Topical Sirolimus 0.2% Gel for the Management of Tuberous Sclerosis Complex-Related Cutaneous Manifestations: An Interim Analysis of Postmarketing Surveillance in Japan.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder affecting several organs, including skin. We sought to assess the real-world effectiveness and safety of a topical sirolimus 0.2% gel treatment for TSC-related cutaneous manifestations. METHODS: We conducted an interim analysis of postmarketing surveillance conducted in Japan over 52 weeks. A total of 635 and 630 patients were included in the safety and efficacy analysis sets, respectively. Improvement rate of overall cutaneous manifestations, responder rate of improvement in individual lesions, adverse events (AEs), adverse drug reactions (ADRs), and patient satisfaction level of topical sirolimus 0.2% gel treatment were evaluated along with patient characteristics associated with the improvement rate of cutaneous manifestations or safety. RESULTS: The mean age of the patients was 22.9 years and 46.1% were men. At week 52 of treatment, the overall improvement rate was 74.8% and the responder rate was the highest for facial angiofibroma (86.2%). Overall, the incidence rates of AEs and ADRs were 24.6% and 18.4%, respectively. Efficacy was associated with age (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.010), duration of use (p < 0.001), and total dosage (p = 0.005). Safety was associated with age (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.011) and duration of use (p < 0.001). However, when the broad age group (≥ 15 to < 65) was subcategorized by 10-year intervals, the incidence of ADRs was similar among the age groups with no significant differences. Hepatic or renal impairment or concomitant use of systemic mTOR inhibitors had no effect on the effectiveness or safety. Overall, 53% of patients were "very satisfied" or "satisfied" with the treatment received. CONCLUSIONS: Topical sirolimus 0.2% gel is effective in the management of TSC-related cutaneous manifestations and generally well tolerated. Age and duration of usage had a significant association with the effectiveness or safety of topical sirolimus 0.2% gel, whereas total dosage had a significant association with the effectiveness.

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database.

BACKGROUND: Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance's Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006. RESULTS: Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11-17 (odds ratio [OR], 2.53) and 18-45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11-17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33). CONCLUSIONS: The presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections.

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug-drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class.

Ceftaroline fosamil use in hospitalized patients with acute bacterial skin and skin structure infections: Budget impact analysis from a hospital perspective.

PURPOSE: The budgetary impact of adding ceftaroline fosamil to a hospital formulary for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) was evaluated. METHODS: A three-year hospital budget impact model was constructed with three initial treatment options for ABSSSIs: ceftaroline fosamil, vancomycin plus aztreonam, and other vancomycin-containing regimens. The target population was hospitalized adult patients with an ABSSSI. Clinical cure rates with initial treatment were assumed to be similar to those from ceftaroline fosamil clinical trials. Patients who did not respond to initial treatment were assumed to be treated successfully with second-line antimicrobial therapy. Length of stay and cost per hospital day (by success or failure with initial treatment) were estimated based on a large database from more than 100 U.S. hospitals. Other model inputs included the annual number of ABSSSI admissions, projected annual case growth rate, proportion of ABSSSI target population receiving vancomycin-containing regimen, expected proportion of ABSSSI target population to be treated with ceftaroline fosamil, drug acquisition cost, cost of antibiotic administration, and cost of vancomycin monitoring. Sensitivity analysis using 95% confidence limits of clinical cure rates was also performed. RESULTS: The estimated total cost of care for treating a patient with an ABSSSI was $395 lower with ceftaroline fosamil ($15,087 versus $15,482) compared with vancomycin plus aztreonam and $72 lower ($15,087 versus $15,159) compared with other vancomycin-containing regimens. CONCLUSION: Model estimates indicated that adding ceftaroline fosamil to the hospital formulary would not have a negative effect on a hospital's budget for ABSSSI treatment.

Lack of pharmacokinetic drug interaction between oral posaconazole and caspofungin or micafungin.

The objective of this phase 1, open-label, parallel, randomized study was to determine the effect of posaconazole on the pharmacokinetics of caspofungin and micafungin in 67 healthy subjects. Caspofungin (70 mg on day 1, 50 mg on days 2-14 once daily; 1-hour intravenous infusion) (cohort 1) or micafungin (150 mg once daily days 1-7; 1-hour IV infusion) (cohort 2) was administered alone or with posaconazole oral suspension 400 mg twice daily, on days 1 to 14 (cohort 1) or days 1 to 7 (cohort 2). Pharmacokinetic parameters, maximum plasma concentration (C(max)), steady-state area under the plasma concentration-time curve over the dosing interval (AUC[τ]), and time to C(max) (T(max)) were assessed. Safety assessments included adverse events, clinical laboratory tests, vital signs, and electrocardiograms. Repeated posaconazole dosing did not affect caspofungin or micafungin pharmacokinetics. Log-transformed ratio estimates of caspofungin with posaconazole C(max) and AUC(τ) were 90% and 98%, respectively, of those with caspofungin alone at day 14; ratio estimates of micafungin with posaconazole C(max) and AUC(τ) were 104% and 109%, respectively, of those with micafungin alone at day 7. Median T(max) (1 hour) did not change. Coadministration of posaconazole with caspofungin or micafungin was generally well tolerated and did not affect the pharmacokinetics of either echinocandin.

Skin concentrations and pharmacokinetics of posaconazole after oral administration.

A randomized, single-center, open-label study of posaconazole (POS) was performed to determine the concentration of POS in the skin of 30 healthy adult human subjects receiving 400 mg POS oral suspension twice daily for 8 days with a high-fat meal. Blood samples for plasma POS level determination were collected at prespecified times on day 1 and day 8. From each subject, two 4-mm skin punch biopsy samples were obtained, one immediately before or after both the first and last doses of POS. A MIC(90) value of 250 ng/ml, which encompasses the majority of common dermatophytes, was used to calculate the time above the MIC(90) in plasma and skin. On days 1 and 8, POS attained peak plasma concentrations at median times of 8 and 5 h, respectively. On days 1 and 8, POS peak skin concentrations were attained at 12 and 3 h, respectively; peak skin concentrations were produced from a single composite profile. On day 8, POS concentrations in skin and plasma for the entire dosing interval were severalfold higher than the MIC(90). POS dosed at 400 mg twice daily per os was well tolerated in healthy subjects. Two subjects reported increased alanine aminotransferase (ALT) levels. The findings of this study demonstrate adequate skin penetration and have certain implications for the treatment of dermatophytic skin and nail infections.

Effect of varying amounts of a liquid nutritional supplement on the pharmacokinetics of posaconazole in healthy volunteers.

The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables--area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUC(tf)), maximum observed plasma concentration (C(max)), time to C(max) (T(max)), and relative bioavailability--were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereas T(max) was unaffected. Compared with the levels reached under fasting conditions, posaconazole C(max) and AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.

Vardenafil in men with stable statin therapy and dyslipidemia.

INTRODUCTION: Phosphodiesterase type-5 (PDE-5) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction (ED) with or without associated comorbidities. AIM: This is the first prospective, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor (i.e., vardenafil) in an exclusive population of men with ED and dyslipidemia. MAIN OUTCOME MEASURES: Three coprimary efficacy measurements (Sexual Encounter Performance [SEP]2, SEP3, International Index of Erectile Function-Erectile Function [IIEF-EF] domain scores) were used to assess the differential effect of vardenafil vs. placebo in this patient population. Adverse events (AEs) safety data were obtained to compare safety outcomes. METHODS: This 12-week of randomized, double-blind, placebo-controlled study was conducted in 59 U.S. centers. Patients received either on-demand, flexible-dose vardenafil 10 mg (titrated to 5 mg or 20 mg based upon efficacy and safety) or placebo. RESULTS: Of the 712 patients screened and entered into the study, 395 were randomized. Baseline demographics for the intent-to-treat population included: mean age, 54.4 years (+/-7.5 standard deviation [SD]); 76% Caucasian; mean body mass index (BMI), 31.7 kg/m(2) (+/-12.7 SD); 47% past/present smoker; and 42% severe ED. Aside from dyslipidemia, other comorbidities included hypertension, 61%; obesity (i.e., BMI >/= 30), 51%; and type 1 or 2 diabetes, 40%. During the 12-week treatment period, the least squares (LS) adjusted mean success rates in patients on vardenafil vs. placebo were: SEP2, 79.09% vs. 51.92%; and SEP3, 66.69% vs. 33.83% (P < 0.001). The LS adjusted mean IIEF-EF domain score for week 12 using LOCF was 21.99 in patients on vardenafil therapy vs. 14.83 in those on placebo (P < 0.001). The most commonly encountered AEs were headache and nasal congestion. CONCLUSIONS: Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia. The results of this study support the role of expanded research on outcomes related to effective ED treatment and aggressive lipid control.