Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling

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.

Keywords: CYP3A4; PBPK; abemaciclib; active metabolites; cyclin-dependent kinases 4 and 6; drug interaction.

Figure 1

A, Simulation strategy. B, Proposed disposition scheme for abemaciclib and active metabolites after a 200‐mg dose. *F_G was set to 1 for a 50‐mg dose of abemaciclib. ADME indicates absorption, distribution, metabolism, and excretion; CL, clearance; Fa, fraction absorbed; Fe, fraction eliminated; F_G, fraction escaping first‐pass metabolism in the gut; F_H, fraction escaping first‐pass metabolism in the liver; fm, fraction metabolized by CYP3A4; fu, fraction unbound; ka, absorption rate constant; pKa, acid dissociation constant; PopPK, population pharmacokinetics; Vd, volume of distribution.

Figure 2

Observed and predicted plasma concentrations for bemaciclib and active metabolites after a 50‐mg dose of abemaciclib alone (green solid squares), a 50‐mg dose of abemaciclib coadministered with 500 mg twice a day clarithromycin (purple solid squares), a 200‐mg dose of abemaciclib alone (blue solid circles), and a 200‐mg dose of abemaciclib coadministered with 600 mg daily rifampin (red solid circles). The solid symbols represent the observed mean concentrations, and the error bars represent the observed SDs. The solid black lines represent the predicted mean concentrations; the dotted gray lines represent the 5th and 95th percentiles.

Figure 3

Predicted vs observed (A) AUC ratios and (B) C_max ratios for abemaciclib, M2, M18, and M20 with rifampin and clarithromycin. Open symbols represent the ratios with clarithromycin and solid symbols the ratios with rifampin. Open squares represent abemaciclib + clarithromycin. Open circles represent M2 + clarithromycin. Open diamonds represent M20 + clarithromycin. Open triangles represent M18 + clarithromycin. Closed squares represent abemaciclib + rifampin. Closed circles represent M2 + rifampin. Closed diamonds represent M20 + rifampin. Open triangles represent M18 + rifampin. The solid black lines represent the lines of unity, the solid gray lines represent the 2‐fold limits, and the dotted lines represent the upper and lower limits defined by Guest and collaborators³⁷ using a Δ value of 1.3. AUC indicates area under the plasma concentration–time curve; C_max, peak plasma concentration.

Figure 4

Sensitivity analysis of the effect of CYP3A4 fm and Fg on the AUC ratio with clarithromycin. A, Effect of changes in fraction metabolized via CYP3A4 (fm) of abemaciclib and active metabolites on the individual species AUC ratio with clarithromycin. B, Effect of changes in fraction metabolized via CYP3A4 of abemaciclib and active metabolites on the potency‐adjusted unbound species AUC ratio with clarithromycin. C, Effect of Fugut on the AUC ratio with clarithromycin for abemaciclib alone (black dotted line) and unbound potency‐corrected AUC active species (gray solid line). D, Effect of Fg on the AUC ratio with clarithromycin for abemaciclib alone (black dotted line) and unbound potency corrected AUC active species (gray solid line). AUC indicates area under the plasma concentration–time curve; Fg, fraction escaping first‐pass metabolism in the gut; fm, fraction metabolized by CYP3A4; Fugut, unbound fraction of Fg.