Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.

BACKGROUND: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. METHODS: A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. RESULTS: The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. CONCLUSIONS: The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.

Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data.

With efforts to reduce cytochrome P450-mediated clearance (CL) during the early stages of drug discovery, transporter-mediated CL mechanisms are becoming more prevalent. However, the prediction of plasma concentration-time profiles for such compounds using physiologically based pharmacokinetic (PBPK) modeling is far less established in comparison with that for compounds with passively mediated pharmacokinetics (PK). In this study, we have assessed the predictability of human PK for seven organic anion-transporting polypeptide (OATP) substrates (pravastatin, cerivastatin, bosentan, fluvastatin, rosuvastatin, valsartan, and repaglinide) for which clinical intravenous data were available. In vitro data generated from the sandwich culture human hepatocyte system were simultaneously fit to estimate parameters describing both uptake and biliary efflux. Use of scaled active uptake, passive distribution, and biliary efflux parameters as inputs into a PBPK model resulted in the overprediction of exposure for all seven drugs investigated, with the exception of pravastatin. Therefore, fitting of in vivo data for each individual drug in the dataset was performed to establish empirical scaling factors to accurately capture their plasma concentration-time profiles. Overall, active uptake and biliary efflux were under- and overpredicted, leading to average empirical scaling factors of 58 and 0.061, respectively; passive diffusion required no scaling factor. This study illustrates the mechanistic and model-driven application of in vitro uptake and efflux data for human PK prediction for OATP substrates. A particular advantage is the ability to capture the multiphasic plasma concentration-time profiles for such compounds using only preclinical data. A prediction strategy for novel OATP substrates is discussed.

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

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).

A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer.

BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC). Part A: 36 patients in 11 dose cohorts ranging from 2 to 24 mg twice daily (BID). RP2D was 16 mg BID. Part B: GC cohort, 29 patients, NSCLC cohort, 27 patients, all treated at the RP2D. RESULTS: LY2874455 was slowly absorbed and generally showed linear PK. The effective half-life was ∼12 h. PD properties of LY2874455 occurred at doses ≥10 mg by increases in serum phosphorus. Phosphate binders were administered to control serum phosphorus. LY2874455 was generally well tolerated; most toxicities were grade 1 or 2; most frequent were hyperphosphatemia, diarrhea, and stomatitis. EFFICACY: part A: 24 patients evaluable: 1 patient in the 14-mg BID cohort with GC had a partial response (PR); 14 patients had stable disease (SD); part B: NSCLC cohort: 11 of 12 evaluable patients had SD; GC cohort: 15 patients evaluable: 1 patient with PR; 12 patients with SD. CONCLUSIONS: LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107).

Early change in tumour size predicts overall survival in patients with first-line metastatic breast cancer.

PURPOSE: Clinical trials using change in tumour size (CTS) as a primary end-point benefit from earlier evaluation of treatment effect and increased study power over progression-free survival, ultimately resulting in more timely regulatory approvals for cancer patients. In this work, a modelling framework was established to further characterise the relationship between CTS and overall survival (OS) in first-line metastatic breast cancer (mBC). METHODS: Data from three randomised phase III trials designed to evaluate the clinical benefit of gemcitabine combination therapy in mBC patients were collated. Two drug-dependent models were developed to describe tumour growth dynamics: the first for paclitaxel/gemcitabine treatment and the second for docetaxel/gemcitabine treatment. A parametric survival model was used to characterise survival as a function of CTS and baseline patient demographics. RESULTS: While the paclitaxel/gemcitabine model incorporated tumour shrinkage by both paclitaxel and gemcitabine with resistance to paclitaxel, the docetaxel/gemcitabine model incorporated shrinkage and resistance to docetaxel alone. Predictors for OS were CTS at week 8, baseline tumour size and ECOG performance status. Model predictions reveal that for an asymptomatic mBC patient with a 6-cm tumour burden, first-line paclitaxel/gemcitabine treatment offers a median OS of 28.6 months, compared to 26.0 months for paclitaxel alone. CONCLUSION: A modelling framework was established, quantitatively describing the tumour growth inhibitory effects of various gemcitabine combotherapies and the effect of the resulting CTS on survival in first-line mBC. This work further supports the use of early CTS as a go/no-go decision point during phase II clinical evaluation of treatments for mBC.

Semi-mechanistic pharmacokinetic/pharmacodynamic modeling of the antitumor activity of LY2835219, a new cyclin-dependent kinase 4/6 inhibitor, in mice bearing human tumor xenografts.

PURPOSE: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. EXPERIMENTAL DESIGN: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. RESULTS: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. CONCLUSIONS: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies.