Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: a placebo-controlled, exploratory study.

PURPOSE: To evaluate the activity of JNJ-26489112 in patients with photosensitive epilepsy and determine the doses that result in reduction or complete suppression of the intermittent photic stimulation (IPS) induced photoparoxysmal-EEG response (PPR). METHODS: In this multicenter, single-blind, within subject, placebo-controlled, sequential dose, exploratory study, 12 adult patients (3 men; 9 women) with idiopathic photosensitive epilepsy, with and without concomitant antiepileptic drug (AED) therapy, underwent standardized IPS under three eye conditions (open, during closure, and closed) for up to 12h after receiving a single oral dose of placebo on day 1, JNJ-26489112 on day 2, and a second dose of placebo on day 3. Based on review of the blinded EEG data, the standardized photosensitive range (SPR) (i.e., upper and lower frequencies of the IPS-induced PPR), was calculated for each eye condition at each time point. A positive response was defined as a reduction of the SPR in ≥3 out of 4 consecutive time points in ≥1 eye condition on either day 2 or 3 compared with baseline (day 1) while complete suppression was defined as disappearance of an IPS-induced PPR (i.e., SPR=0). For the first four patients (Cohort 1), JNJ-26489112 dose was 1000 mg, and the dose was escalated to a maximum of 3000 mg in subsequent cohorts. Blood and plasma samples were collected for pharmacokinetic evaluations along with measurements of concurrent AED concentrations. Safety was also assessed. RESULTS: The majority of patients showed a positive response on day 2 following JNJ-26489112 administration: 3/4 patients (1000 mg dose), 3/4 patients (2000 mg dose), and 2/3 patients (3000 mg). There was an apparent dose-dependent effect observed in patients who exhibited complete suppression of the SPR: 0/4 patients (1000 mg dose), 1/4 patient (2000 mg dose), and 2/3 patients (3000 mg dose). The median tmax of JNJ-26489112 (range: 3.73-5.04 h) in plasma was similar across all 3 dose groups and plasma exposure of JNJ-26489112 increased proportionally with dose; approximate mean Cmax of 16, 28, and 42 µg/mL for the 1000-, 2000-, and 3000 mg cohorts, respectively. Concentrations of other AEDs did not appear to be affected by co-administration of JNJ-26489112. JNJ-26489112 was generally well-tolerated with the most frequent adverse events (>10%) reported being mild headache, dizziness, and nausea. CONCLUSION: Single oral doses of JNJ-26489112 were well-tolerated and the pharmacodynamic effects appeared to be dose-related in patients with idiopathic, photosensitive epilepsy.

Tolerability of fosaprepitant and bioequivalency to aprepitant in healthy subjects.

Fosaprepitant is an intravenous formulation of aprepitant, an oral NK1 antagonist used to prevent chemotherapy-induced nausea and vomiting. This randomized study was designed to evaluate fosaprepitant in polysorbate 80 vehicle for tolerability and bioequivalency to aprepitant. Tolerability was assessed by physical and laboratory examinations and adverse events. Plasma collected for 72 hours was assayed for aprepitant and fosaprepitant. Analysis of variance models were applied to natural log-transformed aprepitant area under the curve (AUC) data. Fosaprepitant up to 150 mg (1 mg/mL) was generally well tolerated. Fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg; the 90% confidence interval for the geometric mean ratio of aprepitant AUC for fosaprepitant 115 mg/aprepitant 125 mg fell within prespecified equivalence bounds of 0.80 to 1.25.

Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients.

PURPOSE: Aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine. PATIENTS AND METHODS: Fourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25 mg/m2 weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1: 125 mg aprepitant, 12 mg dexamethasone, and 32 mg ondansetron; on days 2 and 3: 80 mg aprepitant and 8 mg dexamethasone and on day 4: 8 mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96 h. RESULTS: Two patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively. CONCLUSION: As the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.

Image-derived input function for [11C]flumazenil kinetic analysis in human brain.

PURPOSE: We describe a method for analysis of [11C]flumazenil data using an input curve directly derived from the positron emission tomography (PET) images. PROCEDURE: The shape of the tracer plasma curve was obtained from the product of the intact flumazenil fraction in plasma in six arterial samples and the internal carotid artery time-activity curve (TAC). The resulting curve was calibrated using the [11C]flumazenil concentration in three of the six samples. The curve peak was recovered by adding an exponential function to the scaled curve whose parameters were estimated from simultaneous fittings of several tissue TACs assuming that all regions share the same input. RESULTS: Good agreement was found between the image-derived and the experimental plasma curves in six subjects. Distribution volumes were highly correlated with linear regression slope and intercept values between [0.94, 1.03] and [-0.10, 0.16], respectively. CONCLUSION: The proposed method is suitable for benzodiazepine receptor quantification requiring only a few blood samples.