Scientific Rationale for Determining the Bioequivalence of Inhaled Drugs.

In recent years, pathways for the development and approval of bioequivalent inhaled products have been established for regulated markets, including the European Union (EU), and a number of orally inhaled products (OIPs) have been approved in the EU solely on the basis of in vitro and pharmacokinetic data. This review describes how these development pathways are structured and their implications for the treatment of airway diseases such as asthma. The EU guidance follows a stepwise approach that includes in vitro criteria as the first step. If all in vitro criteria are not met, the second step is based on pharmacokinetic evaluations, which include assessments of lung and systemic bioavailability. If all pharmacokinetic criteria are not met, the third step is based on clinical endpoint studies. In this review, the scientific rationale of the European Medicines Agency guidance for the development of bioequivalent OIPs is reviewed with the focus on the development of bioequivalent OIPs in the EU. Indeed, we discuss the advantages and disadvantages of the weight-of-evidence and stepwise approaches. The evidence indicates that the EU guidance is robust and, unlike clinical endpoint studies, the pharmacokinetic studies are far more sensitive to measure the minor differences, i.e. deposition and absorption rates, in drug delivery from the test and reference products and, thus, should be best suited for assessing bioequivalence. The acceptance range of the 90% confidence intervals for pharmacokinetic bioequivalence (i.e. 80-125% for both the area under the plasma concentration-time curve and maximum plasma concentration) represent appropriately conservative margins for ensuring equivalent safety and efficacy of the test and reference products.

Comparison of pharmacokinetics of two fenofibrate tablet formulations in healthy human subjects.

BACKGROUND: Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg. OBJECTIVE: The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects. METHODS: The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours' postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LC-MS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for Cmax, AUC0-t, and AUC0-∞ for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study. RESULTS: 15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m(2) were recruited into the study. The 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables Cmax, AUC0-t, and AUC0-∞ were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects. CONCLUSIONS: Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent.

Reformulation of existing antiretroviral drugs.

PURPOSE OF REVIEW: In the last decade, there has been marked progress in the treatment of HIV/AIDS. Today, nearly 10 million people are receiving ART. Yet, there are several opportunities for the enhancement of current antiretroviral (ARV) drugs by developing new formulations, which could increase bioavailability, reduce pharmacokinetic variability, and reduce the total daily dose. RECENT FINDINGS: Significant developments are occurring in new formulations of ARV drugs. The introduction of once daily combination pills and combination dispersible pills for children have been important steps. Several researchers and pharmaceutical companies are using nanomedicine for improved formulations and to reduce the dose. Other novel methods include intramuscular depot formulations, vaginal gels for prevention of transmission and sprinkle formulations for children. Regulatory approval, efficacy, safety and cost-effectiveness are factors that will have to be determined for the new formulations. Collaboration between pharmaceutical companies, academic centers, funding agencies and regulatory agencies will be crucial to achieve this goal. SUMMARY: In this review, we describe the objectives of new formulations, recent advances including combinations, copackaged drugs, nanomedicine, pediatric products and new routes of delivery and the challenges that lie ahead.

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.

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.

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.

Development and clinical trial of nano-atropine sulfate dry powder inhaler as a novel organophosphorous poisoning antidote.

The aim of the work was to develop, characterize, and carry out a clinical trial with nano-atropine sulfate (nano-AS) dry powder inhaler (DPI), because this route may offer several advantages over the conventional intramuscular route as an emergency treatment, including ease of administration and more rapid bioavailability. Different batches of nanoparticles of AS were produced using variants of nanoprecipitation method. The influence of the process parameters, such as the types and quantity of solvent and nonsolvent, the stirring speed, the solvent-to-nonsolvent volume ratio, and the drug concentration, was investigated. The methodology resulted in optimally sized particles. Bulk properties of the particles made by the chosen methodology were evaluated. A clinical trial was conducted in six healthy individuals using a single DPI capsule containing 6 mg nano-AS DPI in lactose. Early blood bioavailability and atropinization pattern confirmed its value as a potential replacement to parenteral atropine in field conditions. The formulation seems to have the advantage of early therapeutic drug concentration in blood due to absorption through the lungs as well as sustained action due to absorption from the gut of the remaining portion of the drug.

Nano-salbutamol dry powder inhalation: a new approach for treating broncho-constrictive conditions.

Nanoparticle DPI is known to have deeper lung penetration but its clinical utility as a potentially better treatment option needs to be evaluated in the light of higher expected mucociliary movement of the nanoparticles compared to micronized DPI. The objective of this study was to make nano-salbutamol sulphate (SBS) DPI, radiolabel it with Tc-99m using a novel surface labeling methodology, characterize the formulation and assess its in vitro and in vivo deposition in healthy human volunteers to estimate its bioavailability in the target area. Nano-SBS with a mean particle of 60.71+/-35.99 nm was produced using liquid anti-solvent precipitation method. The drug particles were spherical, pure and crystalline. Anderson cascade impaction showed that blend formulations of Nano-SBS exhibited significantly higher respirable fraction of 45.2% compared to the known behavior of micronized salbutamol sulphate blends. Though the particle size tended to increase due to solid phase interaction after blending with lactose, there was definitive correlation between the radiolabeled and non-radiolabeled forms. In 10 healthy volunteers, lower oropharyngeal depositions (25.3+/-4.5%) were observed with nano-SBS formulation compared to micronized SBS formulation (58.4+/-6.1%). Furthermore, Nano-SBS formulations showed nearly 2.3-fold increase in total lung deposition compared to micronized SBS. The in vivo deposition data and the ratio of peripheral to central lung deposition (P/C) of 1.12+/-0.4 indicate that Nano-SBS is evenly distributed within different lung regions. As demonstrated for SBS, nano-sizing may enhance regional deposition and thus provide an attractive particle engineering option for the development of blend formulations for inhalation delivery.

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.

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.

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.

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.