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

Abstract

Background and ObjectivesAbemaciclib, 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.MethodsA 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.ResultsThe 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.ConclusionThe 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 registrationNCT01394016 (ClinicalTrials.gov).Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0559-8) contains supplementary material, which is available to authorized users.

Drug-drug interactions in breast cancer patients treated with CDK4/6 inhibitors

“…Selection of these dose levels was supported by the clinical dose-response relationship for target engagement and the correlation of p-Rb suppression to clinical activity. Drug doses can be scaled up or down depending on clinical evidence of efficacy and/or toxicity [16]. Data from a phase I trial demonstrated that abemaciclib dose adjustments are not required for adult patients of different sex, age, or body weight [16].…”

“…Drug doses can be scaled up or down depending on clinical evidence of efficacy and/or toxicity [16]. Data from a phase I trial demonstrated that abemaciclib dose adjustments are not required for adult patients of different sex, age, or body weight [16]. The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% and the median T max ranges from 4 to 6 h ( Table 1).…”

CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions

“…Abemaciclib is characterized by an extensive variability in cancer patients, independently from demographics (sex, age, body weight). Data from healthy subjects show that increasing the dose and/or duration of abemaciclib treatment results in a reduction in the fraction of dose absorbed [ 57 ]. Food intake slightly modifies abemaciclib PK profile without relevant clinical consequences; although high fat and high caloric meal increases AUC by 9% and C max by 26%.…”

“…Food intake slightly modifies abemaciclib PK profile without relevant clinical consequences; although high fat and high caloric meal increases AUC by 9% and C max by 26%. Overall PK variability of abemaciclib is not meaningfully influenced by food-effect [ 16 , 57 ].…”

“…Ribociclib is characterized by the longest half-life among CDKis and its toxicity profile prevents a continuous schedule [ 29 , 58 ] as also for the case of palbociclib [ 45 ]. Abemaciclib can be instead administered continuously [ 2 , 15 , 57 , 59 ].…”