Kim Stuyckens

Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors

PURPOSE JNJ-42756493 is an orally administered pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. This first-in-human study evaluates the safety, pharmacokinetics, and pharmacodynamics and defines the recommended phase II dose (RP2D) of JNJ-42756493. PATIENTS AND METHODS Eligible patients with advanced solid tumors received escalating doses of JNJ-42756493 from 0.5 to 12 mg administered continuously daily or JNJ-42756493 10 or 12 mg administered intermittently (7 days on/7 days off). RESULTS Sixty-five patients were enrolled. The most common treatment-emergent adverse events included hyperphosphatemia (65%), asthenia (55%), dry mouth (45%), nail toxicity (35%), constipation (34%), decreased appetite (32%), and dysgeusia (31%). Twenty-seven patients (42%) experienced grade ≥ 3 treatment-emergent adverse events, and one dose-limiting toxicity of grade 3 ALT elevation was observed at 12 mg daily. Maximum-tolerated dose was not defined. Nine milligrams daily was considered as the initial RP2D; however, tolerability was improved with intermittent schedules, and 10 mg administered on a 7-days-on/7-days-off schedule was considered the final RP2D. Pharmacokinetics were linear, dose proportional, and predictable, with a half-life of 50 to 60 hours. Dose-dependent elevations in serum phosphate, a manifestation of pharmacodynamic effect, occurred in all patients starting at 4 mg daily. Among 23 response-evaluable patients with tumor FGFR pathway alterations, four confirmed responses and one unconfirmed partial response were observed in patients with glioblastoma and urothelial and endometrial cancer (all with FGFR2 or FGFR3 translocations); 16 patients had stable disease. CONCLUSION JNJ-42756493 administered at 10 mg on a 7-days-on/7-days-off schedule achieved exposures at which clinical responses were observed, demonstrated pharmacodynamic biomarker activity, and had a manageable safety profile.

Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic.

ObjectivesTo characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle).MethodsThe retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III trials. A total of 18 530 pharmacokinetic samples with valid concentration timepoints were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM® software. The full dataset was divided into an index dataset (model development) and a validation dataset. After validation both the index and validation datasets were combined and the final model was re-run on the full dataset.ResultsThe concentration-time data for paliperidone following intramuscular administration of its palmitate ester were best fitted to a one-compartment model with first-order elimination. The absorption component of the model allowed a fraction of the dose (f2) to enter relatively quickly into the central compartment via a zeroorder process. After a lag time, the remaining fraction then entered the systemic circulation via a first-order process. Interindividual variability (IIV) in clearance (CL), central volume of distribution (Vd) and the absorption rate constant (Ka were estimated at a 40%, 69% and 59% coefficient of variation (CV), respectively. The IIV on f2 for paliperidone absorption via the dual-input process was fitted through logit transformation, and its standard deviation (SD) was 0.064. Similarly, the interoccasion variability (IOV) on CL, Vd and f2 was 26% CV, 14% CV and 0.07 SD, respectively. An additive-error model with log-transformed data was used to describe the residual variability (RV), and its SD was 0.22. The final covariate model indicated that the following variables had a significant influence on ka: sex, age, injection volume (IVOL) and injection site (INJS). Similarly, the following variables had a significant influence on f2: sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CLCR), whereas Vd was related to BMI and sex.ConclusionsA dual-absorption pharmacokinetic model best described the complex pharmacokinetics of paliperidone after intramuscular administration of its palmitate ester. These results suggest that the pharmacokinetics of paliperidone palmitate are mostly influenced by BMI, CLCR, INJS, IVOL and NDLL.

Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients

ObjectiveTo characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis®) in cancer patients.MethodsA total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using good-ness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics.ResultsThe mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline Phosphatase, lactate dehydrogenase, total bilirubin, Creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated.ConclusionsThe integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m2 and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate–Treated Castration-Resistant Prostate Cancer Patients

Purpose: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). Experimental Design: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA-302 (chemotherapy naïve, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. Results: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naïve and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (≥30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ∼0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. Conclusions: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naïve patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. Clin Cancer Res; 21(14); 3170–7. ©2015 AACR.

The association between body composition and toxicities from the combination of Doxil and trabectedin in patients with advanced relapsed ovarian cancer.

Emerging research suggests that body composition can predict toxicity of certain chemotherapeutic agents. We used data from a clinical study to investigate associations between body composition and combined DOXIL (pegylated liposomal doxorubicin; PLD) and trabectedin (Yondelis) treatment, an effective treatment for ovarian cancer that shows high interpatient variation in toxicity profile. Patients (n = 74) participating in a phase III randomized trial of relapsed advanced ovarian cancer receiving PLD (30 mg/m(2)) and trabectedin (1.1 mg/m(2)) were included. Muscle tissue was measured by analysis of computerized tomography images, and an extrapolation of muscle and adipose tissue to lean body mass (LBM) and fat mass (FM) were employed. Toxicity profile after cycle 1 was used and graded according to the National Cancer Institute Common Toxicity Criteria (version 3). Patients presented with a wide range of body composition. In overweight and obese patients (body mass index (BMI) ≥ 25 kg/m(2), n = 48) toxicity was more prevalent in those with lower BMI (p = 0.028) and a lower FM (n = 43, p = 0.034). Although LBM alone was not predictive of toxicity, a lower FM/LBM ratio was the most powerful variable associated with toxicity (p = 0.006). A different pattern emerged among normal weight patients (n = 26) where toxicity was rare among patients with smaller BMI (<21 kg/m(2)). A clear association between both FM and LBM (primarily driven by FM) in explaining PLD plus trabectedin toxicity emerged, but only in individuals with excess body weight, with a lower ratio predicting higher exposure and risk for toxicity.