterolTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 11, Pp 39-50 (2019)
institution DOAJ
collection DOAJ
language EN
topic Enasidenib
modeling and simulation
CYP3A induction
4β-hydroxycholesterol
Therapeutics. Pharmacology
RM1-950
spellingShingle Enasidenib
modeling and simulation
CYP3A induction
4β-hydroxycholesterol
Therapeutics. Pharmacology
RM1-950
Li Y
Connarn JN
Chen J
Tong Z
Palmisano M
Zhou S
Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
description Yan Li,1 Jamie N Connarn,1 Jian Chen,2 Zeen Tong,2 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development, Celgene Corporation, Summit, NJ, USA Background: Enasidenib (IDHIFA®, AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation. Methods: Blood samples for PK and PD assessment were collected. A semi-mechanistic non-linear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity. Results: The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (Emax=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC50 =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC50 value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation. Conclusion: CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway. Keywords: enasidenib, modeling and simulation, CYP3A induction, 4β-hydroxycholesterol
format article
author Li Y
Connarn JN
Chen J
Tong Z
Palmisano M
Zhou S
author_facet Li Y
Connarn JN
Chen J
Tong Z
Palmisano M
Zhou S
author_sort Li Y
title Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
title_short Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
title_full Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
title_fullStr Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
title_full_unstemmed Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment
title_sort modeling and simulation of the endogenous cyp3a induction marker 4β-hydroxycholesterol during enasidenib treatment
publisher Dove Medical Press
publishDate 2019
url https://doaj.org/article/89d8c3d7c95e4600bcda76ac235acd0c
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