A Population Pharmacokinetic and Pharmacodynamic Analysis of Abemaciclib in a Phase I Clinical Trial in Cancer Patients

Sonya C Tate, Amanda K Sykes, Palaniappan Kulanthaivel, Edward M Chan, P Kellie Turner, Damien M Cronier, Sonya C Tate, Amanda K Sykes, Palaniappan Kulanthaivel, Edward M Chan, P Kellie Turner, Damien M Cronier

Abstract

Background and objectives: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels.

Methods: A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib. Data were analyzed by popPK modeling, and patient demographics contributing to pharmacokinetic variability were explored. Target engagement was evaluated by combining the clinical popPK model with a previously developed pre-clinical pharmacokinetic/pharmacodynamic model.

Results: The pharmacokinetic analysis incorporated 4012 plasma concentrations from 224 patients treated with abemaciclib at doses ranging from 50 to 225 mg every 24 h and 75 to 275 mg every 12 h. A linear one-compartment model with time- and dose-dependent relative bioavailability (F rel) adequately described the pharmacokinetics of abemaciclib. Serum albumin and alkaline phosphatase were the only significant covariates identified in the model, the inclusion of which reduced inter-individual variability in F rel by 10.3 percentage points. By combining the clinical popPK model with the previously developed pre-clinical pharmacokinetic/pharmacodynamic model, the extent of target engagement in skin in cancer patients was successfully predicted.

Conclusion: The proportion of abemaciclib pharmacokinetic variability that can be attributed to patient demographics is negligible, and as such there are currently no dose adjustments recommended for adult patients of different sex, age, or body weight.

Trial registration: NCT01394016 (ClinicalTrials.gov).

Conflict of interest statement

Funding

This study was sponsored by Eli Lilly and Company.

Conflict of interest

SCT, AKS, PK, EMC, PKT, and DMC are employees of Eli Lilly and Company. AKS, PK, EMC, PKT, and DMC own stock in Eli Lilly and Company.

Ethical approval

The clinical trial was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation. The study protocol was approved by all institutional review boards.

Informed consent

Written informed consent was collected from all patients before conducting study procedures.

Figures

Fig. 1
Fig. 1
Visual predictive checks of the clinical abemaciclib population pharmacokinetic model after every 12 h dosing at 150 mg (a) or 200 mg (b). The circles denote observed abemaciclib plasma concentration data, and the solid and dotted lines represent the median and the 5th and 95th percentiles of 1000 individual model simulations, respectively
Fig. 2
Fig. 2
The covariate relationships retained in the final population pharmacokinetic model for serum albumin (a) and alkaline phosphatase (b) versus adjusted post hoc estimates of CL/F (i.e., CL/F × 1/Frel). The circles denote observed patient covariates and model-predicted parameter estimates, and the solid line denotes the estimated covariate–parameter relationship. CL/F apparent clearance, Frel relative bioavailability
Fig. 3
Fig. 3
Simulated change in p-Rb expression from baseline using the abemaciclib clinical population pharmacokinetic model in combination with the semi-mechanistic pre-clinical pharmacodynamic model. Curtailed axes are used in the main plot to aid interpretation of the dose-response curve; the complete plot with all observed data is provided in the inset pane. The boxplots represent the observed change in p-Rb expression in epidermal keratinocytes at day 15 (pre-dose) compared to baseline for the most populated daily doses (150 mg [combined as 75 mg q12h and 150 mg q24h], 300 mg [150 mg q12h], and 400 mg [200 mg q12h]), where the box is constructed using the median, 25th, and 75th percentiles, and the whiskers extend to the most extreme datapoints not considered outliers; boxplot outliers are represented by red crosses. For the less populated doses (50, 100, and 225 mg q24h, and 100 and 275 mg q12h), the observed change in p-Rb expression at day 15 (pre-dose) for individual patients is represented by red circles. The solid and dotted lines represent the median, and the 5th and 95th percentiles of 1000 individual model simulations, respectively. CI confidence interval, p-Rb phosphorylated retinoblastoma protein, q12h every 12 h, q24h every 24 h

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