Bioequivalence study of two losartan tablet formulations with special emphasis on cardiac safety.

OBJECTIVES: To study the bioequivalence of Losartan Potassium Tablets 50 mg manufactured by Micro Labs Ltd. India to Cozaar® Tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in normal healthy adult subjects under fasting condition along with the comparative safety evaluation of both treatments. MATERIALS AND METHODS: The in vitro dissolution studies were carried out on 12 units each of test and reference products using the paddle method and dissolution media like water, 0.1 N hydrochloric acid with pH 1.2, pH 4.5 acetate buffer and pH 6.8 phosphate buffer. An open label, randomized, two-treatment, two-period, two-sequence, crossover bioequivalence study with a washout period of 7 days was conducted in 60 healthy Indian male subjects. Serial blood samples were collected after drug administration in each study period. Plasma concentrations of losartan and losartan acid were determined using a validated LC-MS-MS method. The pharmacokinetic parameters of losartan and losartan acid were determined using a non compartmental model. Occurrence of adverse events, change in systolic blood pressure, diastolic blood pressure, heart rate and QT interval from the baseline to 3.50 h post dose were studied and compared between the two treatments as safety parameters. RESULTS: The in vitro study proved the essential similarity of both the formulations as evident from the similarity factor of > 50% in all the dissolution media. The ratios for geometric least square means and 90% confidence intervals were within the acceptance criteria of 80% to 125% for log transformed C(max), AUC(0-t) and AUC(0-∞) for losartan. No statistically significant difference between the two treatments was observed for either of the safety parameters. CONCLUSIONS: The test product Losartan Potassium tablets 50 mg manufactured by Micro Labs Limited, India was bioequivalent to Cozaar® tablets 50 mg, manufactured by Merck Sharp and Dohme Ltd., UK in terms of rate and extent of absorption. Both treatments were well tolerated and had similar non significant effect on the safety parameters.

Comparative pharmacokinetic and pharmacodynamic evaluation between a new biosimilar and reference recombinant human growth hormone.

OBJECTIVE: To extend available dosing options in the treatment of growth hormone deficiency, a comparative pharmacokinetic and pharmacodynamic phase-1 clinical study involving subcutaneous administration of growth hormone was conducted. DESIGN: The test formulation (biosimilar recombinant human growth hormone; r-hGH; Somatotropin) and reference formulation (Genotropin®) were tested in 38 adult healthy subjects after their subcutaneous administration of 12.8IU in an open label, single dose, randomized, two period cross over study separated with a washout period of 11days. Endogenous growth hormone release was suppressed by a continuous Octreotide infusion up to 24h after r-hGH administration. All the subjects were evaluated for local tolerance using Wong-Baker Faces pain rating scale and an injection site reaction (ISR) score. Detection of serum levels of r-hGH, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) was done by suitable validated bio-analytical methods. Assessment of bioequivalence for pharmacokinetic parameters was done using log-transformed area under the curve (AUC) and maximum concentration (Cmax) for r-hGH. The pharmacodynamic assessment was done by comparing the area under the effect-time curve (AUEClast) and maximum measured effect concentration (Emax) of IGF-1 and IGFBP-3. RESULTS: The biosimilar formulation of recombinant human growth hormone fulfilled the predefined bioequivalence criteria for pharmacokinetic and pharmacodynamic parameters. CONCLUSION: The new biosimilar recombinant human growth hormone bears the potential to become an alternative option for the treatment of growth hormone deficiency.

Comparative bioequivalence studies of tramadol hydrochloride sustained-release 200 mg tablets.

BACKGROUND: Tramadol hydrochloride is available as 50 mg immediate-release (IR) and 100 mg, 200 mg, and 300 mg sustained-release (SR) tablets. The recommended dose of tramadol is 50-100 mg IR tablets every 4-6 hours. The tramadol SR 200 mg tablet is a better therapeutic option, with a reduced frequency of dosing, and improved patient compliance and quality of life. The present study evaluated the bioequivalence of a generic tramadol SR 200 mg tablet. METHODS: A comparative in vitro dissolution study was performed on the test and reference products, followed by two separate single-dose bioequivalence studies under fasting and fed conditions and one multiple-dose bioequivalence study under fasting conditions. These bioequivalence studies were conducted in healthy human subjects using an open-label, randomized, two-treatment, two-period, two-sequence, crossover design. The oral administration of the test and reference products was done on day 1 for both the single-dose studies and on days 1-5 for the multiple-dose study in each study period as per the randomization code. Serial blood samples were collected at predefined time points in all the studies. Analysis of plasma concentrations of tramadol and O-desmethyltramadol (the M1 metabolite) was done by a validated liquid chromatography-mass spectrometry analytical method. The standard acceptance criterion of bioequivalence was applied on log-transformed pharmacokinetic parameters for tramadol and its M1 metabolite. RESULTS: The ratios for geometric least-square means and 90% confidence intervals were within the acceptance range of 80%-125% for log-transformed primary pharmacokinetic parameters for tramadol and its M1 metabolite in all the three studies. CONCLUSION: The test product is bioequivalent to the reference product in terms of rate and extent of absorption, as evident from the single-dose and multiple-dose studies. Both the treatments were well tolerated.