Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants.

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

Efficacy and Safety of Once-Weekly Somatrogon Compared with Once-Daily Somatropin (Genotropin®) in Japanese Children with Pediatric Growth Hormone Deficiency: Results from a Randomized Phase 3 Study.

INTRODUCTION: Somatrogon is a long-acting recombinant human growth hormone being developed as a once-weekly treatment for children with growth hormone deficiency (GHD). The objective of this phase 3 study (NCT03874013) was to compare the efficacy and safety of once-weekly somatrogon with once-daily Genotropin in Japanese children with GHD. METHODS: In this open-label, randomized, active-controlled study, 44 prepubertal Japanese children with GHD (boys: 3 to <11 years; girls: 3 to <10 years) were randomized 1:1 to receive once-weekly somatrogon or once-daily Genotropin (0.025 mg/kg/day) for 12 months. Dose escalation for somatrogon-treated subjects occurred in the first 6 weeks (0.25, 0.48, and 0.66 mg/kg/week; 2 weeks each) with the remaining 46 weeks at a dose of 0.66 mg/kg/week. The study's primary endpoint was annualized height velocity (HV) at 12 months. RESULTS: Baseline characteristics were similar between treatment groups. Compared with Genotropin-treated subjects, somatrogon-treated subjects had higher least-squares mean HV at 12 months (9.65 cm/year vs. 7.87 cm/year). Once-weekly somatrogon was concluded as being comparable to once-daily Genotropin as the mean treatment difference (somatrogon-Genotropin) in HV was +1.79 cm/year (95% confidence interval, 0.97-2.61), which was greater than the preestablished margin (-1.8 cm/year). For both treatment groups, most adverse events were mild to moderate in severity and a similar proportion of subjects reported injection-site pain, although the somatrogon group reported more painful injections. CONCLUSION: In prepubertal Japanese children with GHD, once-weekly somatrogon was comparable to once-daily Genotropin in terms of annualized (12-month) HV. Both treatments had similar safety and tolerability profiles.

The Efficacy and Safety of Dexmedetomidine for Sedation During Surgery Under Epidural or Spinal Anesthesia: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Only a few studies have been reported on the use of dexmedetomidine for sedating surgical patients requiring epidural or spinal anesthesia. We conducted a randomized, double-blind, placebo-controlled, parallel-group study at 12 hospitals in Japan. METHODS: Adult patients were randomly allocated to receive an intravenous administration of placebo or dexmedetomidine at 0.067, 0.25, 0.5 or 1.0 µg/kg over 10 min after epidural or spinal anesthesia. All dexmedetomidine groups received dexmedetomidine 0.2-0.7 µg/kg/h to maintain an Observer's Assessment of Alertness/Sedation Scale (OAA/S) score of ≤ 4; however, propofol was administered to rescue patients who exceeded this score. Surgery was then started 15 min after study drug infusion in patients with OAA/S score of ≤ 4. The primary endpoint was the percentage of patients not requiring rescue propofol to achieve and maintain an OAA/S score of ≤ 4. RESULTS: Of the 120 enrolled and randomized patients, 119 were treated the study: 22 received placebo and 97 received dexmedetomidine (23-25 patients per dose). Significantly more patients did not require propofol in the dexmedetomidine 0.5 and 1.0 µg/kg groups (68.0% and 80.0%, respectively) compared to the placebo group (22.7%) (P = 0.003 and P < 0.001, respectively). Common adverse events (AEs) were protocol-defined respiratory depression, bradycardia and hypotension. There was no significant difference in the incidence of AEs between the dexmedetomidine and the placebo groups. CONCLUSION: We concluded that loading doses of 0.5 and 1.0 µg/kg dexmedetomidine, followed by an infusion at a rate of 0.2-0.7 µg/kg/h, provide effective and well-tolerated sedation for surgical patients during epidural or spinal anesthesia.Clinical trials.gov identifier: NCT01438957.

The Efficacy and Safety of Dexmedetomidine for Procedural Sedation in Patients Receiving Local Anesthesia Outside the Intensive Care Unit: A Prospective, Double-Blind, Randomized Clinical Phase III Trial in Japan.

BACKGROUND: Few studies (in other countries than the US) have reported on the efficacy and safety of dexmedetomidine for sedation of patients undergoing surgical or medical procedures under local anesthesia without intubation outside the intensive care unit. We performed a randomized, double-blind study in Japan. METHODS: Adult patients were randomly allocated to receive placebo, dexmedetomidine 0.5 µg/kg (DEX 0.5 group), or dexmedetomidine 1.0 µg/kg (DEX 1.0 group) over 10 min. Then, both dexmedetomidine groups received dexmedetomidine 0.2-0.7 µg/kg/h for maintaining an Observer's Assessment of Alertness/Sedation Scale (OAA/S) score of ≤ 4; however, propofol was administered to rescue patients whose score exceeded this value. The primary endpoint was the percentage of patients who did not require rescue propofol to achieve and maintain an OAA/S score of ≤ 4. RESULTS: In total, 162 patients were included in the placebo (n = 53), DEX 0.5 (n = 53), and DEX 1.0 (n = 56) groups. Propofol was not required in significantly more patients in the dexmedetomidine 0.5 and 1.0 µg/kg groups (52.8% and 57.1%, respectively) compared with the placebo group (1.9%) (P < 0.001 for both). Common adverse events were protocol-defined hypotension, respiratory depression and bradycardia. The incidence of bradycardia was significantly higher in the DEX 0.5 (26.4%) and DEX 1.0 (30.4%) groups than in the placebo group (9.4%) (P = 0.041 and P = 0.008, respectively). CONCLUSION: We concluded that a loading dose of 0.5 or 1.0 µg/kg dexmedetomidine followed by infusion at a rate of 0.2-0.7 µg/kg/h provided effective and well-tolerated sedation in patients undergoing surgical or medical procedures under local anesthesia without intubation.Clinical trials.gov identifier: NCT01438931.

Long-term safety and treatment outcomes of pegvisomant in Japanese patients with acromegaly: results from the post-marketing surveillance.

This post-marketing surveillance is to investigate the long-term safety and effectiveness of the growth hormone receptor antagonist pegvisomant, which is used in patients with acromegaly in routine clinical practice. This surveillance included all cases treated with pegvisomant during the study period from the start of marketing (June 5, 2007) to December 2015. Data for 251 patients with acromegaly treated with pegvisomant were collected from 119 institutions nationwide in Japan. Eighty-five patients received pegvisomant monotherapy throughout their treatment, while 165 patients were treated with somatostatin analogue or dopamine agonist in combination with pegvisomant. Mean dose of pegvisomant was 10.6 ± 6.1 mg/day in the entire treatment period (except for initial loading dose). The incidence of adverse drug reactions was 35.6% (89/250). No new safety concerns related to long-term treatment were observed. The major investigation items of incidence of abnormal liver function and tumor enlargement were 16.0% (40/250), and 5.2% (13/250) respectively. Efficacy at the final evaluation point was 96.4% (217/225) based on the overall clinical judgement of attending physicians, and efficacy in each observation period was over 94%. Improvement in IGF-I levels and clinical symptoms scores were also observed by comparing the data at baseline with each observation point during treatment. IGF-I normalization rate was 68.2% at 5 years. Pegvisomant monotherapy showed similar improvement here as well. These results suggest that long-term treatment with pegvisomant is effective in clinical practice.

Double-Blind, Randomized, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Eplerenone in Japanese Patients With Chronic Heart Failure (J-EMPHASIS-HF).

BACKGROUND: The mineralocorticoid receptor antagonist eplerenone improved clinical outcomes among patients with heart failure with reduced ejection faction (HFrEF) in the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure) study. However, similar efficacy and safety have not been established in Japanese patients. We evaluated the efficacy and safety of eplerenone in patients with HFrEF in a multicenter, randomized, double-blind placebo-controlled outcome study (ClinicalTrials.gov Identifier: NCT01115855). The aim of the study was to evaluate efficacy predefined as consistency of the primary endpoint with that of EMPHASIS-HF at a point estimate of <1 for the hazard ratio.Methods and Results:HFrEF patients with NYHA functional class II-IV and an EF ≤35% received eplerenone (n=111) or placebo (n=110) on top of standard therapy for at least 12 months. The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The primary endpoint occurred in 29.7% of patients in the eplerenone group vs. 32.7% in the placebo group [hazard ratio=0.85 (95% CI: 0.53-1.36)]. Hospitalization for any cause and changes in plasma BNP and LVEF were favorable with eplerenone. A total of 17 patients (15.3%) in the eplerenone group and 10 patients (9.1%) in the placebo group died. Adverse events, including hyperkalemia, were similar between the groups. CONCLUSIONS: Eplerenone was well-tolerated in Japanese patients with HFrEF and showed results consistent with those reported in the EMPHASIS-HF study.

Efficacy and safety of a single oral 150 mg dose of fluconazole for the treatment of vulvovaginal candidiasis in Japan.

Vulvovaginal candidiasis is the second most common cause of vaginal infections following bacterial vaginosis. For the treatment of vulvovaginal candidiasis, antifungal agents are used either as topical (vaginal tablets and cream) or oral formulations. A single oral 150 mg dose of fluconazole has been recommended as the standard therapy for uncomplicated, acute vulvovaginal candidiasis in global guidelines; however, in Japan oral fluconazole therapy has not been approved. We conducted a phase 3 study to evaluate the efficacy and safety of a single oral 150 mg dose of fluconazole in Japanese subjects with vulvovaginal candidiasis for regulatory submission. A total of 157 subjects received a single oral 150 mg dose of fluconazole. Candida species (104 strains) were identified by fungal culture from 102 subjects at baseline, including Candida albicans (100 strains). The efficacy rate for the therapeutic outcome (assessed based on a comprehensive evaluation of the clinical and mycological efficacy in each subject) was 74.7% (74/99) on Day 28 in the modified Intent-To-Treat (m-ITT) population. Concerning the clinical and mycological efficacy on Day 28 in the m-ITT population, the cure, cure or improvement, and eradication rates were 81.6%, 95.9%, and 85.9%, respectively. The most common treatment-related adverse events were diarrhea and nausea (1.9% for each). No clinically significant safety issues were reported. A single oral 150 mg dose of fluconazole demonstrated excellent therapeutic efficacy and was well tolerated in Japanese subjects with vulvovaginal candidiasis. CLINICAL REGISTRATION NUMBER: NCT01806623.

Pharmacokinetics and safety of voriconazole intravenous-to-oral switch regimens in immunocompromised Japanese pediatric patients.

The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-to-oral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and ≥50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC0-12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0-12,ss values for the intravenous and oral regimens were 51.1 µg · h/ml (68%) and 45.8 µg·h/ml (90%), respectively; there was a high correlation between AUC0-12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.).