Bioequivalence Criteria Research Articles

Pharmacokinetic characteristics of fentanyl iontophoretic trandermal system over a range of applied current

Objective: To evaluate the pharmacokinetic (PK) characteristics of a modified fentanyl iontophoretic transdermal system (ITS).Research design and methods:This was a prospective, open-label, single-center, randomized, 3-period, 5-treatment, 6-sequence study. Each subject was randomly assigned to receive three treatments in a sequence consisting of intravenous fentanyl citrate, fentanyl ITS at 170 μA, and then one of three other fentanyl ITS treatments at 140, 200 or 230 μA.Main outcome measures: The following PK parameters were determined: Cmax, tmax, t1/2, AUC23 – 25 and amount of fentanyl absorbed into systemic circulation (i.e., Dose Absorbed).Results: Fifty-two subjects received at least one fentanyl treatment. Serum exposure (Cmax and AUC23 – 25) and Dose Absorbed increased with increasing current. The median tmax ranged from 23.0 to 23.2 h across the 4 ITS groups. Mean t1/2 values ranged from 11.0 to 13.0 h. The Dose Absorbed from the fentanyl ITS at 170 μA met bioequivalence criteria when compared to data from an earlier version of the fentanyl ITS.Conclusions: Exposure of fentanyl and the amount of fentanyl absorbed increased with the magnitude of applied current with the ITS. The fentanyl ITS at 170 μA is bioequivalent to an earlier version of the system.

Evaluation of Pharmacists' Opinion and Knowledge Regarding Generic Medicinal Products in Poland.

Introduction of rules that enabled registration of generic medicinal products constituted one of the major breakthroughs in pharmacotherapy. Generic drugs currently available on the market meet the criteria of bioequivalence that have been agreed upon by registration agencies all over the world. They allow treatment that is as effective and safe, as the one achieved with their reference products. Lower prices of generic drugs are due to the reduced costs of obtaining the marketing authorization, and these drugs meet the same quality requirements as the reference products. However, some cases of lack of therapeutic equivalence may be found in the literature. As in Poland pharmacists are allowed to switch between reference and generic drugs the aim of our study was to evaluate pharmacists’ perception, views and knowledge regarding generic medicines. We also explored their perception of safety, quality and efficacy of generic drugs. The questionnaire, consisting of 16 questions was sent to Polish pharmacists. We show, that pharmacists are aware of law aspects of approval and marketing authorization for generic medicinal product in Poland. Moreover, they are familiar with various aspects and limitations of reference-generic products switch. In conclusion, our comprehensive analysis of pharmacists role allows to have a broad picture of actions that have been made in the area of generic drug safety monitoring in Poland.

Use of generic tacrolimus in elderly renal transplant recipients: precaution is needed.

Proper bioequivalence studies comparing original with generic immunosuppressive drugs in patients are limited, especially in the increasing population of elderly renal transplant recipients. We performed an open-label, single-center, prospective, randomized, cross-over study and compared steady-state pharmacokinetics (PK) of a generic tacrolimus (Tacni) formulation with the original (Prograf) in renal transplant recipients older than 60 years. Twenty-eight patients, with a median age of 69 years (range, 60 to 78), were randomized at time of transplantation to receive original or generic tacrolimus, and 25 (21 men, 4 women) provided two evaluable 12-hr PK profiles. The PK investigations were performed in a stable phase approximately 6 and 8 weeks postengraftment. After the first PK investigation, tacrolimus formulations were switched (1:1 dose ratio). Generic tacrolimus did not meet the bioequivalence criteria; the area under the curve(0-12) ratio of generic-original tacrolimus formulation was 1.17 (90% confidence interval, 1.10-1.23) and the Cmax ratio was 1.49 (90% confidence interval, 1.35-1.65). The generic formulation also showed a shorter time to C(max) (T(max)) (P=0.04). Importantly, the lack of bioequivalence was not reflected in the standard monitoring parameter, trough concentrations (P=0.80). Generic tacrolimus (Tacni) was not found to be bioequivalent to the original formulation in elderly renal transplant recipients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects.

Use of Geometric Mean in Bioequivalence Trials

Bioequivalence data often do not follow the normality assumption on the linear (original) scale, therefore in that situation, the use of the logarithmic transformation is recommended. In the bioequivalence analysis, confusion arises about the use of geometric mean ratio when the logarithmic transformation is recommended by the regulatory authorities. The purpose of this research paper is to clear this confusion. Different average bioequivalence criteria are also reviewed in this paper.

Assessing Pharmacokinetic Interactions Between the Sodium Glucose Cotransporter 2 Inhibitor Empagliflozin and Hydrochlorothiazide or Torasemide in Patients With Type 2 Diabetes Mellitus: A Randomized, Open-Label, Crossover Study

PurposeEmpagliflozin is a potent, selective sodium glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus. Thiazide or loop diuretics are commonly prescribed in patients with type 2 diabetes mellitus. This study investigated potential pharmacokinetic drug−drug interactions between empagliflozin and hydrochlorothiazide (HCTZ) or torasemide (TOR). MethodsThis was an open-label, crossover study. Patients with type 2 diabetes mellitus were randomized to receive empagliflozin 25 mg once daily for 5 days and either HCTZ 25 mg once daily for 4 days followed by HCTZ 25 mg once daily plus empagliflozin 25 mg once daily for 5 days or TOR 5 mg once daily for 4 days followed by TOR 5 mg once daily plus empagliflozin once daily for 5 days in 1 of 4 sequences, with at least a 7-day washout period between treatments. Pharmacokinetic parameters of empagliflozin, HCTZ, and TOR were assessed and standard bioequivalence criteria (80%−125%) were applied. Tolerability assessments included the frequency of adverse events and an investigator assessment of global tolerability. FindingsMean (SD) age of the 22 patients treated was 54.0 (8.1) years and body mass index was 27.1 (3.7) kg/m2. Coadministration of empagliflozin with HCTZ or TOR had no effect on exposure to empagliflozin, HCTZ, or TOR. Geometric mean ratios (90% CIs) for empagliflozin AUC over a uniform dosing interval and Cmax at steady state were 107.1% (90% CI, 97.1−118.1) and 102.8% (90% CI, 88.6−119.3), respectively, when coadministered with HCTZ versus administration alone, and 107.8% (90% CI, 100.1−116.1) and 107.5% (90% CI, 97.9−118.0), respectively, when coadministered with TOR versus administration alone. For HCTZ, the geometric mean ratios for AUC over a uniform dosing interval and Cmax at steady state were 96.3% (90% CI, 89.1−104.0) and 101.8% (90% CI, 88.6−116.9), respectively, and for TOR were 101.4% (90% CI, 99.1−103.9) and 104.4% (90% CI, 93.8−116.3), respectively, for combined treatment versus administration alone. The pharmacokinetic profiles of empagliflozin, HCTZ, and TOR were similar after administration alone and in combination. Global tolerability was good for all patients after each treatment, and no severe or serious adverse events were reported. ImplicationsNo pharmacokinetic drug−drug interaction was observed between empagliflozin and HCTZ or TOR. ClinicalTrials.gov identifier: NCT01276288.

Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel.

The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80–1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0–24 h) for semaglutide steady-state/semaglutide-free; 1.11 (1.06–1.15). AUC0–24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15–1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (–1.1 ± 0.6%) and weight (–4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

Comparative pharmacokinetic analysis with two omeprazole formulations “Proceptin®” and “Losec®” in healthy subjects

The pharmacokinetics of omeprazole pharmaceutical products Proceptin® 20mg capsule and Losec® 20mg MUPS tablet were compared in healthy subjects. The study was an open-­‐label, randomized, two-­‐treatment, two-sequence, two-way crossover, single-dose bioavailability study conducted under fasting conditions with a wash out period of seven days between the two administrations. Blood samples were collected pre-­‐dosing and at 0.5–24.0 h post administration of a single oral dose of either of the formulation followed by HPLC analysis. Twenty-eight healthy male subjects (20-­‐28 years) participated in the study. Only four subjects dropped from the study and the other 24 completed the study and were included in the pharmacokinetic and statistical analysis. Evaluated mean (±SD) values of prime pharmacokinetic parameters for reference and test products were Cmax - 345.28 (±42.38) and 316.23 (±26.12) ng/mL, tmax - 2.28 (±0.16) and 2.69 (±0.23) h, AUC0-­‐24 - 710.01 (±92.51) and 771.13 (±102.35) h-­‐ng/ml and AUC0-­‐∞ - 848.21 (±65.31) and 902.56 (±45.23) h.ng/mL, respectively with no significant (p>0.05) differences in paired t-­‐test. Moreover, 90% CI for the AUC0-­‐24, and Cmax values were 89.245-­‐ 103.154% and 81.634-­‐102.211% respectively were within the predetermined FDA bioequivalence range of 80–125%. On the basis of the pharmacokinetic parameters AUC0-­‐24, the relative bioavailability of the test preparation Proceptin 20 capsule was 108.61% of that of the reference preparation Losec 20mg MUPS tablet. This study stipulated that, the test and reference formulations of omeprazole meet the regulatory criteria for bioequivalence. Thus the test product Proceptin® 20mg may be supplanted for reference product Losec® 20mg MUPS tablet in oral administration.KEY WORDS: Omeprazole; Cross-­‐over design; HPLC; Comparative pharmacokinetics

Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta® (Janssen-Cilag).

The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta® of ln-transformed area under the curve (AUC0–t) and Cmax were within the acceptance range of 80–125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0–t and Cmax were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta®, confirmed by bioequivalence of the partial metrics AUC0–2h, AUC2-24 h, Cmax(0–2 h) and Cmax(2–24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta® in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions.

The effect of food on the high clearance drug asenapine after sublingual administration to healthy male volunteers

To determine the effects of food on the pharmacokinetics of sublingual asenapine. Healthy male volunteers (n=26, age 19-53 years) randomly received a single sublingual dose of asenapine 5 mg after ≥ 10 h fasting (Treatment A, reference), after a high-fat meal (Treatment B) and after ≥ 10 h fasting with a high-fat meal at 4 h post-dose (Treatment C). Blood samples were drawn over 72 h to measure asenapine plasma concentrations. Effects of food intake on asenapine pharmacokinetics were assessed using bioequivalence criteria and evaluated using a compartmental modelling analysis. Compared with the reference, mean asenapine exposure (AUC0-last and AUC0-∞) was approximately 20 % lower after intake of a high-fat meal prior to dosing, whereas Cmax decreased by only about 10 %. When a high-fat meal was taken 4 h post-dose in the fasting state, asenapine concentrations were similar to the reference during the first 4 h post-dose. After the meal intake, asenapine concentrations decreased quickly for several hours. Compartmental modelling indicated that a transient 2.5-fold increase in asenapine clearance after eating could explain the asenapine concentration-time profiles for both food regimens. To our knowledge, this is the first study investigating the effect of food upon the sublingual administration of a drug. A high-fat meal taken before or 4 h post-dose of sublingual asenapine indirectly caused a transient increase in liver blood flow that resulted in a temporal increase in asenapine clearance. As the effects on asenapine exposure were small and not clinically relevant, no additional restrictions are required for the timing of food intake in relation to asenapine dosing.

Bioavailability Comparison of Two Zopiclone Formulations in Healthy Colombian Volunteers

Zopiclone is a hypnotic short-acting agent used in the treatment of primary insomnia. The aim of this study was to compare the Bioequivalence of two formulations of Zopiclone available in the Colombian market: Zopiclone 7.5 mg commercialized as Zopiclone MK® and Zopicloteg TG® (Test product) manufactured by Tecnoquimicas S.A (Cali, Col.) and Imovane® (Reference product) from Sanofi-Aventis Farmaceutica Ltda (Brasil). With this purpose, a single dose, randomized, crossover, with two periods, two sequences and a washout period of one week study was developed. Blood samples were drawn from 0 to 24 hours following the drug administration. Zopiclone plasma levels were determined by HPLC method, validated under the FDA parameters. The 90% confidence intervals for the ratios of the ln AUC0-∞ and ln Cmax means between the Test and Reference product were constructed. The 80/125 rule was used as bioequivalence criterion. The study was conducted in 26 healthy volunteers. The estimated pharmacokinetic parameters for Zopiclone, either for the Test product or Reference product were Cmax 72.815 ± 20.54 ng/mL, 74.315 ± 18.04 ng/mL; AUC0-t 467.297 ± 92.21 ng.h/mL, 460.996 ± 115.81 ng.h/mL, and AUC0-∞ 560.298 ± 118.58 ng.h/ mL, 543.549 ± 136.97 ng.h/mL, respectively. The 90% confidence intervals for the ratio between the averages of ln-transformed data of AUC0-∞ and Cmax were 97.38% - 110.59% and 89.97% - 104.84%, respectively. Conclusion: In the present study of single dose, the Test product, Zopiclone 7.5 mg, meets the Bioequivalence criterion regarding the rate and extent of absorption.

Generic and Branded Enoxaparin Bioequivalence: A Clinical and Experimental Study

Our aim is to compare a new generic version of enoxaparin (Enoxa®) with the parent brand (Lovenox®). We included patients with acute coronary syndrome (ACS) for the clinical study and healthy volunteers for the experimental study. ACS patients randomly assigned to receive a bolus of Enoxa® (n=86) or Lovenox® (n=83) and serum anti-Xa activity was measured 4 hours thereafter. For experimental study, blood from healthy volunteers was used to compare the effect of both formulations on thrombin generation in citrated platelet-poor plasma (PPP). The half maximal inhibitory concentration of the drug (IC50) that is required to inhibit 50% in-vitro thrombin generation parameters, mean rate index (MRI) and endogenous thrombin potential (ETP). Both IC50 MRI and IC50 ETP were calculated in PPP. In ACS patients, serum anti-Xa activity was found not different between Enoxa® and Lovenox®. Median anti Xa activity measured 4 hours after the initial bolus was 0.39 IU anti-Xa/ml [95 % CI 0.31-0.53] and 0.34 IU anti-Xa/ml [95% CI 0.27-0.53], for the Enoxa® group and Lovenox® group respectively. No difference in major cardiovascular events was observed during hospital stay. In healthy volunteers, IC50 MRI and IC50 ETP were similar between Lovenox® and Enoxa® in PPP [(2.5 μg/ml ± 0.2 μg/ml) versus (2.3 μg/ml ± 0.1μg/ml) respectively for IC50 MRI; (p=0.2)] and [(4.8 μg/ml ± 0.8 μg/ml) versus (4.1 μg/ml ± 0.1 μg/ml) respectively for IC50 ETP; (p=0.2)]. With both formulations, anti-Xa activity and anti-Xa/anti-IIa ratio were similar. The generic enoxaparin Enoxa® met the main regulatory criteria of bioequivalence with the branded product.

Bioequivalence of Fixed-Dose Repaglinide/Metformin Combination Tablet and Equivalent Doses of Repaglinide and Metformin Tablet: A Randomized, Single-Dose, Two-Period, Two-Sequence Crossover Study in Healthy Korean Male Volunteers

T aim of this study was to evaluate the bioequivalence of a fixed-dose repaglinide/metformin combination (FDC) tablet at a dose of 2/500 mg with co-administration of equivalent doses of repaglinide (2 mg) and metformin (500 mg) as individual (EDI) tablets in healthy Korean male volunteers.This study was conducted as an open-label, randomized, single-dose, 2-period 2-squence crossover design in 48 healthy Korean male volunteers who received an FDC tablet or EDI tablets after a 12-hour overnight fast in each period. Plasma concentrations of repaglinide and metformin up to 24 hours were determined using a UPLC-MS/MS method. The pharmacokinetic parameters such as AUC0-t, AUC0-∞, Cmax, Tmax and t1/2, were analyzed. Analysis of variance was carried out using logarithmically transformed AUC0-t, AUC0-∞ and Cmax. The formulations were considered bioequivalent if the log-transformed ratios of AUC0–t, AUC0–∞, and Cmax were within the predetermined bioequivalence range (80-125%) established by the US Food and Drug Administration. Tolerability was assessed throughout the study. No significant sequence effect was detected. The point estimates (90% CIs) for AUC0-t, AUC0-∞ and Cmax based on EDI tablets were 1.101 (1.023-1.185), 1.099 (1.022-1.184) and 1.126 (1.015-1.249) for repaglinide, and 0.952 (0.896-1.011), 0.950 (0.897-1.007) and 0.984 (0.927-1.045) for metformin, respectively, satisfying the bioequivalence criteria of 80-125% as proposed by the US FDA. This single-dose study found that both Repaglinide and Metformin in a fixed-dose combination tablet were bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg in these fasting, healthy Korean male volunteers.

Bioequivalence of Two Oral Tablet Formulations of Betahistine 24 Mg: Single-Dose, Open-Label, Randomized, Two-Period Crossover Comparison in Healthy Individuals

A bioequivalence study of betahisitine tablets was conducted. Thirty two healthy Mexican mestizo volunteers received each test (T) and reference (R) formulations of betahistine at a dose of 24 mg in a 2 × 2 cross-over study. There was a three-day washout period between the two formulations. Plasma concentrations of betahistine were monitored by an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) for over a period of 24 h after the administration. AUC0-t (the area under the plasma concentration–time curve from time 0 to last sampling time) and AUC 0-∞ (that from time 0 to infinity) were calculated by the linear-log trapezoidal rule method. Cmax (maximum plasma drug concentration) and Tmax (time to reach Cmax) were compiled from the plasma concentration–time data. Analysis of variance was carried out using logarithmically transformed AUC and Cmax, and untransformed Tmax. The mean of AUC0-t was 7139.8 ng mL−1 h−1 (test medication) and 6714.4 ng mL−1 h−1 (reference medication) and that of AUC0-∞ were 7660.2 (test) and 6850.3 ng mL-1 h-1 (reference). Cmax values of 1716.2 and 1677.3 ng mL−1 were achieved for the test and the reference medication, respectively. Tmax were determined at 0.86 h for the test and 0.87 h for the reference formulations. The 90% confidence intervals for AUC0-t, AUC0-∞ and Cmax were 0.994-1.102, 0.994-1.131 and 0.969-1.069, respectively, satisfying the bioequivalence criteria of the Mexican Comision Federal Para la Proteccion Contra Riesgos Sanitarios, the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. These results indicate that the two medications of betahistine are bioequivalent and, thus, may be prescribed interchangeably.

Human bioequivalence evaluation of two losartan potassium tablets under fasting conditions.

The bioequivalence of two different tablet formulations containing losartan potassium 100 mg was determined in healthy volunteers after a single oral dose in a randomized crossover study. Test and reference products were administered to 60 volunteers with 240 ml water after overnight fasting. Plasma concentrations of losartan and its active carboxylic acid metabolite were monitored over a period of 36 h after drug administration by validated LC/MS/MS analytical method. The pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞, AUC0-t/AUC0-∞, tmax, Kel and t½ were determined from plasma concentration time profile of both formulations for losartan and its active metabolite losartan carboxylic acid and were found to be in good agreement. The carboxylic acid metabolite was considered for profiling purpose only. The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals for the ratio of Cmax (84.89-104.09%), AUC0-t (95.84-102.84%) and AUC0-∞ (96.43-103.25%) values for losartan between the test and reference products were within the 80-125% interval, satisfying the bioequivalence criteria of the US FDA guidelines. These results indicate that the test and the reference products of losartan potassium are bioequivalent and, thus, may be prescribed interchangeably.

The Role of Metabolite in Bioequivalence Decision Making

Purpose: To investigate whether the combined concentrations of the parent drug and its corresponding metabolite impacts the experimental design of bioequivalence studies. Methods: Enalpril and sildenafil were selected to assess bioequivalence as both drugs have active metabolites. The bioequivalence study of enalpril was conducted under fasting conditions, while the bioequivalence assessment of sildenafil was conducted under both fasting and fed conditions. For the three studies, the bioequivalence criteria of 80-125% was applied to assess the parent compounds alone, the active metabolites alone, and both the parent drugs and the active metabolites. Results: Similar statistical results to assess bioequivalence were obtained for the parent drug, metabolite, and the sum of the parent drug and metabolite for AUC. In the case of Cmax, the intra subject variability of the bioequivalence statistical results with regards to the metabolite and the sum of the parent and the metabolite was lower than that for the parent drug while the power of the bioequivalence decision was higher for the metabolite and the sum of the parent drug and the metabolite. Conclusions: An improved intra subject variability resulted in higher power with a smaller sample size in the Cmax values with regards to decision making in bioequivalence studies.

Use of Physiologically Based Pharmacokinetic Models Coupled with Pharmacodynamic Models to Assess the Clinical Relevance of Current Bioequivalence Criteria for Generic Drug Products Containing Ibuprofen

Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator(®) using reported biopharmaceutics parameters for ibuprofen was coupled with two published PD models: one for antipyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as "reference (R)" drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be interpreted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose-response relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models demonstrated that gastric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that current bioequivalent guidance might be unnecessarily restrictive for ibuprofen products.

Formulation and Evaluation of Mouth Dissolving Tablets of Tramadol Hydrochloride

Purpose: To prepare, and evaluate in vitro and in vivo tramadol hydrochloride mouth dissolving tablets (MDT).Methods: Tramadol HCl MDT were prepared by direct compression using Pharmaburst as coprocessed excipient and compared with a reference product (Rybix ODT, 50 mg). Physicochemical parameters including hardness, friability, weight variation, disintegration time and dissolution studies were determined for all the formulations. In-vivo studies were performed for the optimized formulation (F13), using as reference, a commercial product (Trambax IR, 50 mg), by a two-way crossover design under fasting conditions on eight healthy adult human subjects. Drug-plasma concentrations obtained from the bioequivalence study for test and reference products were analyzed in each subject by high performance liquid chromatography (HPLC), and basic pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½ and λz, were calculated.Results: The tablet formulation prepared with Pharmaburst (F13) showed good flow properties, low disintegration time (15 s) and improved drug release (99 % at 30 min) compared with those of the reference product (88 % at 30 min) and passed 6 months accelerated stability test. Bioequivalence of the test product with that of the reference product under fasting conditions was established by computing 90 % confidence interval for the In-transformed pharmacokinetic parameters of Cmax, AUC0-t and AUC0-∞ for tramadol. The 90 % confidence intervals for Cmax were 99.70 - 114.31, for AUC0-t 97.31 - 108.87 and for AUC0-∞ 97.17 - 109.75. This confidence interval, in each case, was within bioequivalence criteria limitConclusion: A suitable preparation of tramadol HCl MDT that is bioequivalent with a reference commercial product under fasting condition can be obtained when Pharmaburst is used as a disintegrant.Keywords: Bioequivalence, dissolution, Mouth dissolving tablets, Pharmaburst, Tramadol hydrochloride, Disintegration time

Pharmacokinetic evaluation of different generic triclabendazole formulations in heifers

AIMS: To assess the comparative drug systemic exposure of a reference (RF) and four test (Test I, Test II, Test III and Test IV) formulations of triclabendazole (TCBZ) in heifers.METHODS: Thirty Holstein heifers were randomly distributed into five groups (n=6 per group). Animals in the RF group received the reference formulation (Fasinex), and those in the other groups received different commercially available TCBZ formulations (Test I, Test II, Test III and Test IV). All treatments were orally administered at 12 mg/kg bodyweight. The concentrations of TCBZ metabolites in plasma between 0 and 168 hours after treatment were quantified by high-performance liquid chromatography (HPLC).RESULTS: Triclabendazole sulphoxide (TCBZ.SO) and TCBZ-sulphone (TCBZ.SO2) were the only analytes recovered in plasma. Only the Test I formulation did not differ from the RF for all pharmacokinetic parameters measured for either metabolite (p>0.8). The TCBZ.SO area under the concentration vs. time curve for Test II formulation (268.9 µg.h/mL) was lower, and for Test III (619.9 µg.h/mL) and Test IV (683.4 µg.h/mL) was higher, than the RF (418.1 µg.h/mL) (p<0.005).CONCLUSION: Based on the currently available bioequivalence criteria, the only test formulation under evaluation that could be considered equivalent to the RF was the Test I formulation, which demonstrated an equivalent systemic exposure for the active TCBZ.SO metabolite. This comparison of TCBZ pioneer and test formulations in cattle raises awareness of the need for further quality control for drug approval in the veterinary pharmaceutical field in many regions of the world.

Generic Tacrolimus Is NOT Bioequivalent in Elderly Renal Transplant Recipients.

Introduction: Generic immunosuppressants are entering the market worldwide and local authorities approve and applaud their introduction. The approval of generic immunosuppressants is based on bioequivalence studies in healthy volunteers receiving single drug doses. In contrast, proper bioequivalence studies in patients on repeated dosing regimens are limited, especially in the increasing population of elderly renal transplant recipients (RTxR). We aimed to compare steady state pharmacokinetics (PK) of a generic tacrolimus (Tac) formulation (Tacni®, Teva Pharmaceutical Industries Ltd.) with the original (Prograf®, Astellas Pharma Inc.) in elderly RTxR. Methods: An open label, single-center, prospective, randomized, crossover study in RTxR > 60 years was performed. Immunosuppression consisted of basiliximab induction, prednisolone, mycophenolate 1500 mg/day in addition to Tac. At time of RTx patients were randomized to receive original or generic Tac. Two full 12-hr PK profiles were determined in stable phase, approximately 6 (PK1) and 8 (PK2) weeks after Tx. Following PK1, Tac formulations were switched in a 1:1 dose ratio. From 1 week before PK1 and throughout the study, doses of Tac and co-medications remained unchanged. International guidelines were used to determine the bioequivalence. Results: We enrolled 28 RTxR at transplantation. Twenty-five patients (22 men/3 women) with a mean age of 69 years (range 60-78) provided 2 evaluable PK profiles. The generic Tac formulation (Tacni®) did not meet the bioequivalence criteria: the mean AUC0-12-ratio of generic:original Tac formulation was 1.17 (90% CI: 1.10-1.23) and the Cmax-ratio was 1.49 (90% CI: 1.35-1.65). The absolute Cmax was 30.2±11.6 vs 19.6±6.3 μg/L (P<0.01) and the rate of absorption was faster for generic Tac resulting in a shorter time to reach Cmax (Tmax); 1.1±0.5 hr as compared to 1.4±0.7 hr for original Tac (P=0.03). The significant lack of bioequivalence between the two formulations was not identified by the trough concentrations: 6.6±1.5 μg/L and 6.6±1.4 μg/L for generic and original Tac, respectively (P=0.80). Conclusions: In stable elderly RTxR (>60 years) generic (Tacni®) and original Tac (Prograf®) were not bioequivalent. Patients on generic Tac experienced significantly higher systemic drug exposure, which may increase the risk of nephrotoxicity and other adverse effects with negative impact on long-term patient outcome.

Application of New Bioequivalence Testing Procedures To Tacrolimus Formulations in Stable Kidney Recipients: Global Regulatory Impact.

Bioequivalence(BE) studies are an integral component of innovator and generic drug approval processes. Worldwide regulatory bodies have and continue to modify BE testing approaches for narrow therapeutic index(NTI) drugs such as tacrolimus. Modifications of BE approaches for NTI drugs essentially include two approaches 1)Direct tightening of average BE limits and 2) reference scaled average BE(RSCABE) based upon the within subject variability of the innovator product in healthy volunteers. The transplant community has encouraged testing in the transplant population. A recent publication of a prospective, two-center, randomized, two-period, two sequence, crossover, steady-state pharmacokinetic study comparing Sandoz generic tacrolimus (TS) vs Prograf (TP) in stable renal transplants revealed the following. The TS:TP ratio for AUC 0-12 was 1.02 with a 90% CI of 97-108% and Cmax was 1.09 with a 90% CI of 101-118%. Methods: Various BE testing approaches were applied to these data in stable renal transplants including tighter BE limits and RSCABE. Results: In the renal transplant population, tighter average BE limits for most regulatory bodies (Health Canada, South Africa, Asia and Latin America) were met for AUC and Cmax, however the Cmax did not meet 2010 regulatory standards of the EMA and the Danish Medicine Agency due to Cmax CI outside the 90.0-111.11% approval range and by not including 100% respectively. However in 2013, the EMA Efficacy Working Party recommended acceptable Cmax CI for tacrolimus of 80-125%. Calculations for RSCABE resulted in within subject variability of the innovator product (TP) of 14.9% and 24.2% for AUC and Cmax respectively. Using the RSCABE procedure, the 90% CI to meet BE standards for AUC was 86-117% and Cmax was 80-125%. Conclusion: TS in renal transplants met all current FDA and EMA modified bioequivalence criteria. Also, application of RSCABE to the variability of 24.2% of TP Cmax in the renal transplants showed that the confidence interval of 80-125% is acceptable and allows for adjustment to the variability of the innovator product, TP, in transplant recipients. The RSCABE approach dynamically adjusts to the variability of tacrolimus PK parameters of renal transplants, and may be more appropriate than fixed BE acceptance limits. DISCLOSURES:Wiland, A.: Employee, Novartis. McCague, K.: Employee, Novartis.