Venkateswarlu Vobalaboina

Bioequivalence of two lansoprazole delayed release capsules 30 mg in healthy male volunteers under fasting, fed and fasting-applesauce conditions: a partial replicate crossover study design to estimate the pharmacokinetics of highly variable drugs.

An open-label, 2-treatment, 3-sequence, 3-period, single-dose, partial replicate crossover studies under fasting (n=48), fed (n=60) and fasting-applesauce (n=48) (sprinkled on one table spoonful of applesauce) modalities were conducted in healthy adult male volunteers to evaluate bioequivalence between 2 formulations of lansoprazole delayed release capsules 30 mg. In all the 3 studies, as per randomization, either test or reference formulations were administered in a crossover manner with a required washout period of at least 7 days. Blood samples were collected adequately (0-24 h) to determine lansoprazole plasma concentrations using a validated LC-MS/MS analytical method. To characterize the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞, Tmax, Kel and T1/2) of lansoprazole, non-compartmental analysis and ANOVA was applied on ln-transformed values. The bioequivalence was tested based on within-subject variability of the reference formulation. In fasting and fed studies (within-subject variability>30%) bioequivalence was evaluated with scaled average bioequivalence, hence for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞, the 95% upper confidence bound for (μT-μR)2-θσ2 WR was ≤0, and the point estimates (test-to-reference ratio) were within the regulatory acceptance limit 80.00-125.00%. In fasting-applesauce study (within-subject variability<30%) bioequivalence was evaluated with average bioequivalence, the 90% CI of ln-transformed data of Cmax, AUC0-t and AUC0-∞ were within the regulatory acceptance limit 80.00-125.00%. Based on these aforesaid statistical inferences, it was concluded that the test formulation is bioequivalent to reference formulation.

Pharmacokinetics of two formulations of alendronate sodium/cholecalciferol (vitamin D3) tablets 70 mg/5600 IU: An open-label, randomized, single-dose, two-treatment, two-period, two-sequence, cross-over, bioequivalence study

Abstract A fixed dose combination of alendronate and cholecalciferol (vitamin D3) 70 mg/5600 IU tablets has been indicated for the treatment of osteoporosis. This study was aimed to assess bioequivalence between test and reference formulations of alendronate sodium/cholecalciferol (vitamin D3) tablets 70 mg/5600 IU in 110 healthy adult male volunteers under fasting conditions. This was an open label, randomized, single dose, two way cross-over study, separated by a washout period of 14 days. All possible efforts were made to stabilize the baseline endogenous levels of cholecalciferol. Blood samples were collected from 96 h pre-dose to 96 h post-dose and 0–24 h for cholecalciferol and alendronate, respectively. Quantification of alendronate and cholecalciferol was done using distinct validated LC-MS/MS methods. Two baseline adjusted methods, method-I (subtraction of the average concentration from each post-dose concentration) and method-II (subtraction of the individual AUC from post-dose AUC) were applied for deriving the AUC0–t parameter of cholecalciferol, among which bioequivalence was concluded based on data obtained using method-I. The 90% CI of Cmax and AUC0–t for alendronate and baseline adjusted cholecalciferol were within the regulatory acceptance limit of 80.00–125.00% and considered as bioequivalent.

Comparative bioavailability study of capecitabine tablets of 500 mg in metastatic breast cancer and colorectal cancer patients under fed condition

Capecitabine (oral prodrug of 5-fluorouracil) is the first-line treatment for the metastatic breast and colorectal cancer. The objective of the study was to determine the bioequivalence between the test product (capecitabine tablets 500 mg) of Dr. Reddy’s Laboratories Limited relative to that of reference product XELODA® (capecitabine) 500 mg tablets of Roche Registration Inc. in patients of metastatic breast or colorectal cancer stabilized with twice daily dosing of capecitabine monotherapy. This was an open-label, randomized, single dose, two-way cross-over bioequivalence study under fed conditions. The subjects received either of the treatments (test or reference) 30 min after consumption of a high fat, high calorie breakfast as a single morning dose of 2000 mg on two separate days (days 1 and 2) based on their body surface area. Blood samples were collected up to 10 h post-dose and analyzed for capecitabine using the validated liquid chromatographic mass spectrometric (LC-MS/MS) method. The least square mean ratio and 90% confidence intervals of Cmax, AUC0–t and AUC0–∞ were within the regulatory acceptance criteria of 80.00–125.00% and considered as bioequivalent.

Bioequivalence study of two subcutaneous formulations of dalteparin: randomized, single-dose, two-sequence, two-period, cross-over study in healthy volunteers

Abstract Objective: This study assessed relative bioavailability of a new subcutaneous formulation, test (T) (dalteparin sodium 95000 IU/3.8 mL) with the branded product (R) in healthy subjects to meet the regulatory requirements of bioequivalence in the US. Methods: This was an open label, randomized, single dose, two-sequence, two-period cross-over study under fasting conditions. A total of 88 healthy adult volunteers were randomized to either of the treatment arms (T or R) separated by a washout period of 7 days. Pharmacodynamic surrogates, namely anti-Xa and anti-IIa activity, heparin clotting assay (heptest), and activated partial thromboplastin time (aPTT) were used as a tool to establish bioequivalence between these two formulations. Blood samples were collected up to 36 h post-dose to characterize the primary pharmacokinetic parameters Amax, AUC0–t, and AUC0–∞ for anti-Xa and anti-IIa and heptest; parameters (Δt )max and AU(Δt ) for aPTT. Results: For anti-Xa activity, the means (SD) of Amax (IU/mL) were 1.34 (0.25) [range = 0.59–2.03] and 1.39 (0.35) [range = 0.65–2.69]; AUC0–t (IU•h/mL) values were 11.4 (2.76) [range = 2.89–19.5] and 12.1 (2.87) [range = 2.52–21.30]; AUC0–∞ (IU•h/mL) values were 13.1 (3.59) [range = 3.15–28.2] and 14.5 (4.97) [range = 2.79–36.1] for test and branded formulations, respectively. For anti-IIa activity, the means (SD) of Amax (IU/mL) were 0.34 (0.12) [range = 0.14–0.72] and 0.34 (0.13) [range = 0.11–0.84]; AUC0–t (IU•h/mL) values were 2.05 (0.72) [range = 0.61–4.69] and 2.11 (0.76) [range = 0.84–4.80]; AUC0–∞ (IU•h/mL) values were 2.47 (0.80) [range = 0.76–6.29] and 2.61 (0.86) [range = 1.31–5.36], for test and branded formulations, respectively. The 90% CI for all the primary pharmacokinetic parameters of all the pharmacodynamic surrogates tested met the regulatory bioequivalence criterion of 80.00–125.00%. Conclusion: The test product met the US regulatory criteria of bioequivalence relative to the branded product in this single dose bioequivalence study. Study limitations include open-label single dose design.

Bioequivalence of fixed dose combination of atorvastatin 10 mg and aspirin 150 mg capsules: a randomized, open-label, single-dose, two-way crossover study in healthy human subjects.

The present study evaluated the bioavailability and bioequivalence of fixed dose combination test formulation (atorvastatin 10 mg and aspirin 150 mg capsule) against marketed reference formulations (Lipitor® tablets 10 mg and Nu-Seals tablets 75 mg). This study was an open label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover trial in 80 healthy adult human volunteers under fasting conditions. Plasma concentrations of atorvastatin, aspirin and salicylic acid were quantified using LC-MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental model and mean pharmacokinetic parameters were comparable between test and reference formulations. The mean pharmacokinetic parameters (AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞) for atorvastatin test and reference formulations were (52.69 ng.h/mL, 55.64 ng.h/mL, 9.45 ng/mL, 0.18 1/h and 0.17 1/h) and (52.20 ng.h/mL, 55.38 ng.h/mL, 10.25 ng/mL, 0.20 1/h and 0.19 1/h) respectively; and for aspirin were (1 378.62 ng.h/mL, 1 383.90 ng.h/mL, 1 022.18 ng/mL, 0.75 1/h and 0.75 1/h) and (1 314.17 ng.h/mL, 1 314.50 ng.h/mL, 985.90 ng/mL, 0.75 1/h and 0.75 1/h) respectively. Where as for salicylic acid, above parameters were (42 357.57 ng.h/mL, 44 139.47 ng.h/mL, 9 820.15 ng/mL, 0.24 1/h and 0.23 1/h) and (40 217.08 ng.h/mL, 42 032.44 ng.h/mL, 9 569.18 ng/mL, 0.24 1/h and 0.24 1/h) respectively for test and reference formulations. The 90% confidence intervals of atorvastatin and salicylic acid for AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞ parameters were found to be within the acceptable regulatory bioequivalence limits. In conclusion, the new fixed dose combination test formulation was bioequivalent to the reference formulations under fasting conditions.

Steady state bioequivalence study of dipyridamole ER and acetyl salicylic acid 200 mg + 25 mg capsules in adult healthy male and female volunteers under fasting condition

Abstract The aim of the study was to evaluate the steady state pharmacokinetics and establish bioequivalence between the test (dipyridamole ER and acetyl salicylic acid 200 mg + 25 mg capsules of Dr. Reddy’s Laboratories Limited, India) against equal doses of reference (AGGRENOX® retard capsule of Boehringer Ingelheim Pharma GmbH & Co., KG 55216 Ingelheim am Rhein, Germany) formulations in 72 healthy adult male and female volunteers under fasting conditions. This was an open-label, block randomized, multiple dose, two-period, two-sequence, cross-over study separated by a washout period of 8 days. On day 5 of each period, post-dose blood samples were collected up to 12 h and analyzed for dipyridamole, salicylic acid and acetyl salicylic acid using a validated LC-MS/MS method. The 90% CI for dipyridamole (AUC(0–τ).ss, Cmax.ss and Cmin.ss) and for salicylic acid (AUC(0–τ).ss, Cmax.ss and %ptf) lie within the accepted bioequivalence range of 80.00–125.00%, thus permitting one to conclude for bioequivalence. In conclusion, both the formulations were well tolerated and the test product was bioequivalent to the reference product in terms of the rate and extent of absorption at steady state.

Single dose pharmacokinetics and bioequivalence of conjugated estrogens (0.625 mg × 2) tablets in healthy post-menopausal female subjects in fasting and fed studies

Abstract Conjugated estrogens are sulfate esters of naturally occurring estrogens. The pharmacokinetics of various estrogen formulations is complex and varying due to its endogenous availability. The present studies were designed to evaluate pharmacokinetic parameters and bioequivalence between two formulations of conjugated estrogens (0.625 mg tablets). Both the studies were designed as two-treatment, four-period, replicate cross-over single dose studies in 60 healthy post-menopausal female subjects under fasting and fed conditions, respectively. Since estrone is present endogenously, for baseline correction three pre-dose samples were obtained for total and unconjugated estrone. Plasma samples were analyzed by validated LC-MS/MS method and pharmacokinetic parameters were estimated for total and unconjugated forms of both estrone and equilin. The least square mean ratios and its 90% confidence interval for primary pharmacokinetic parameters Cmax, AUC0–t and AUC0–inf were found to be within bioequivalence limits of 80.00–125.00% for total and unconjugated forms of baseline corrected estrone and baseline un-corrected equilin. In conclusion, both test and reference products were well-tolerated and the test product was bioequivalent with the reference product in terms of the rate and extent of absorption in both fasting and fed studies.

Steady-state pharmacokinetics and bioequivalence study of quetiapine fumarate film-coated tablets 300 mg in adult schizophrenic patients

Quetiapine is a dibenzothiazepine derivative approved for the treatment of schizophrenia and related psychoses. The objective of the present study was to design and evaluate the bioequivalence between quetiapine fumarate film-coated tablets of Dr. Reddy’s Laboratories Ltd., Hyderabad, India (test) and Seroquel® tablets (containing quetiapine) of AstraZeneca Pharmaceuticals LP Wilmington, DE, USA (reference). It was a two-way crossover steady-state multiple dose study in 54 adult schizophrenic patients under fasting conditions. Quetiapine was analyzed in plasma samples by using a validated liquid chromatographic mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters were estimated by noncompartmental method and mean (±SD) of Cmax,ss (ng/mL) for test and reference products were 1436.5 (±810.2) and 1413.1 (±905.5), respectively. The mean (±SD) of AUCτ,ss (ng·h/mL) for test and reference products were 6949.8 (±3879.8) and 6532.2 (±4279.4), respectively. The ratio of least square means and its 90% confidence interval for Cmax,ss and AUCτ,ss were found to be within bioequivalence limits 80.00–125.00%. In conclusion, test product was bioequivalent to the reference product in terms of both rate and extent of absorption under steady-state conditions.