Randomized phase 3 study of the anti-disialoganglioside antibody dinutuximab and irinotecan vs irinotecan or topotecan for second-line treatment of small cell lung cancer.

INTRODUCTION: Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC. MATERIALS AND METHODS: Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0-1 were randomized 2:2:1 to receive dinutuximab 16-17.5 mg/m2 intravenous (IV)/irinotecan 350 mg/m2 IV (day 1), irinotecan 350 mg/m2 IV (day 1), or topotecan 1.5 mg/m2 IV (days 1-5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed. RESULTS: A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia. CONCLUSIONS: Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days. CLINICALTRIALS: gov Identifier. NCT03098030.

Aggressive Afterload Lowering to Improve the Right Ventricle: A New Target for Medical Therapy in Pulmonary Arterial Hypertension?

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

Factors associated with adherence to phosphodiesterase type 5 inhibitors for the treatment of pulmonary arterial hypertension.

OBJECTIVES: To assess factors associated with adherence to phosphodiesterase type 5 inhibitors (PDE5Is) in the management of pulmonary arterial hypertension (PAH). METHODS: This study analyzed pharmacy benefit claims of naïve Adcirca and Revatio users between January 1, 2008 and December 31, 2010. Patients were considered adherent if their proportion of days covered (PDC) was ≥ 80% over a 6-month period. Logistic regressions were estimated to assess the factors associated with adherence. Analyses were stratified by use of a specialty pharmacy or retail pharmacy. A sensitivity analysis was performed by excluding individuals with 90-day supply. RESULTS: Of the total of 2143 patients included, 46.8% were adherent. Adherence was higher among 930 specialty pharmacy users (65.6%) than 1213 retail pharmacy users (32.3%, p < 0.001). Adherence was higher among Adcirca users (60.7%; approved dose 40 mg once-daily) than Revatio users (44.3%, p < 0.001; approved dose 20 mg thrice-daily). Among retail pharmacy users, adherence was higher in patients using Adcirca (OR = 2.59; 95% CI = 1.60-4.22) and patients with an index prescription given by pulmonologists (OR = 1.70; 95% CI = 1.15-2.50), while lower in patients with higher copayment ($51-$250: OR = 0.61, 95% CI = 0.42-0.90; $251+: OR = 0.57, 95% CI = 0.39-0.83). Among specialty pharmacy users, only high copayment ($251+: OR = 0.56, 95% CI = 0.35-0.90) was found to be a significant factor for non-adherence. After excluding individuals with 90-day supply, adherence rate was 29.6% in retail pharmacy and 57.9% in specialty pharmacy (p < 0.001), and regression results were similar. LIMITATIONS: Diagnosis of PAH was not confirmed without access to medical claims. Pharmacy refill records might not reflect actual consumption. Adherence evaluated for 6 months might not be generalizable to longer periods. CONCLUSION: Adherence to PDE5Is for PAH is sub-optimal. The findings suggest that adherence to PDE5Is in patients with PAH is associated with the use of specialty pharmacy, simpler dosing frequency, a lower financial barrier, and a prescription given by pulmonologists.

Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5 mg: a randomized, open-label, crossover study in healthy male subjects.

BACKGROUND AND OBJECTIVE: Food has reportedly not affected the systemic bioavailability of the atypical antipsychotic drug clozapine. However, searches of the medical literature could find no studies to support this food claim for any formulation of clozapine. The purpose of the current study was to assess the effect of food on the bioavailability and pharmacokinetics of clozapine orally disintegrating tablet (ODT) following single 12.5 mg doses in the healthy subjects in fasted and fed conditions. METHODS: This was a randomized, open-label, two-way crossover study in which healthy males aged 18-45 years completed two dosing periods. In period I, subjects received one dose of clozapine ODT 12.5 mg after an overnight fast and in period II they received one dose of clozapine ODT 12.5 mg within 30 minutes of consuming a high-fat/-calorie breakfast. Venous blood samples were taken at regular intervals before and after study drug administration, and plasma concentrations of clozapine and desmethylclozapine were measured from each blood sample. Standard pharmacokinetic parameters were calculated. Safety and tolerability were also assessed. RESULTS: Twenty-four subjects were enrolled: all the subjects completed the study and were included in the pharmacokinetic analyses. Pharmacokinetic results demonstrated significant differences in mean plasma concentration-time curves between fasted and fed conditions for both clozapine and desmethylclozapine at various time points after administration of a single clozapine ODT 12.5 mg dose. For both clozapine and desmethylclozapine, the lower limits of the 90% confidence intervals (CIs) for the geometric mean fed-to-fasted maximum plasma concentration (C(max)) ratios (0.73 for both clozapine and desmethylclozapine) were below the bioequivalence lower limit, 0.80. The mean C(max) of both clozapine and desmethylclozapine was decreased by approximately 20% when clozapine ODT was administered after a high-fat/-calorie breakfast. However, the 90% CIs for the fed-to-fasted ratios of geometric means of area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) [1.01, 1.15 for clozapine; 1.00, 1.18 for desmethylclozapine) and from time zero to infinity (AUC(infinity)) [1.03, 1.14 for clozapine; 1.01, 1.15 for desmethylclozapine] were within the bioequivalence boundaries of 0.80-1.25. There were no serious adverse events, discontinuations due to adverse events, or abnormalities in clinical laboratory evaluations. Seventy-one adverse events were reported and 96% were mild in intensity - the most common adverse event was somnolence (42/71 events). Two severe adverse events (syncope, n = 1 fasted subject; vasovagal syncope, n = 1 fed subject) were reported approximately 4 hours after administration of clozapine ODT and asystole (5-10 seconds) was associated with syncope in the fasted subject. CONCLUSIONS: When compared with drug administration in the fasted state, coadministration of food was shown to decrease the rate of clozapine absorption from clozapine ODT 12.5 mg as assessed by C(max) but had no effect on the extent of clozapine absorption as assessed by AUC(last) and AUC(infinity). The C(max) value for clozapine was approximately 20% lower in the fed versus the fasted state. Thus, clozapine ODT should be administered at least 1 hour before meals or after a light meal. The reported adverse events in 24 healthy male subjects were consistent with those expected from healthy subjects taking oral clozapine.

Bioequivalence of clozapine orally disintegrating 100-mg tablets compared with clozapine solid oral 100-mg tablets after multiple doses in patients with schizophrenia.

BACKGROUND: This study compared the bioequivalence of FazaClo (clozapine orally disintegrating tablets) 100 mg to Clozaril (clozapine standard oral tablets) 100 mg after multiple doses in patients with schizophrenia. METHODS: This was a randomized, open-label, multiple-dose study in which patients with schizophrenia received FazaClo or Clozaril 100 mg twice daily for 5 days before crossing over to the alternate therapy. Blood samples were obtained at regular intervals during and after the completion of treatment, and standard pharmacokinetic parameters were calculated. Safety and patient satisfaction with FazaClo were also assessed. RESULTS: Thirty-six patients were enrolled, of whom 33 completed the study and 30 were included in the steady-state analyses. All pharmacokinetic parameters for clozapine and desmethylclozapine (the major metabolite of clozapine) were similar between FazaClo and Clozaril in both the completer and steady-state populations. Geometric mean values for steady-state maximum and minimum concentrations and area under the plasma concentration-time curve for FazaClo were all within 95-105% of those for Clozarilwell within the range considered by the US FDA as acceptable for bioequivalence (80-125%). Patients also expressed a high level of satisfaction with the FazaClo orally disintegrating tablet formulation. CONCLUSIONS: FazaClo produced pharmacokinetic profiles almost identical to those of Clozaril. This should provide clinicians with reassurance that patients who receive FazaClo will achieve plasma drug concentrations similar to those produced by the same daily dose of Clozaril, and that no cross-titration is necessary when switching from one of these clozapine formulations to the other.

Medical education and communication companies: an updated in-depth profile.

INTRODUCTION: The integrity of medical education and communication companies (MECCs) and their role in continuing medical education (CME) are frequently challenged, perhaps because of a lack of published information characterizing these providers. Published in 1998, a survey of MECCs began the identification and description of these organizations so that meaningful conclusions could be drawn about their role in CME. The present study enhances the profile created by that original survey. METHODS: A 21-item questionnaire was mailed to 182 companies identified from 3 commercially available lists. RESULTS: Forty-six (25.2%) companies responded. Surveys revealed that 25 (54%) of the respondent companies have 1 to 25 employees, 66.6% have separate CME divisions, 64.4% are accredited to provide CME, 77.7% have at least 1 licensed health care professional on staff, and 33.2% of their leaders hold a doctoral degree and 28.8% hold professional licensure, whereas 88.6% have advisory boards, 93.1% of which review each CME activity. DISCUSSION: MECCs comprise a diverse group differing in size and accreditation status. They contribute to the CME community by providing a variety of services, with highly trained staff. Future studies of CME providers should continue to expand the base of knowledge regarding these organizations, resulting in better understanding among all types of providers, opportunities for collaboration, and, ultimately, education that improves patient care.