Bioequivalence and Pharmacokinetic Comparison between Extended Release Capsules of Carvedilol Phosphate 40mg: An Open Label, Balanced, Randomized-Sequence, Single-Dose, Two-Period Crossover Study in Healthy Male Volunteers

I. Sarath Chandiran^1*, Raghunadha Reddy Seelam², Seelam Sai Satyanaraya Reddy³, Ravindra Reddy S^3
1Professor, Ratnam Institute of Pharmacy, Pidathapolur, SPSR Nellore-524346, Andhra Pradesh, India
²Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, Pine Street, Baltimore, Maryland 21201, USA.
³Vardhaman College of Engineering, Hyderabad, Telangana, India.

A B S T R A C T
This present bioequivalence study was designed to determine the pharmacokinetic, bioavailability and bioequivalence of carvedilol phosphate 40mg Extended Release Capsules in comparison with Coreg CRTM Extended Release Capsules after single dose administration under fed conditions in healthy adult male subjects. Therefore the design of an open label, balanced, randomized, two-sequence, single dose, two ways crossover study with a wash-out period of at least 7 days was used. An open-labeled, balanced, single-dose with food, 2-treatment, 2-period, 2-sequence, randomized crossover study was conducted in 18 healthy male volunteers. Each volunteer received a 40 mg capsule of the reference (or) test drug respectively. On the day of dosing, blood samples were collected before dosing and at various time points up to 50 hours after dosing. Analysis of carvedilol and its metabolite 4-Hydroxy phenyl Carvedilol concentrations was performed using a validated LC-MS/MS method. The pharmacokinetic parameters were analyzed using the non-compartmental model. Drug safety and tolerability were assessed. The primary pharmacokinetic parameters at 90% CI were within the 80 to125% interval required for bioequivalence as stipulated in the current regulations of the USFDA acceptance criteria. The geometric mean ratios (Test/Reference) between the two products of extended-release carvedilol capsule under fed condition were 114.41% (93.68% – 116.74%) and 113.15% (96.67% – 122.45%) for C_max ratios, 101.54% (95.73 – 104.85%) and 102.72% (95.12% – 113.35%) for AUC_0-t ratios and 104.56% (103.24% – 107.58%) and 105.73% (95.45% – 110.50%) for AUC_0-inf ratios of carvedilol and its metabolite 4-Hydroxy phenyl Carvedilol respectively. 18 volunteers had completed both treatments. There was no significant difference of the T_max parameter between the two formulations (p >0.05). No serious adverse events related to the study drugs were found. This single dose study found that  the test formulation carvedilol phosphate ER capsules is bioequivalent to the reference formulation Coreg CR^TM ER capsules the extent & the rate of absorption, of 40 mg under fed condition in healthy adult male volunteers according to the USFDA regulatory guidance.
Keywords: Carvedilol, 4-Hydroxy phenyl carvedilol, Bioavailability, Bioequivalence, Intrasubject Variability