A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979)

People want user interfaces to services that are functional and well suited to the device they choose for access. To provide this, services must be able to offer device specific user interfaces for the wide range of devices available today. We propose to combine the two dominant approaches to platform independence, "Write Once, Run Every-where\u99" and "different version for each device", to create multiple device specific user interfaces for mobile services. This gives possibilities to minimize the work with development and maintenance, while still keeping the control of how the user interface is presented to the end user. A calendar service has been implemented with user interfaces for Java Swing, HTML and std I/O

A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979)

AIMS: To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl. METHODS: The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg x m(-2) or 225 mg x m(-2)) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1. RESULTS: The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor ELTM impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 microg x l(-1) x h to 19115 microg x l(-1) x h following paclitaxel 175 mg x m(-2)) when zosuquidar Cmax was greater than 350 microg x l(-1). This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 microg x l(-1)). A standard dose of 175 mg x m(-2) of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition. CONCLUSIONS: This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 microg x l(-1)) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials

Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab

Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. FWN – Publicaties zonder aanstelling Universiteit Leide