Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.
J Clin Pharmacol
; 60(7): 915-930, 2020 07.
Article
en En
| MEDLINE
| ID: mdl-32080863
ABSTRACT
Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Bencimidazoles
/
Quinasas Ciclina-Dependientes
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Inductores del Citocromo P-450 CYP3A
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Inhibidores del Citocromo P-450 CYP3A
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Aminopiridinas
Tipo de estudio:
Guideline
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
J Clin Pharmacol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos