Gadobenate dimeglumine is a capable diagnostic agent for MRI of the breast. Although preliminary, our results suggest that 0.1 mmol/kg of gadobenate dimeglumine may offer advantages over doses of 0.05 and 0.2 mmol/kg of gadobenate dimeglumine and 0.1 mmol/kg of gadopentetate dimeglumine for breast lesion detection and characterization.

BackgroundBilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries.ObjectiveThis study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects. The need for a dose adjustment in patients with renal insufficiency was assessed by comparing the exposure to bilastine in these subjects with the estimated exposure of a dose corresponding to the safety margin.MethodsThe study was an open-label, single-dose, parallel-group study of the pharmacokinetics and safety of a single dose of bilastine. The study was conducted as an in-patient setting at a clinical pharmacology facility. A total of 24 male or female subjects aged 18–80 years were to be enrolled in four groups of six subjects each. The groups were as follows: (1) healthy [glomerular filtration rate (GFR) >80 mL/min/1.73 m2]; (2) mild renal insufficiency (GFR 50–80 mL/min/1.73 m2); (3) moderate renal insufficiency (GFR 30–50 mL/min/1.73 m2); and (4) severe renal insufficiency (GFR ≤30 mL/min/1.73 m2). A single 20 mg bilastine tablet was administered in a fasted state. Blood and urine samples were collected from pre-dose up to 72 h post-dose for bilastine pharmacokinetic analysis. Pharmacokinetic results were summarized using appropriate descriptive statistics.ResultsThere was a clear trend of increasing area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) through the groups 1–4. The mean AUC from time zero to infinity (AUC∞) ranged from 737.4 to 1708.5 ng·h/mL in healthy subjects and severely impaired subjects, respectively. No significant differences among groups in median time to reach Cmax (tmax) or in the mean terminal disposition rate constants for bilastine were found. Renal and plasma clearance paralleled GFR. In all groups of renally impaired subjects the corresponding 90 % confidence interval of both AUC∞ and AUC from time zero to time of last measurable plasma concentration (AUClast) were not within the 0.8–1.25 interval, indicating that bioequivalence between groups could not be demonstrated. The majority of bilastine was excreted within the first 12 h, and elimination was essentially complete by 72 h.ConclusionAn oral dose of bilastine (20 mg) was well-tolerated in renal insufficiency, despite the increase in exposure. The oral plasma clearance to renal clearance ratio [(CLP/F)/CLR] was approximately equal in the different groups, suggesting that renal excretion was the main elimination route for bilastine, and no alternative elimination routes were used even in severe renal insufficiency. Although exposure to bilastine was higher in renally impaired subjects, it remained well with...

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Seventy-four patients with one to eight proven intraaxial metastatic lesions to the brain received a total gadobenate dimeglumine dose of 0.3 mmol/kg of body weight, administered as three sequential bolus injections of 0.1 mmol/ kg, at 10-minute intervals over a 20-minute period. Quantitative and qualitative assessments of efficacy were performed after each injection and a full evaluation of safety was conducted. Cumulative dosing produced significant (P < 0.01) dose-related increases in lesion-to-brain (L/B) ratio and lesion signal intensity (SI) enhancement. Two independent, blinded assessors noted additional lesions, compared to unenhanced images in 31% and 33%, 49% and 42%, and 50% and 48% of patients after each cumulative dose, respectively. Significantly more lesions were noted after the first injection, compared to unenhanced images (P ‫؍‬ 0.002 and P < 0.001; assessors 1 and 2, respectively), and after a second injection, compared to the first (P < 0.001 and P ‫؍‬ 0.039; assessors 1 and 2, respectively). Neither assessor noted significantly more lesions after the third injection. For patients with just one lesion observed on unenhanced T1-and T2-weighted images, additional lesions were noted by assessors 1 and 2 for 27% and 26%, 48% and 35%, and 42% and 41% of patients, respectively, following each injection. Contemporaneously, diagnostic confidence was increased and lesion conspicuity improved over unenhanced magnetic resonance imaging (MRI). For patients with one lesion observed after 0.1 mmol/kg of gadobenate dimeglumine, additional lesions were noted for 24% and 17% of patients Index terms: gadobenate dimeglumine; Gd-BOPTA; MRI; CNS metastases; lesion detection THE CHOICE BETWEEN SURGERY AND TUMOR irradiation for the treatment of metastatic lesions to the central nervous system (CNS) is highly dependent on the number and size of lesions detected, as well as on their location (1). At present, contrast-enhanced magnetic resonance imaging (MRI) with gadolinium-based MR contrast agents is the diagnostic technique of choice for the detection of CNS metastases, offering greater sensitivity and specificity than unenhanced MRI and contrast-enhanced computed tomography (1-6). However, as regards the specific contrast agent to use for MRI of CNS metastases, there appears little to choose between the majority of agents available; traditional agents (i.e., gadopentetate dimeglumine, Schering AG, Berlin, Germany; gadoterate meglumine, Guerbet, Aulnay-sous-Bois, France; gadodiamide, Nycomed-Amersham, Oslo, Norway; and gadoteridol, Bracco Imaging SpA, Milano, Italy), as well as newer agents, such as gadoversetamide (Mallinckrodt, St. Louis, MO) and new formulations of existing agents (e.g., gadovist, Schering AG, Berlin, Germany), all possess similar T1 relaxivities in plasma or protein-containing aqueous solution (between 4.3-5.6 mM -1 second -1 ) (7-9) and may be expected to produce similar signal intensity (SI) enhancement when administered at equal dose. Studies at the recommended and approved standard dose of ...

The global development of a biosimilar product is a methodologically complex affair, lined with potential design pitfalls and operational missteps to be avoided. Without careful attention to experimental design and meticulous execution, a development programme may fail to demonstrate equivalence, as would be anticipated for a biosimilar product, and not receive regulatory approval based on current guidance. In order to demonstrate similarity of a biosimilar product versus the originator (ie, the branded product), based on regulatory guidance, a stepwise approach is usually taken, starting with a comprehensive structural and functional characterisation of the new biological moiety. Given the sequential nature of the review process, the extent and nature of the non-clinical in vivo studies and the clinical studies to be performed depend on the level of evidence obtained in these previous step(s). A clinical efficacy trial is often required to further demonstrate biosimilarity of the two products (biosimilar vs branded) in terms of comparative safety and effectiveness. Owing to the focus on demonstrating biosimilarity and not safety and efficacy de novo, designing an adequate phase III (potentially pivotal) clinical efficacy study of a biosimilar may present some unique challenges. Using adalimumab as an example, we highlight design elements that may deserve special attention.