A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours.

BACKGROUND: The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours. METHODS: Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42 mg m(-2) with 75 mg m(-2) docetaxel, then from 30 to 35 mg m(-2) with 100 mg m(-2) docetaxel. Recommended phase II dose cohorts were expanded. RESULTS: Fifty-eight patients were treated. Recommended phase II doses were 35 mg m(-2) ombrabulin with 75 mg m(-2) docetaxel (35/75 mg m(-2); 13 patients) and 30 mg m(-2) ombrabulin with 100 mg m(-2) docetaxel (30/100 mg m(-2); 16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients; 42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/100). Toxicities were consistent with each agent; mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mg m(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mg m(-2) ombrabulin), eight lasting >3 months. CONCLUSIONS: Sequential administration of ombrabulin with 75 or 100 mg m(-2) docetaxel every 3 weeks is feasible.

Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization.

BACKGROUND: Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non-small-cell lung cancer with high baseline alpha1-acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit from dose intensification, we initiated a series of clinical trial simulations. METHODS: Pharmacokinetic and pharmacodynamic models for time to progression, death, and drop-out were developed and validated with the use of phase II data from 151 patients with non-small-cell lung cancer. The simulation process, in which these models were combined with a previously reported model for safety, was evaluated by comparison of the original phase II data with the predicted results. Simulations were undertaken for the evaluation of whether a trial (phase III) of 125 mg/m2 of docetaxel versus 100 mg/m2 of docetaxel in patients with high alpha1-acid glycoprotein levels would show improved survival. RESULTS: The hazard models showed that lower alpha1-acid glycoprotein levels, fewer number of organs involved, and higher docetaxel cumulative area under plasma concentration-time curve were significantly associated with enhanced time to progression and time to death. The simulation process produced data patterns similar to actual patterns. In the simulated phase III trial, although median survival was slightly longer in the 125 mg/m2 docetaxel group than in the 100 mg/m2 group (5.49 months versus 5.31 months, respectively), the difference was significant in only 6 of 100 trials. CONCLUSIONS: The low power to detect a difference due to dose intensification was the basis for the decision not to perform such a trial. The simulation exercise yielded valuable insight into how pharmacokinetic- and pharmacodynamic-based simulation of clinical trials may have an impact on decision making in drug development.

Physiology of chemotherapy-induced emesis and antiemetic therapy. Predictive models for evaluation of new compounds.

The physiology of emesis has been studied for several hundred years, focusing on the different centres involved and the mechanics of expulsion. The vomiting centre receives inputs from various emetic detectors such as the gut, the vestibular labyrinths and the chemoreceptor trigger zone. Emesis is a common disabling effect in motion sickness, postoperative conditions and in radio- and chemotherapy. Our current understanding of the mechanisms has been provided mainly by the recent introduction of serotonin 5-HT3 receptor antagonists into therapeutic use. Nevertheless, despite the considerable advances made in the understanding of the different pathways involved in emesis, there are number of areas that still require experimental investigation. Different animal and human models are available to study the physiology of emesis and to evaluate the antiemetic activity of new compounds, but they need to be predictors of clinical situations.

The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials.

BACKGROUND: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. OBJECTIVES: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. PATIENTS AND METHODS: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance<30 mL min(-1)). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. RESULTS: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h(-1), 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux--rapid onset of action and long-acting anticoagulant effect--offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.

Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel.

The population approach has been implemented prospectively in the clinical development of docetaxel (Taxotere). Overall 640 patients were evaluable for the population PK/PD analysis. The PK analysis evidenced significant covariates explaining the inter-patient variability of docetaxel clearance and the PK/PD analysis demonstrated that the variability in clearance was a significant predictor of several safety endpoints. In patients with clinical chemistry suggestive of mild to moderate liver function impairment (SGOT and/or SGPT > 1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN), total body clearance was lowered by an average of 27%. Specific safety analyses demonstrated that these patients are at a significantly higher risk than others for the development of severe docetaxel-induced side effects. Population PK/PD data were fully integrated into the regulatory dossier and in the labeling of docetaxel worldwide. Population PK/PD models are being used to elaborate a simulation model to predict the survival of patients with non-small cell lung cancer treated with docetaxel.

A population pharmacokinetic-pharmacodynamic analysis of repeated measures time-to-event pharmacodynamic responses: the antiemetic effect of ondansetron.

This paper presents and illustrates methodology for specifying, estimating, and evaluating a predictive model for repeated measures time-to-event responses. The illustrative example specifies a model of the antiemetic effect vs. concentration relationship for the 5-HT3 antagonist ondansetron in the human ipecac model for emesis. A key part of this model is a time-dependent log hazard function for emesis that is increased by ipecac administration and decreased by ondansetron concentration. The model is fit using an approximate maximum likelihood method. The data consist of the time free of emeses and, for those individuals with emetic episodes, the time(s) of the episode(s). Model evaluation is accomplished using residual plots adapted to time-to-event data and a "posterior predictive check" wherein observed data statistics are compared to those obtained from data simulated from the fitted model. The ondansetron concentration required to obtain a 50% reduction in the hazard of emesis is estimated to be 1.4 +/- 0.2 ng/ml, and the rate constant for elimination of ipecac-induced hazard is 1.5 +/- 0.2 hr-1.