An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib

BACKGROUND: Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400 mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation. PATIENTS AND METHODS: Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers. RESULTS: Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65 % of patients in the randomized expansion phase eventually required dose reduction to 300 mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts. CONCLUSIONS: The recommended monotherapy dose of olaparib tablet for Phase III trials was 300 mg twice daily, simplifying drug administration from 16 capsules to four tablets per day. CLINICAL TRIAL NUMBER: NCT00777582 (ClinicalTrials.gov

First results of the FP7 SOAP Project

* About the project * Highlights: Gold OA journals today * Results from the large-scale survey of researcher

Open Access Publishing - Models and Attributes

The SOAP (Study of Open Access Publishing) project has compiled data on the present offer for open access publishing in online peer-reviewed journals. Starting from the Directory of Open Access Journals, several sources of data are considered, including inspection of journal web site and direct inquiries within the publishing industry. Several results are derived and discussed, together with their correlations: the number of open access journals and articles; their subject area; the starting date of open access journals; the size and business models of open access publishers; the licensing models; the presence of an impact factor; the uptake of hybrid open access. In addition, a number of qualitative features of open access publishing, relevant to understand the present landscape, are described

The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib.

PURPOSE: We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, multicenter studies. METHODS: In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (n = 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (n = 18), moderate (n = 16), or severe (n = 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days. RESULTS: In Study 1, the geometric mean area under the plasma concentration-time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts. CONCLUSIONS: We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification