Efficacy and safety of ipratropium bromide/salbutamol sulphate administered in a hydrofluoroalkane metered-dose inhaler for the treatment of COPD.

BACKGROUND: The use of chlorofluorocarbons (CFCs) has contributed to the depletion of the stratospheric ozone layer resulting in serious health concerns. Ipratropium bromide/salbutamol sulphate CFC-pressurized metered-dose inhalers (IB/SAL-CFC pMDI) have been in widespread use for many years without any apparent ill consequences. This combination has now been reformulated using the hydrofluoroalkane (HFA) propellant. This study sought to establish the clinical noninferiority of a new HFA-containing IB/SAL pMDI to the conventional IB/SAL-CFC pMDI in subjects with mild/moderate COPD. METHODS: This was a randomized, double-blind, parallel-group, multicenter study in two consecutive periods: a 14-day run-in period followed by a 85-day treatment period. Eligible mild-to-moderate stable COPD subjects aged 40-75 years were enrolled into the study and entered the run-in period during which subjects withdrew all the bronchodilators, except for salbutamol as rescue medication. Subjects were randomized to 85 days treatment with either IB/SAL-HFA or IB/SAL-CFC, 20 µg qid. RESULTS: Of the 290 randomized patients, 249 completed the study. The primary efficacy variable was the change in forced expiratory volume in one second from predose to 60 minutes after dosing on day 85. At the end of the treatment period, the adjusted mean change in forced expiratory volume in one second at 60 minutes was 123 mL in the IB/SAL-HFA pMDI group and 115 mL in the IB/SAL-CFC pMDI group. Because the lower limit of the 95% confidence interval for the between-group difference (-62 mL) was well within the noninferiority margin (-100 mL), the HFA formulation was deemed clinically noninferior to the CFC formulation. This finding was supported by secondary efficacy assessments. Both formulations of IB/SAL were well tolerated during the prolonged multiple dosing. CONCLUSION: It is concluded that IB/SAL-HFA pMDI provides effective bronchodilation of similar degree to that achieved with IB/SAL-CFC pMDI. Therefore, IB/SAL-HFA pMDI is a valuable alternative to IB/SAL-CFC pMDI.

A combined-formulation tablet of lamivudine/nevirapine/stavudine: bioequivalence compared with concurrent administration of lamivudine, nevirapine, and stavudine in healthy Indian subjects.

Generic fixed-dose combinations of antiretrovirals are frequently prescribed for the treatment of human immunodeficiency virus infection. A randomized, 2-way study was conducted in 24 fasting, healthy, Indian male subjects to assess bioequivalence between a single combination tablet containing lamivudine, stavudine, and nevirapine (treatment A) with respect to separate marketed tablets administered simultaneously (treatment B). Each subject received treatments A and B separated by 19 days of a drug-free washout period. Plasma concentrations of antiretrovirals, determined by a validated liquid chromatography/tandem mass spectrometry assay, were used to assess pharmacokinetic parameters such as maximum observed plasma concentration and area under the plasma concentration curve. Pharmacokinetic parameters were comparable for either treatment. As geometric mean ratios (% treatment A/treatment B) of log-transformed parameters of area under the plasma concentration curve and plasma concentration, as well as their resultant 90% confidence intervals, were within 80% to 125% and 75% to 133%, respectively, 2 treatments were considered bioequivalent in the extent and rate of absorption. Both treatments exhibited similar tolerability under fasting conditions.

Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India.

This article describes regulatory approaches for approval of "generic" orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the "original" product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as "generic" and "reference" drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.

Comparison of pharmacokinetics and safety profiles of two capecitabine tablet formulations in patients with colon, colorectal or breast cancer.

PURPOSE: The objective of this study was to compare the pharmacokinetics and safety of two tablet formulations containing 500 mg of capecitabine (CAS number 154361-50-9) in patients with colon, colorectal or breast cancer. METHODS: The study was a multicentric, open label, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study in patients of either sex with colon, colorectal or breast cancer. Eligible patients received each treatment in a crossover manner under fed conditions according to the randomization schedule. The pre-dose blood sample was taken within 90 min prior to dosing, and serial blood sampling was done up to 10.00 h post-dose under monochromatic light. The analysis of plasma samples for concentrations of capecitabine and 5'-deoxy-5-fluorocytidine (5'-DFCR) was carried out using a validated liquid chromatography mass spectrometry method. Bioequivalence was to be concluded if the confidence intervals so constructed were within the range of 80-125 % for C(max), AUC(0-t) and AUC(0-∞) of capecitabine and 5'-DFCR. Patients were monitored for safety and tolerability throughout the study. RESULTS: The 90 % confidence intervals for the "test/reference" mean ratios of the ln-transformed pharmacokinetic variables C(max), AUC(0-t) and AUC(0-∞) were clearly within the conventional bioequivalence range of 80-125 %. Both the formulations were reasonably tolerated after a single oral dose in patients. CONCLUSIONS: Both the capecitabine tablet formulations demonstrated equivalent rate and extent of systemic absorption, and hence were considered bioequivalent. Therefore, the two formulations can be considered as equivalent in terms of pharmacokinetics and safety profiles.

Comparative bioavailability of two hydrofluoroalkane formulations of formoterol fumarate both delivered by pressurised metered dose inhaler.

A randomised, open-label, single dose, four-period crossover study was performed in healthy male human subjects to compare the pharmacokinetics of formoterol fumarate (CAS 43229-80-7) after inhalation from two different hydrofluoroalkane (HFA) pressurised metered dose inhaler (pMDI) formulations at two dose levels, 12 and 24 microg. This is the first study which has evaluated two HFA formulations of formoterol. Fourteen subjects were randomised, of which 13 completed the study. Each subject received in separate periods a single dose of 12 microg or 24 microg of each formulation. Blood samples for determination of formoterol plasma concentrations were taken pre-administration of study treatments and subsequently at 2, 5, 10, 20, 30, 45, 60, 90 min and 2, 3, 4, 6, 8, 12, 24 and 36 h post-administration of the study treatments. The pharmacokinetic profiles of both the formulations were similar in shape and a dose-related increase in formoterol plasma concentration was seen at all time points for both the test and reference formoterol HFA formulations between the dose levels 12 microg and 24 microg. Overall, the findings indicate that treatment with the test formoterol HFA preparation has a lung absorption pattern and systemic exposure comparable to the already licensed reference formoterol HFA preparation.

Bioequivalence study of two fixed dose combination tablet formulations of lopinavir and ritonavir in healthy volunteers.

The study was designed to compare the rate and extent of absorption of two fixed dose combination tablet formulations of lopinavir (CAS 192725-17-0) and ritonavir (CAS 155213-67-5). This bioequivalence study was conducted using a standard preparation as reference and a generic alternative as test in 72 adult healthy volunteers within 18-45 years of age who received a single dose of the test or reference product under fasting conditions. A washout period of 10 d was maintained between period I and period II dosing. After dosing, blood samples were collected from 0 h (pre-dose) to 72 h postdose administration. Lopinavir and ritonavir were quantified using a validated LC-MS/MS method. The data obtained for each subject was evaluated for primary pharmacokinetic variables C(max), AUC(0-72), and AUC(0-Inf) with respect to % ratio and 90% confidence interval for log-transformed data. The 90% confidence intervals (obtained by analysis of variance, ANOVA) were well within the bioequivalence acceptance range of 80% to 125%. Thus, it can be concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption. The safety profiles of both the test and reference formulations were comparable.

Bioequivalence evaluation of a fixed dose combination lamivudine + stavudine tablet with concurrent administration of lamivudine tablet and stavudine capsule in healthy volunteers.

The study was designed to compare the rate and extent of absorption of a fixed dose combination tablet of lamivudine (CAS 134678-17-4) and stavudine (CAS 3056-17-5) with the concurrent administration of lamivudine tablet and stavudine capsule in 24 healthy volunteers under fasting conditions. The volunteers were randomly assigned to the test or reference treatment, with the two treatment periods separated by a washout period of at least 7 days. Plasma samples were analyzed for both analytes lamivudine and stavudine by a validated analytical method. Since the 90% confidence intervals for the "test/reference" mean ratio of the In-transformed pharmacokinetic variables C(max) AUC(0-t) and AUC(0-infinity) were clearly within the conventional bioequivalence range of 80% to 125%, the two treatments were considered bioequivalent. The safety profiles of both the test and reference formulations were comparable.

Pharmacokinetic profiling and bioequivalence evaluation of 2 lamivudine tablet formulations after single oral administration in healthy human Indian volunteers.

The present study compared pharmacokinetic (PK) profile and single-dose tolerability of 2 marketed brands of lamivudine (3TC) 150-mg tablets, Lamivir (Cipla, Mumbai, India) and Epivir (GSK, Basingstoke, UK). The randomized, 2-treatment study was conducted in 24 fasting, healthy, Indian male subjects. Each subject received Epivir and Lamivir formulation separated by 7 days of drug-free washout period. Plasma concentrations of 3TC were used to estimate PK parameters such as maximum observed plasma concentration (Cmax) and area under plasma concentration-time curve (AUCinfinity). Geometric mean ratios (relative to Epivir) and resultant 90% CI of 3TC for Cmax and AUCinfinity were 1.00 (0.89-1.12) and 1.01 (0.94-1.07), respectively. As 90% CIs were entirely within 0.80-1.25 for log-transformed data, the 2 formulations were considered bioequivalent in the extent (AUCinfinity) and rate of absorption (Cmax and time to Cmax [tmax]). The means of primary PK parameters of 3TC, Cmax, and AUCinfinity in Indian subjects were comparable to those previously reported in the literature. Both formulations exhibited similar tolerability under fasting conditions.

Pharmacokinetic profiling and bioequivalence assessment of two marketed brands of nevirapine tablets in healthy Indian volunteers.

Nevirapine (CAS 129618-40-2), a non-nucleoside reverse transcriptase inhibitor, has been effectively used for treatment of HIV-infected patients. A randomized, two-way, crossover study was conducted in 24 fasting, healthy, Indian male subjects to compare plasma pharmacokinetic profile and single-dose tolerability of a new nevirapine tablet formulation (test, T) with that of a reference (R) tablet. Each volunteer received T and R formulations separated by at least 19 days of drug free wash-out period. Plasma concentrations of nevirapine, determined up to 288 h post dose by a sensitive and validated HPLC assay, were utilized to assess pharmacokinetic parameters such as the maximum observed plasma concentration (Cmax), time to Cmax (tmax), and area under plasma concentration curve (AUCinfinity). The primary plasma pharmacokinetic parameters of anti-retroviral substances, Cmax and AUCinfinity, were comparable for either of the formulations. Oral absorption of nevirapine was almost complete within 5 h. Geometric mean ratios (% reference) of AUCinfinity and Cmax and their 90% confidence intervals were 96.9 [93.69-100.24] and 100.8 [94.61-107.4], respectively. As the 90% confidence intervals of the geometric mean ratio were entirely within 80 to 125% for log-transformed parameters, the two formulations were considered bioequivalent in the extent and rate of absorption. Both formulations exhibited similar tolerability under fasting conditions.

Bioequivalence evaluation of two marketed brands of stavudine 40 mg capsules in healthy human South African volunteers.

Stavudine (d4T), a thymidine nucleoside analogue has been effectively used for treatment of patients infected with HIV. A randomized, two-way, crossover study was conducted in 24 fasting, healthy, Caucasian male volunteers to compare plasma pharmacokinetic (PK) profile and single-dose tolerability of a new d4T formulation (Stavir, Cipla Ltd, India; 40 mg capsule, test, T) with that of reference (R) formulation (Zerit), Bristol-Myers Squib, NJ, USA; capsule, 40 mg). Each volunteer received T and R formulation separated by at least 10 days of drug free wash-out period. Plasma concentrations of d4T, determined upto 24h post-dose by a validated LC-MS/MS assay were utilized to assess PK parameters such as maximum observed plasma concentration (Cmax), time to Cmax (tmax), and area under plasma concentration curve (AUC(infinity)). The primary plasma PK parameters, Cmax, and AUC(infinity), of anti-retroviral were comparable for either of the formulations. tmax was achieved within an hour suggesting rapid absorption of d4T from both formulations. Geometric mean ratios (GMR) (percentage reference) of AUC(infinity) and Cmax, and their 90% confidence intervals (CI) were 106.32 [102.52-110.26] and 102.32 [90.25-116.00], respectively. As the 90% CI of GMR were entirely within 80-125% for log-transformed parameters, two formulations were considered bioequivalent, in the extent and rate of absorption. Both formulations exhibited similar tolerability under fasting conditions.