Comparison of In Vitro and In Vivo Percutaneous Absorption Across Human Skin Using BAY1003803 Formulated as Ointment and Cream.

Direct comparisons between skin absorption data and clinical pharmacokinetic data are rare. Here we use the lipophilic nonsteroidal selective glucocorticoid receptor agonist BAY1003803 to make such a comparison. The objective is to find the extent to which measurements of skin permeation in vitro can be used to predict the corresponding permeation in vivo for human pharmacokinetics of topically applied substances. BAY1003803 was prepared in various formulations: ointment, hydrophilic cream, lipophilic cream, and milk. Its ability to permeate healthy human skin was measured in vitro in static diffusion cells, and percutaneous absorption as well as dermal delivery was measured thereafter, for 2 selected formulations, in vivo in healthy volunteers. Absorption in vivo comparing ointment and lipophilic cream was correlated with expectation based on the dermal delivery obtained in vitro. A 2.17-fold higher systemic exposure to BAY1003803 was achieved by the ointment formulation. This is well in line with the predicted exposure difference of 2.74 based on the in vitro data. In conclusion, in vitro skin absorption studies using human skin are suitable for the prediction of systemic exposure and formulation effects in vivo; they can therefore be applied to guide the design of clinical investigations of dermatological preparations.

First clinical results of (D)-18F-Fluoromethyltyrosine (BAY 86-9596) PET/CT in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

UNLABELLED: (D)-(18)F-fluoromethyltyrosine (d-(18)F-FMT), or BAY 86-9596, is a novel (18)F-labeled tyrosine derivative rapidly transported by the l-amino acid transporter (LAT-1), with a faster blood pool clearance than the corresponding l-isomer. The aim of this study was to demonstrate the feasibility of tumor detection in patients with non-small cell lung cancer (NSCLC) or head and neck squamous cell cancer (HNSCC) compared with inflammatory and physiologic tissues in direct comparison to (18)F-FDG. METHODS: 18 patients with biopsy-proven NSCLC (n = 10) or HNSCC (n = 8) were included in this Institutional Review Board-approved, prospective multicenter study. All patients underwent (18)F-FDG PET/CT scans within 21 d before d-(18)F-FMT PET/CT. For all patients, safety and outcome data were assessed. RESULTS: No adverse reactions were observed related to d-(18)F-FMT. Fifty-two lesions were (18)F-FDG-positive, and 42 of those were malignant (34 histologically proven and 8 with clinical reference). Thirty-two of the 42 malignant lesions were also d-(18)F-FMT-positive, and 10 lesions had no tracer uptake above the level of the blood pool. Overall there were 34 true-positive, 8 true-negative, 10 false-negative, and only 2 false-positive lesions for d-(18)F-FMT, whereas (18)F-FDG was true-positive in 42 lesions, with 10 false-positive and only 2 false-negative, resulting in a lesion-based detection rate for d-(18)F-FMT and (18)F-FDG of 77% and 95%, respectively, with an accuracy of 78% for both tracers. A high d-(18)F-FMT tumor-to-blood pool ratio had a negative correlation with overall survival (P = 0.050), whereas the (18)F-FDG tumor-to-blood pool ratio did not correlate with overall survival. CONCLUSION: d-(18)F-FMT imaging in patients with NSCLC and HNSCC is safe and feasible. The presented preliminary results suggest a lower sensitivity but higher specificity for d-(18)F-FMT over (18)F-FDG, since there is no d-(18)F-FMT uptake in inflammation. This increased specificity may be particularly beneficial in areas with endemic granulomatous disease and may improve clinical management. Further clinical investigations are needed to determine its clinical value and relevance for the prediction of survival prognosis.

Pharmacokinetics of drospirenone and ethinylestradiol in Caucasian and Japanese women.

OBJECTIVE: To investigate the pharmacokinetics of drospirenone (DRSP) and ethinylestradiol (EE) in Caucasian and Japanese women. METHOD: Three open-label, non-randomised studies were performed to assess the pharmacokinetics following single doses of EE 0.02 mg/DRSP 3 mg or DRSP monotherapy (1, 3 or 6 mg) in Caucasian (Study 1) and Japanese (Study 2) women, and daily doses with EE 0.02 mg/DRSP 3 mg over 21 consecutive days in Caucasian and Japanese women (Study 3). RESULTS: In Studies 1 and 2, there was a linear dose-dependent increase in DRSP C(max) and systemic exposure across the range of doses used in both ethnic groups. The co- administration of EE had no relevant effect on the pharmacokinetic parameters of 3 mg DRSP. In Study 3, steady-state DRSP concentrations were achieved after about eight days of treatment in both ethnic groups with approximately a threefold accumulation. There was about a twofold EE accumulation over 21 days in both ethnic groups. There were no differences in DRSP or EE exposure at day 21 between ethnic groups; the ratio of the geometric means (Japanese/Caucasian) of the AUC(0-24h) were 1.05 (90% CI: 0.95-1.17) and 1.02 (90% CI: 0.76-1.38), respectively. CONCLUSION: Ethnic origin had no clinically relevant influence on the pharmacokinetics of DRSP and EE.

A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours.

PURPOSE: The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery. METHODS: Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design. RESULTS: Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria. CONCLUSIONS: There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.

Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery).

PURPOSE: The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI(trade mark)), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points. MATERIALS AND METHODS: Patients (n=40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6-7 patients should a dose-limiting toxicity occur. RESULTS: ZK 304709 was safely administered up to 360mg. However, above 90mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or pharmacodynamic end-points. CONCLUSIONS: Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early.

Biological response genes after single dose administration of interferon beta-1b to healthy male volunteers.

Treatment with interferon beta-1b (IFNB-1b) is clinically effective in multiple sclerosis patients. However, the mechanism of action is only partially understood, and validated biological response markers are lacking. We assessed IFNB-1b-induced transcriptional changes by microarray technology. Healthy male volunteers received 250 mug IFNB-1b or placebo in a double-blind, randomized controlled trial (n=5 per group). Most transcripts demonstrated peak levels after 6-12 h and returned to baseline after 48 h. We identified 227 differentially regulated genes including novel and previously described markers. This panel may become a valuable tool for development of new IFNB-1b formulations and assessment of clinical drug effects.