Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects.

An investigational wearable injector (WI), the BD Libertas Wearable Injector (BD Libertas is a trademark of Becton, Dickinson and Company), was evaluated in an early feasibility clinical study for functional performance, tissue effects, subject tolerability, and acceptability of 5 mL, non-Newtonian ~ 8 cP subcutaneous placebo injections in 52 healthy adult subjects of 2 age groups (18-64 years and ≥ 65 years). Randomized WI subcutaneous injections (n = 208, 4/subject) were delivered to the right and left abdomen and thigh of each subject, 50% (1 thigh and 1 abdomen) with a defined movement sequence during injection. Injector functional performance was documented. Deposition was qualified and quantified with ultrasound. Tissue effects and tolerability (pain) were monitored through 24 hours with corresponding acceptability questionnaires administered through 72 hours. WI (n = 205) automatically inserted the needle, delivered 5 mL ± 5% in 5.42 minutes (SD 0.74) and retracted. Depots were entirely (93.2%) or predominantly (5.4%) localized within the target subcutaneous tissue. Slight to moderate wheals (63.9%) and erythema (75.1%) were observed with ≥ 50% resolution within 30-60 minutes. Subject pain (100 mm Visual Analog Scale) peaked mid-injection (mean 9.1 mm, SD 13.4) and rapidly resolved within 30 minutes (mean 0.4 mm, SD 2.6). Subjects' peak pain (≥ 90.2%), injection site appearance (≥ 92.2%) and injector wear, size, and removal (≥ 92.1%) were acceptable (Likert responses) with 100% likely to use the injector if prescribed. Injection site preference was divided between none (46%), abdomen (25%), or thigh (26.9%). The investigational WI successfully delivered 5 mL viscous subcutaneous injections. Tissue effects and pain were transient, well-tolerated and acceptable. Neither injection site, movement or subject age affected injector functional performance or subject pain and acceptability.

Bioequivalence studies of tacrolimus capsule under fasting and fed conditions in healthy male and female subjects.

The bioequivalence of tacrolimus (CAS 104987-11-3) 5 mg capsules was assessed in two single-dose, open-label, randomIzed 2-way crossover trials with a minimum washout period of 14 days; one trial was conducted under fasting condition (n = 44) and the other one under fed condition (n = 48). Blood samples were collected over a 120-h period and concentrations were assayed using a liquid chromatography tandem mass spectrometry (LCMS/MS) method. A non-compartmental method was used for calculation of pharmacokinetic parameters. Under fasting conditions, mean AUC(0-t), AUC(0-inf) and C(max) were comparable between the test (296 ng x h/mL, 318 ng x h/mL and 32 ng/ mL, respectively) and the reference formulations (289 ng x h/mL, 309 ng x h/mL and 33 ng/mL, respectively). T(max) was reached between 1.5 and 2 h post-dose. Mean AUC(0-t), AUC(0-inf) and C(max) were also comparable under fed conditions (154 ng x h/mL, 169 ng x h/mL and 7.6 ng/mL, respectively, for the test and 161 ng x h/mL, 176 ng x h/mL and 7.5 ng/mL, respectively, for the reference formulation). Under fed conditions, T(max) was reached between 5 and 6 h post-dose. 90% geometric confidence intervals were all within the acceptable 80-125% limit, suggesting bioequivalence between the generic product and the innovator product.

In vitro disintegration and dissolution and in vivo bioequivalence of two alendronate once-weekly formulations.

Bioequivalence of two tablet formulations of 70 mg alendronate (CAS 121268-17-5) was assessed in a single-dose, open-label, randomised, fasted state crossover trial, with a washout period of 21 days, in 80 healthy subjects. Urine samples were collected up to +36 h post dosing and the concentrations of alendronic acid were assessed using a high-performance liquid chromatographic method with pre-derivatization and fluorescence detection (HPLC/FL) method. The 90 % confidence intervals (90 % CI) obtained for Ae0-36 (cumulative urinary excretion) and Rmax (maximum rate of urinary excretion) were 98.67-118.99 % and 102.22-122.46 %, respectively. The intra-subject coefficient of variation was between 32-35 % for both parameters. No relevant tolerability problems were detected. Both formulations can be considered bioequivalent. In vitro testing was performed to confirm the adequacy of the quality control conditions and no significant differences were detected neither in the disintegration test nor in the dissolution tests conducted in HCl 0.1 N and H2O and thus in these conditions the lack of statistically significant differences in vitro was accompanied by in vivo bioequivalence.

Comparative bioavailability of two formulations of terbinafine. Data from a cross-over, randomised, open-label bioequivalence study in healthy volunteers.

An open-label, randomised, cross-over single dose study, using 2 periods x 2 sequences, with a minimum washout period of 21 days, was conducted in order to assess the comparative bioavailability of two formulations of terbinafine (CAS 78628-80-5) 250 mg tablets. Plasma samples were obtained at baseline, +0.333; 0.667; 1.00; 1.33; 1.67; 2.00; 2.33; 2.67; 3.00; 3.50; 4.00; 6.00; 8.00; 12.0; 24.0; 36.0; 48.0 and 72.0 h post-administration. Terbinafine levels were determined by high pressure liquid chromatography with tandem mass detection (HPLC-MS/MS) and the lower limit of quantification was set at 9.99 ng/mL. The pharmacokinetic parameters used for the bioequivalence assessment (AUClast, AUCinf and Cmax) were determined from the terbinafine concentration data using non-compartmental analysis. Classical 90% confidence intervals (90CI) were calculated for the overall sample, and for males and females separately, and gender effects were investigated using an appropriate model. The results showed that overall classical 90CI were 96.08-105.40% for AUCinf, 95.68-105.33 for AUClast and 88.24-112.83 for Cmax, that is, all within the predefined ranges for bioequivalence acceptance. Separate gender analysis showed very similar results for males and females when analysed independently, and no gender effects were detected (p>0.05 for all of the tested model effects). It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

Bioequivalence studies on bisphosphonates: the example of alendronate.

The study was designed to evaluate the bioequivalence of two formulations of alendronate (CAS 121268-17-5, Osalen 10 mg tablets, in the following referred to as "test" vs. the originator product, in the following referred to as "reference") in 89 healthy male and female volunteers, who were administered four 10 mg alendronate tablets under fasting conditions. The trial was performed according to an open, randomized, cross-over design with a wash-out period of 14 days in one study center. Urine samples were taken up to 36 h post dose, and the concentrations of alendronate were determined by HPLC/Fl method. The mean Ae0-36 were 102.89 +/- 57.52 microg and 96.23 +/- 60.81 microg for the test and reference formulations, respectively, while the mean Rmax were 36.15 +/- 21.07 microg/h and 35.36 +/- 22.88 microg/h, respectively. The test and reference tablets Tmax were 0.592 +/- 0.858 h and 0.583 +/- 0.858 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence interval for the primary target parameters, intra-individual ratios of Ae0-36 and Rmax of alendronate were between 1.01 and 1.17 for Ae0-36 and between 0.96 and 1.11 for Rmax, and thus within the acceptance range for bioequivalence trials. In the light of the present study it can be concluded that alendronate test tablets are bioequivalent to the reference formulation.

Bioequivalence study of clopidogrel bisulfate film-coated tablets.

The aim of the present study was to evaluate the bioequivalence of two clopidogrel (CAS 120202-66-6) formulations. The study was performed according to an open, cross-over design in one study center in 36 healthy male and female volunteers, comparing a new generic product (tablets containing clopidogrel bisulfate, 75 mg) with the originator product (reference). In each of the two study periods (separated by a wash-out of 7 days) a single dose of 150 mg (test or reference) was administered. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of clopidogrel were determined by an LC/MS/MS method. AUC0-inf, AUC0-t, Cmax, Tmax and T(1/2 el) were calculated for both formulations. The mean AUC0-inf, AUC0-t and Cmax were 29.94 ng x h/mL, 29.53 ng x h/mL and 7.386 ng/mL, respectively, for the test formulation and 29.24 ng x h/mL, 28.83 ng x h/mL and 7.921 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1.25 h. The point estimators of the ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 101.17%, 101.13% and 90.96%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf and AUC0-t were narrow and symmetrical around 100%, i.e. from 96.38% to 106.21% for AUC0-inf and from 96.20% to 106.30% for AUC0-t, whereas the confidence interval for Cmax was 84.07% to 98.41%. In can be concluded that the two clopidogrel formulations (test formulation of clopidogrel bisulfate and reference formulation) are bioequivalent in terms of the rate and extent of absorption.

In vivo bioequivalence of oral antidiabetic agents: pioglitazone tablets.

The study was designed to evaluate the bioequivalence of two pioglitazone (CAS 112529-15-4) formulations. The trial was performed in 26 healthy male volunteers with the aim of comparing a new generic product (tablets containing 30 mg pioglit-azone hydrochloride, test) with the originator product (reference). The trial was performed according to an open, crossover design in one study centre. In each of the two study periods (separated by a wash-out of 14 days) a single oral dose of 30 mg (test or reference) formulation was administered. Blood samples were taken up to 120 h post dose, the plasma was separated and the concentrations of pioglitazone and its principal active metabolite hydroxypioglitazone were determined by LC-MS-MS method. AUC0-inf, AUC0-t, Cmax, and Tmax were calculated for both formulations. The mean Cmax of pioglitazone ranged between 1.01 microg/mL and 1.05 microg/mL, while the mean AUC0-inf and AUC0-t ranged between 10.89 microg x h/mL and 10.98 microg x h/mL as well as between 10.56 microg x h/mL and 10.62 microg x h/mL for the test and reference formulations, respectively. The median Tmax for the test tablets was 1.50 h and for the reference was 1.75 h. The ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 99.70%, 100.13% and 99.17%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf were narrow and symmetrical around 100%, i.e. 90.59% to 109.72%, for AUC0-t, 90.69% to 110.55%, whereas for Cmax they were 87.52% to 112.37%. As in the case of pioglitazone, mean values of the principal bioequivalence parameters of hydroxypioglitazone did not differ significantly after administration of the test and reference formulations. In the light of the present study it can be concluded that the two evaluated pioglitazone formulations, i.e. test formulation of pioglitazone hydrochloride and reference formulation, are bioequivalent in terms of the rate and extent of absorption.