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Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

ABSTRACT: INTRODUCTION:Hypogonadism is one of the most common male endocrine problems. Although many treatments are currently available, unmet need exists for new testosterone (T) replacement therapies that are simple to administer and use, are safe, and mimic physiologic T levels. AIM:The study aim was to determine the pharmacokinetics (PK), safety, and tolerability of T enanthate (TE) administered via a novel single-use autoinjector system, which was designed to eject high-viscosity solutions from a prefilled syringe fitted with a five-eighths-inch 27-gauge needle. METHODS:Thirty-nine men with hypogonadism entered this dose-finding, open-label, parallel-group study. Patients were washed out of their topical T regimens and randomized to receive 50 or 100?mg of subcutaneous (SC) TE weekly. The reference group were patients with hypogonadism who were maintained on standard 200-mg intramuscular (IM) TE. MAIN OUTCOME MEASURE:The primary outcome measure was the PK profile of SC TE, analyzed in reference to T levels used by the Food and Drug Administration to approve T products. Secondary outcome measures were safety and tolerability assessments. RESULTS:Both doses of SC TE achieved normal average concentrations of serum T within a 168-h dosing interval after injection. Concentration ranges were similar at all time points following 50-mg SC TE injections and following the third injection in the 100-mg arm. Mean steady-state T concentration at week 6 was 422.4 and 895.5?ng/dL for the 50- and 100-mg SC TE arms, respectively. SC TE demonstrated PK dose proportionality. SC TE restored normal serum T with low variation relative to 200-mg IM without clinically significant adverse events. CONCLUSIONS:Administration of TE via this novel injection system restored T levels to normal range in men with hypogonadism. SC TE dosed weekly demonstrated steady, dose-proportional measures of exposure and was well-tolerated. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic profile of subcutaneous testosterone enanthate delivered via a novel, prefilled single-use autoinjector: A phase II study. Sex Med 2015;3:263-273.

SUBMITTER: Kaminetsky J

PROVIDER: S-EPMC4721027 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

Kaminetsky Jed J Jaffe Jonathan S JS Swerdloff Ronald S RS

Sexual medicine 20150917 4

<h4>Introduction</h4>Hypogonadism is one of the most common male endocrine problems. Although many treatments are currently available, unmet need exists for new testosterone (T) replacement therapies that are simple to administer and use, are safe, and mimic physiologic T levels.<h4>Aim</h4>The study aim was to determine the pharmacokinetics (PK), safety, and tolerability of T enanthate (TE) administered via a novel single-use autoinjector system, which was designed to eject high-viscosity solut ...[more]

PMID: 26797061

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Project description:IntroductionPegfilgrastim-cbqv (UDENYCA®; Coherus BioSciences, Redwood City, CA, USA) is a pegfilgrastim (Neulasta®; Amgen, Thousand Oaks, CA, USA) biosimilar approved for administration by prefilled syringe (PFS). The recently approved pegfilgrastim-cbqv prefilled autoinjector (AI) was developed as another method of self-administration and to aid in-office use, providing flexibility in drug delivery. The objectives of the study were to assess the pharmacokinetics (PK) and pharmacodynamics (PD) to determine bioequivalence of the prefilled AI and the PFS for administration of pegfilgrastim-cbqv and to assess the safety profile of the prefilled AI.MethodsDuring this open-label, two-period crossover study, healthy adult males (N = 155) were randomly assigned (1:1 ratio) to receive a subcutaneous injection of pegfilgrastim-cbqv using a prefilled AI (n = 76) or a PFS (n = 79) in period 1. During period 2, participants received an injection using the other method. Primary PK and secondary PD parameters were calculated to assess the bioequivalence of the treatment as administered by the two delivery methods. Safety and immunogenicity were also assessed.ResultsThe 90% CIs of the geometric mean ratios for the PK and PD parameters were within the required range (80-125%), demonstrating bioequivalence between the pegfilgrastim-cbqv prefilled AI and PFS. Treatment-emergent adverse events (TEAEs) were reported by 75% and 74.1% of participants in the prefilled AI and PFS groups, respectively. The most common TEAEs in both treatment groups were myalgia, bone pain, and headache. AI-device-related TEAEs were injection site pain (1.4%) and injection site bruising (0.7%). The incidence of antidrug antibodies and neutralizing antibodies was low and was similar in both treatment sequences.ConclusionsThe bioequivalence of pegfilgrastim-cbqv administered using a prefilled AI and a PFS was established. The safety, including immunogenicity profiles, of pegfilgrastim-cbqv administered using the prefilled AI and the PFS were similar, with no new safety findings.

Project description:Abstract BACKGROUND: In men, obesity is often associated with low testosterone (T) levels, but information is limited as to how body weight affects the pharmacokinetic profile or dosing of testosterone therapy (TTh) in men with T deficiency. Historically, men with body mass index (BMI) >32.4 kg/m2 required higher doses of T 2% gel to achieve physiological T levels than men with BMI ≤29.1 or 29.2–32.4 kg/m2.(1) In a phase 3 trial (N=150) of subcutaneous (SC) testosterone enanthate (TE) administered weekly, concentration-guided dosing raised T levels to within physiological range in 92.7% of patients.(2) Here, we report a post hoc analysis evaluating the association between body weight and serum T levels attained with SC TE. Methods: SC TE was evaluated in an open-label, single-arm, dose-blinded, 52-week phase 3 trial (NCT02159469). Patients self-administered 75 mg SC TE weekly during the titration phase; blinded dose-adjustments in 25 mg increments occurred at pre-defined time points beyond the sixth dose. The primary endpoint of this study was the percentage of patients achieving an average serum T concentration (Cavg0-168h) of 300 to 1,100 ng/dL at week 12. For this post hoc analysis, a linear regression model with weight and dose as independent variables was used to assess differences in mean minimum T concentration (Cmin) and Cavg0-168h at week 12. Results: For this analysis, 137 patients were included. Doses were 50 mg (n=25), 75 mg (n=93), and 100 mg (n=19). The mean weight was 84.4 kg, 102.2 kg, and 112.0 kg for the 50 mg, 75 mg, and 100 mg dose groups, respectively (range, 49.9–146.5 kg). The dose-normalized T Cmin was 9.2 ng/dL, 5.7 ng/dL, and 4.3 ng/dL per 1 mg of SC TE for the 50 mg, 75 mg, and 100 mg groups, respectively. The dose-normalized T Cavg0-168h was 12.0 ng/dL, 7.2 ng/dL, and 5.7 ng/dL per 1 mg of SC TE. In an overall linear regression model, 48.2% (P<0.0001) and 55.0% (P<0.0001) of the total variance in Cmin and Cavg0-168h, respectively, can be predicted from the independent weight and dose variables. Conclusion: Our results show an inverse relationship between body weight and T exposure. Men with higher mean body weights required higher doses of SC TE to achieve physiologic T levels compared with men with lower mean body weights. The available doses provide effective options to reach target exposures. These findings highlight the impact of weight and dose selection on SC TE exposure. References: (1) Dobs et al., J Sex Med 2014;11:857–864; (2) Kaminetsky et al., J Urol. 2019;201:587–94.

Project description:The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS).To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices.In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80-100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160-mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (Cmax ) and area under the curve (AUC0-tlast ) where tlast is the time of last sample (14 days ± 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety.Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean Cmax (90% CI) [15.0 ?g/mL (13.9-16.1) vs. 14.8 ?g/mL (13.8-15.9)] and geometric mean AUC0-tlast (90% CI) [157 ?g × day/mL (147-168) vs. 154 ?g × day/mL (144-165)]. When comparing Cmax and AUC0-tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab.The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191.

Dataset Information

Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

Publications

Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study.

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