Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer.

PURPOSE: Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin. EXPERIMENTAL DESIGN: Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m(2) and cisplatin doses were either 60 or 75 mg/m(2). Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers. RESULTS: Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (> or =250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation. CONCLUSIONS: Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.

Prevalence of medicinal drugs in suspected impaired drivers and a comparison with the use in the general Dutch population.

The aim of this study was to investigate the prevalence of psychotropic medicines in drivers suspected of driving under the influence of medicinal and illicit drugs in The Netherlands and to compare the prevalence of selected impairing medicines with the use of these medicines in the general Dutch population. In total, 3038 blood samples of suspected impaired drivers in The Netherlands have been analyzed for the presence of medicinal and illicit drugs between January 2009 and December 2012. In 94% (2842/3038) of the cases medicinal and/or illicit drugs were detected. Medicinal drugs were found in 33% of the blood samples, with the highest prevalence for anxiolytics. In 86% of the cases illicit drug-positive results were obtained, with the highest prevalence for cannabis. At least in 56% of the blood samples poly-drug use was determined, including medicinal and/or illicit drugs. The highest prevalence of poly-medicine use was found for combinations including anxiolytic and hypnotic drugs. In general, the prevalence of driving impairing medicines in suspected impaired drivers is higher than the use of these medicines in the general Dutch population, due to a positive selection bias in the first population. Differences between both populations may be explained by the used methodological approach (e.g., classification criteria of analytical findings, sample selection bias) and abuse of certain medicinal drugs (e.g., diazepam). Negative effects of medicinal drugs on driving performance determine largely the prevalence in the population of suspected impaired drivers. The degree of impairment depends on different factors, including pharmacokinetic properties of the drug and pharmacodynamic aspects. More research is needed to study the prevalence of all prescribed driving impairing medicines and to investigate if providing additional information to medicinal drug users on driving impairing medicines would lower the prevalence of medicinal drug positive drivers.