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.

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.

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

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 A max, 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 A max (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 A max (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.

Comparative bioavailability of two sertraline tablet formulations after single-dose administration in healthy Thai volunteers.

OBJECTIVE: To compare the bioavailability of two sertraline tablet (50 mg) formulations (Serlift from Ranbaxy Laboratories Ltd., Gurgaon Haryana, India, as a test formulation and Zoloft from Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia, as a reference formulation) in 24 healthy Thai male volunteers under fasting condition. MATERIALS AND METHODS: A randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover study with a washout period of 3 weeks, was conducted in 24 healthy Thai male volunteers. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 48, 72, 96 and 120 hours following drug administration. Plasma concentrations of sertraline were determined using validated LC-MS/MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS software for Windows, release 9.1 (SAS Institute Inc., Cary, NC, USA). RESULTS: The ratio of least square means and the 90% confidence intervals (CI) of the log-transformed data were 0.9950 (0.9111-1.0866) for Cmax, 1.0153 (0.9576-1.0764) for AUC(0-t) and 1.0110 (0.9510-1.0747) for AUC(0-infinity). In addition, the median tmax values for the test and reference formulations were similar (5.00 h). The 90% CI for Cmax, AUC(0-t) and AUC(0-infinity) were within the 0.8-1.25 interval of the US-FDA. CONCLUSIONS: The test formulation (Serlift, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India) is bioequivalent to the reference formulation (Zoloft, Pfizer Australia Pty Ltd., West Ryde, New South Wales, Australia) both in terms of rate and extent of absorption after single-dose administration under fasting condition.

A bioequivalence study comparing two formulations of lopinavir/ritonavir capsules.

This investigation was carried out to evaluate the bioavailability of a new single fixed-dose combination formulation of lopinavir and ritonavir, relative to reference product, Kaletra (133.3 mg lopinavir/33.3 mg ritonavir) capsules, manufactured by Abbott Laboratories, Chicago, IL, USA. The bioavailability study was carried out on 72 healthy male and female volunteers who received a single dose of 3 capsules (133.3 mg lopinavir/33.3 mg ritonavir) of the test (T) and the reference (R) products in the fasting state, in a randomized, balanced, 2-way crossover design. After dosing, serial blood samples were collected for a period of 72 hours. Plasma harvested from blood was analyzed for lopinavir and ritonavir by a sensitive and validated simultaneous liquid-chromatographic and mass-spectrometric (LC-MS/MS) assay. Mean oral clearance (Cl/F) values of the FDC were 4.92 and 23.54 l/h for lopinavir and ritonavir, respectively, the maximum plasma concentrations (C(max)), area under the plasma concentration-time curve up to the last measurable concentration (AUC(0-t)), and to infinity (AUC(0-infinity)), were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (t(max)) was analyzed assuming an additive model. The parametric confidence intervals (90%) were calculated by Schuirmann's two 1-sided t-test criteria. It was found that the test/reference (T/R) ratios for the pharmacokinetic parameters AUC(0-t), AUC(0-infinity) and C(max) (after initial log transformation) were well within the bioequivalence acceptance range of 80-125% as per international regulatory guidelines. Therefore, the two formulations were considered to be bioequivalent [Food and Drug Administration 2003].

Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products.

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC(0-t), AUC(0-infinity), and C(max) for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.

Comparative bioavailability/bioequivalence of two different stavudine 40 mg capsule formulations: a randomized, 2-way, crossover study in healthy volunteers under fasting condition.

PURPOSE: The aim of this study was to compare the single-dose oral bioavailability of two formulations of stavudine 40 mg capsules in healthy human subjects. METHODS: A bioequivalence study of two oral capsule formulations of 40 mg stavudine was carried out in 40 healthy volunteers following a single-dose, 2-sequence, crossover and randomized design. The two formulations were stavudine 40 mg capsules (Ranbaxy Laboratories Ltd., Haryana, India) as test and zerit 40 mg capsules (Bristol-Myers Squibb, Princeton, NJ, USA) as reference product. Test and reference capsules were administered to each subject in each period separated by a 3-day washout period. Serial blood samples were collected for a period of 10 h. Blood plasma was analyzed for stavudine using a sensitive, reproducible, accurate and validated LC-MS/MS method. Pharmacokinetic parameters, including AUC(0-t), AUC(0-inf), C(max), t(max), t(1/2) and lambda(z), were determined from plasma concentrations for both formulations. AUC(0-t), AUC(0-inf) and C(max) were tested for bioequivalence after log-transformation of data. RESULTS: The LC-MS/MS method, used to quantify stavudine in human plasma, was specific and sensitive for stavudine. Plasma concentration profiles of stavudine test and reference treatments were similar. Geometric mean ratios and 90% confidence intervals for C(max), AUC(0-t) and AUC(0-inf) for stavudine were 99.9 (93.9-106), 99.9 (98.4-101) and 99.8 (98.2-101), respectively. Untransformed results for the same parameters were consistent with the natural log-transformed data. CONCLUSION: The two stavudine 40 mg capsule formulations examined were bioequivalent and may be used interchangeably in medical practice.

Nevirapine/lamivudine/stavudine as a combined-formulation tablet: bioequivalence study compared with each component administered concurrently under fasting condition.

OBJECTIVE: The objective of the study was to compare the bioequivalence of a fixed-dose combination of a nevirapine 200 mg, lamivudine 150 mg and stavudine 30 mg combination tablet with application of the 3 medications, at the same dosage, concurrently as separate formulations, in healthy, adult subjects under fasting conditions. MATERIAL AND METHODS: An open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose, crossover bioavailability study was conducted in 40 subjects with 21-day washout period between each treatment. Blood samples were collected for 168 hours. Plasma concentrations of nevirapine, lamivudine and stavudine were determined using a validated LC-MS-MS method. Noncompartmental pharmacokinetics and statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA) software (SAS System under Windows, Version 8.02). RESULTS: The ratios of least-square means and the 90% confidence intervals of the log-transformed data were calculated for AUC(0-t), AUC(0-inf), and Cmax. The 90% confidence interval for least-square mean ratio between test and reference formulation for log-transformed parameters Cmax, AUC(0-t) and AUC(0-inf) were within the requirements of the 80-125% range. CONCLUSION: The test formulation (Ranbaxy Laboratories Ltd., Gurgaon, India) is bioequivalent to the reference formulations both in terms of rate and extent of absorption after single-dose administration under fasting condition.

Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions.

OBJECTIVE: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. MATERIAL AND METHODS: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. RESULTS: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.

Comparative bioavailability study of zidovudine administered as two different tablet formulations in healthy adult subjects.

AIM: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. VOLUNTEERS AND METHODS: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. CONCLUSION: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.

Comparative bioavailability of a generic capsule formulation of the reverse transcriptase inhibitor efavirenz and the innovator product.

OBJECTIVE: Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been used successfully for more than a decade to treat human immunodeficiency virus (HIV) infection. The objective of the current study was to determine the bioequivalence between a generic capsule formulation of efavirenz and the innovator product. MATERIAL AND METHODS: A total of 41 healthy subjects (34 males and 8 females) received a single 200 mg oral dose of efavirenz as the generic (Ranbaxy-Efavirenz, Ranbaxy Laboratories Ltd.) and innovator (Sustiva, Bristol-Myers Squibb) capsule formulations under fasting conditions in a randomized, 2-way crossover study. Multiple blood samples were collected over 72 hours and plasma concentrations of efavirenz were assayed using an LC/MS/MS method. Pharmacokinetic (PK) parameters were calculated using non-compartmental methods. RESULTS: Plasma concentrations of efavirenz peaked within 2.5 hours and then declined in a multi-exponential manner for both formulations. At 72 hours post dose, all plasma concentrations of efavirenz were above the LOQ of the assay (10 ng/ml). Mean area under the curve from 0 - 72 hours (AUC0-72) and maximum plasma concentrations (Cmax) of efavirenz for the generic capsule formulation were 22,840 ng x h/ml and 1,199 ng/ml, respectively. Ratios and 90% confidence intervals of PK parameters between the two formulations were within 80.0 - 125.0%, suggesting that the two capsule formulations resulted in similar rate and extent of bioavailability under fasting conditions. Adverse events were similar in nature and frequency for the two formulations. CONCLUSIONS: Based on the above results, the generic capsule formulation of efavirenz developed by Ranbaxy should be as effective as the innovator product.