Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment .

Objective: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment.

Methods: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC.

Investigation of bioequivalence of a new fixed-dose combination of nifedipine and candesartan with the corresponding loose combination as well as the drug-drug interaction potential between both drugs under fasting conditions.

Objective: To determine the bioequivalence of a nifedipine and candesartan fixed-dose combination (FDC) with the corresponding loose combination, and to investigate the pharmacokinetic drug-drug interaction potential between both drugs.

Methods: 49 healthy, white, male subjects received: 60 mg nifedipine and 32 mg candesartan FDC, the loose combination of 60 mg nifedipine GITS and 32 mg candesartan, 60 mg nifedipine GITS alone, or 32 mg candesartan alone in a randomized, non-blinded, 4-period, 4-way crossover design with each dosing following overnight fasting. Treatment periods were separated by washout periods of ≥ 5 days.

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours.

Aim: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a phase I, dose-escalation trial.

Methods: Twenty-seven patients in four cohorts received docetaxel on day 1 (cohorts 1 and 4: 75 mg/m2; cohorts 2 and 3: 100 mg/m2) plus sorafenib on days 2-19 (cohorts 1 and 2: 200 mg twice-daily (bid); cohorts 3 and 4: 400 mg bid) in 21-day cycles.

Results: Most common adverse events (AEs) (grade 3-5) included neutropenia (89%), leucopaenia (81%), hand-foot skin reaction (30%) and fatigue (30%).

Phase I trial of sorafenib in combination with 5-fluorouracil/leucovorin in advanced solid tumors.

This dose escalation, uncontrolled phase I study evaluated the tolerability, pharmacokinetics (PK), and antitumor activity of oral sorafenib 100, 200, or 400 mg twice daily (bid, continuous regimen) in combination with 5-fluorouracil/leucovorin (5-FU/LCV, intravenous infusion or bolus) in patients with advanced, solid tumors. A total of 47 patients (median age 57 years; colon cancer, 55%; pancreatic cancer, 21%; prior systemic therapy, 96%) received treatment; 24 were included in the PK analyses, and 38 were evaluable for tumor response. Treatment-emergent adverse events were observed in 98% of patients (≥grade 3, 55%); the most frequently reported were fatigue (51%), stomatitis/pharyngitis (47%), and hand-foot skin reaction (45%).

Safety and pharmacokinetics of sorafenib combined with capecitabine in patients with advanced solid tumors: results of a phase 1 trial.

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated.

Workshop/conference report on EMA draft guideline on validation of bioanalytical methods.

This is a summary report of the workshop on the EMA Draft Guideline on Validation of Bioanalytical Methods held April 15-16th 2010 in Brussels (Belgium) and jointly organised by the European Bioanalysis Forum (EBF) and the European Federation for Pharmaceutical Sciences (EUFEPS). Aim of the workshop was to discuss the current scientific knowledge in the area of bioanalysis, the regulatory requirements with special focus on the new Draft Guideline and their subsequent implementation to the work in bioanalytical laboratories. Comments on the Draft Guideline were presented and discussed with representatives from regulatory authorities in Europe.

Pharmacokinetic results of a phase I trial of sorafenib in combination with dacarbazine in patients with advanced solid tumors.

Purpose: Sorafenib, a multikinase inhibitor of Raf and several growth factor receptors, is under investigation in combination with dacarbazine, a commonly used chemotherapeutic agent for the treatment of many cancers. The current phase I study investigates the effects of sorafenib on the pharmacokinetic (PK) profile of dacarbazine and its metabolite 5-amino-imidazole-4-carboxamide (AIC). (AIC is formed in amounts equimolar to the active alkylating moiety, methane diazohydroxide, which is undetectable by known validated assays.

Phase I evaluation of telatinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in combination with irinotecan and capecitabine in patients with advanced solid tumors.

Purpose: We studied the safety and tolerability of telatinib, an orally available, small-molecule tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR-2/VEGFR-3), platelet-derived growth factor receptor beta, and c-Kit in combination with capecitabine and irinotecan.

Experimental Design: Telatinib twice daily continuously, irinotecan once every 3 weeks, and capecitabine oral twice daily on day 1 to 14 were administered in cycles of 21 days in escalating doses in successive cohorts. Toxicity was evaluated to conform to the Common Terminology Criteria for Adverse Events version 3.

Comparison of two marketed nifedipine modified-release formulations: an exploratory clinical food interaction study.

Objective: The objective of this study was to compare the in vitro and in vivo characteristics of 2 nifedipine modified-release tablet formulations for once-daily dosing marketed in the European community, which were expected to be bioequivalent.

Methods: In vitro dissolution was tested at different pH values prior to the clinical part of the study. Either 1 tablet of a test formulation or of the reference formulation, both containing 30 mg nifedipine, were administered to healthy white male volunteers immediately after a high-fat breakfast in a randomized, open-label, 2-period crossover design.

Pupillography as a sensitive, noninvasive biomarker in healthy volunteers: first-in-man study of BAY 63-9044, a new 5-HT1A-receptor agonist with dopamine agonistic properties.

Objective: BAY 63-9044 is a new full 5-HT(1A)-agonist with functional dopamine agonist properties aimed for the treatment of Parkinson's disease. This first-in-man study investigated the pharmacodynamics, safety and tolerability as well as the pharmacokinetics of BAY 63-9044 in a randomized, single-blind, placebo-controlled group-comparison dose escalation study.

Methods: 45 healthy men received BAY 63-9044 as an oral solution in single doses of 0.

Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.

Background: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin.

Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.

Purpose: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors.

Patients And Methods: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule.

Simultaneous determination of capecitabine and its metabolite 5-fluorouracil by column switching and liquid chromatographic/tandem mass spectrometry.

A liquid chromatographic/tandem mass spectrometric method was developed and validated for the quantitation of capecitabine and its metabolite 5-fluorouracil in human plasma. The simultaneous determination of both analytes was achieved by a column switching method using a trapping column and two analytical columns with different stationary phases. Isocratic elution was used for the separation of capecitabine on a C18 column whereas 5-fluorouracil was separated using gradient elution on an non-polar carbon phase.

Formulation-dependent food effects demonstrated for nifedipine modified-release preparations marketed in the European Union.

The objective of this study was a comparative investigation of the influence of concomitant food intake on the bioavailability of two nifedipine-containing controlled-release formulations. Adalat OROS and CORAL were compared in a randomised, non-blind, four-way crossover design in 24 healthy, male subjects after single dose administration following a high fat American breakfast or an overnight fast of 12 h, respectively. Plasma samples were withdrawn until 48 h post-dose.