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-class, t...
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Dove Medical Press,
2019-02-01T00:00:00Z.
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| 001 | doaj_89d8c3d7c95e4600bcda76ac235acd0c | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Li Y |e author |
| 700 | 1 | 0 | |a Connarn JN |e author |
| 700 | 1 | 0 | |a Chen J |e author |
| 700 | 1 | 0 | |a Tong Z |e author |
| 700 | 1 | 0 | |a Palmisano M |e author |
| 700 | 1 | 0 | |a Zhou S |e author |
| 245 | 0 | 0 | |a Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment |
| 260 | |b Dove Medical Press, |c 2019-02-01T00:00:00Z. | ||
| 500 | |a 1179-1438 | ||
| 520 | |a 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 | ||
| 546 | |a EN | ||
| 690 | |a Enasidenib | ||
| 690 | |a modeling and simulation | ||
| 690 | |a CYP3A induction | ||
| 690 | |a 4β-hydroxycholesterol | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Clinical Pharmacology: Advances and Applications, Vol Volume 11, Pp 39-50 (2019) | |
| 787 | 0 | |n https://www.dovepress.com/modeling-and-simulation-of-the-endogenous-cyp3a-induction-marker-4beta-peer-reviewed-article-CPAA | |
| 787 | 0 | |n https://doaj.org/toc/1179-1438 | |
| 856 | 4 | 1 | |u https://doaj.org/article/89d8c3d7c95e4600bcda76ac235acd0c |z Connect to this object online. |