Pharmacokinetics and pharmacodynamics of carboplatin administered in a high-dose combination regimen with thiotepa, cyclophosphamide and peripheral stem cell support.

The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR

Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152)

Introduction Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib. Methods Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials. Results The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial. Discussion The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal. Conclusion Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels

Максим Рильський у світлі теорії та практики перекладу

У запропонованій статті проаналізовано актуальні проблеми теорії і практики перекладу у світлі завдань сучасного перекладознавства, зокрема, об’єктом аналізу є переклади М. Т. Рильським визначних творів зі світової літературної скарбниці.В данной статье анализируются актуальные проблемы теории и практики перевода в соответствии с задачами современного переводоведения, в частности, объектом анализа выступают переводы М. Т. Рыльским выдающихся произведений мировой литературы.In the offered article the issues of the day of theory and practice of translation are analysed in the light of tasks of modern translation theory in particular as an object of analysis translations of Maksym Rylski come forward prominent works from a world literary treasury

Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m2 in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m2 as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration–time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 ± 1.67 μM.h. In our previously performed study of 120 mg/m2 oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 ± 2.29 μM.h. After i.v. administration of paclitaxel the mean AUC was 15.92 ± 2.46 μM.h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel. © 2001 Cancer Research Campaign http://www.bjcancer.co