Bioequivalence Studies of Sildenafil Citrate Orodispersible Film Administered with and without Water vs ViagraⓇ Film-Coated Tablets in Healthy Male Volunteers.

Background: Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objectives: These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (ViagraⓇ; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods: Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. Forty-two and 80 healthy male volunteers were recruited in the first and second study, respectively. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results: In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the ViagraⓇ FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91-108.78) and area under the plasma concentration-time curve: 1.09 (104.49-113.21) for sildenafil citrate ODF administered with water vs ViagraⓇ FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also showed bioequivalence for sildenafil citrate ODF (without water) compared with ViagraⓇ FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47-109.36) and area under the plasma concentration-time curve: 1.06 (103.42-108.40) for sildenafil citrate ODF administered without water vs ViagraⓇ FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity. Conclusions: These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with ViagraⓇ FCT administered with water under fasted conditions in healthy adult male volunteers. The new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form.

A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL-1401O vs. EU-trastuzumab and US-trastuzumab.

AIMS: Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2-overexpressing breast cancer. MYL-1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL-1401O, reference EU-trastuzumab and US-trastuzumab. METHODS: This single-centre, randomized, double-blind, three-arm, parallel-group, phase 1 study was conducted in healthy adult male volunteers. Subjects were randomized 1:1:1 to receive a single 8 mg kg-1 dose of MYL-1401O, EU-trastuzumab or US-trastuzumab as a 90-min intravenous infusion. The primary objective was to assess PK similarity among all three products. Primary endpoints assessed were peak serum concentration (Cmax), area under the serum concentration-time curve from time of dosing to time of last quantifiable concentration and from time of dosing to infinity. Secondary endpoints included time of Cmax, elimination rate constant, half-life, safety and immunogenicity. RESULTS: Of 132 subjects enrolled (44/treatment), 120 (MYL-1401O, n = 42; EU-trastuzumab, n = 41; US-trastuzumab, n = 37) were included in the PK analysis. The 90% confidence intervals of the ratios of geometric means for the primary endpoints were bounded within the predefined bioequivalence criterion of 80-125%. Secondary endpoints time of Cmax, elimination rate constant and half-life were similar among groups. All treatment-emergent adverse events were mild or moderate, similar across groups and no serious adverse events were reported. No treatment-related antidrug antibodies were detected. CONCLUSIONS: MYL-1401O was well tolerated and demonstrated PK and safety profiles similar to EU-trastuzumab and US-trastuzumab in healthy volunteers (ClinicalTrials.gov, NCT02594761).

A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim.

PURPOSE: Pegfilgrastim is a long-acting granulocyte colony-stimulating factor indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy by promoting neutrophil recovery. METHODS: This phase 1, randomized, double-blind, three-way crossover trial in healthy volunteers evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the proposed biosimilar, comparing MYL-1401H, reference pegfilgrastim (Neulasta®, Amgen Inc, Thousand Oaks, CA, USA) sourced from the European Union, and reference pegfilgrastim sourced from the USA. Primary PK end points were peak plasma concentration of pegfilgrastim (Cmax) and area under the plasma concentration-time curve from the time of dosing to infinity (AUC0-inf). Primary PD end points were area under the curve above baseline for absolute neutrophil counts (ANC AUC0-t) and maximum change from baseline for ANC (ANC Cmax). Adverse events were also recorded. RESULTS: The primary PK and PD end points were similar across all groups. For the PK parameters, the 90% confidence intervals (CIs) of the ratios of geometric means ranged between 0.91 and 1.18, which were within the predefined bioequivalence interval of 0.8000 to 1.2500 for all comparisons. For the PD parameters, the 95% CIs of the ratios of geometric means ranged between 0.94 and 1.06 for all comparisons, which were within the predefined PD equivalence interval of 0.8500 to 1.1765. The safety profiles were similar, with the most common adverse events being back pain and headache. CONCLUSIONS: MYL-1401H demonstrated similar PK, PD, and safety to reference pegfilgrastim in healthy volunteers and may be an equivalent option for the prevention of febrile neutropenia.