Comparative Bioavailability of Two Daily Subcutaneous Doses Versus a Single Dose of Intramuscular and Vaginal Progesterone Formulations in Healthy Postmenopausal Females.

Progesterone is a naturally occurring endocrine hormone. It is used for luteal phase support to improve success rates in assisted reproduction. This was a single-center, comparative bioavailability, open-label, randomized, 3-period, 6-sequence, crossover study to compare the rate and extent of absorption of subcutaneous (SC) progesterone 25 mg twice daily, versus vaginal (Vag) gel once daily (90 mg progesterone) and 50 mg of intramuscular (IM) progesterone injection once daily in healthy postmenopausal females. Eighteen healthy, postmenopausal, female nonsmokers aged 55-65 years were dosed. Data from 17 subjects who completed at least 2 study periods, including the test and 1 reference, were included in the pharmacokinetic analysis. The SC progesterone product administered twice daily showed a higher exposure than a single dose of the Vag formulation, with least-squares mean (LSM) ratios (SC/Vag gel) of 219.7% for AUC0-inf and 391.8% for Cmax . The SC progesterone product administered twice daily showed comparable extent of exposure to that of the IM product, but showed higher peak concentration, with LSM ratios (SC/IM) of 92.4% for AUC0-inf and 138.0% for Cmax . Mean (SD) relative bioavailability (Frel ) for SC/Vag gel was 449.6 (233.1)%, and for SC/IM was 92.3 (6.3)%. Mild injection site reactions were reported with similar frequency for SC and IM progesterone. With further research, twice-daily SC progesterone may offer an alternative to existing available treatments for luteal phase support.

Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering Drug Development Trends and Regulatory Requirements.

A 505(b)(2) application is a type of US new drug application (NDA) that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. Most 505(b)(2) applications consist of changes to a previously approved drug product (ie, a new dosage form, new routes of administration, etc). Sponsors often face challenges determining the studies to be conducted to support approval via 505(b)(2) pathway. This 5-year (2012-2016) retrospective analysis reviewed approved 505(b)(2) NDAs available on the FDA website, to determine the nature of studies (preclinical, clinical pharmacology, and efficacy/safety) conducted for various types of submissions and to better understand the trends in terms of regulatory requirements. The database consisted of 226 NDAs. One hundred twelve of those 226 had complete FDA review information, with the following FDA submission classes being more prevalent: type 3, new dosage form; type 4, new combination; and type 5, new formulation or new manufacturer. Therefore, only these 112 NDAs were further examined as they could show trends in terms of the studies conducted for various types of applications. Based on the investigation of NDA review documents, coupled with guidance documents, decision trees for studies to be conducted have been developed, which may serve as a guide of recommendations for a successful 505(b)(2) development program and NDA submission.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV-0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC0-t (91.2%; CI, 88.1-94.3%), and AUC0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets.

Pharmacokinetics and Comparative Bioavailability of a Levothyroxine Sodium Oral Solution and Soft Capsule.

A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit-dose ampules. A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions. The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150-µg unit-dose ampules, with or without water, or reference, as 4 × 150-µg capsules in a crossover design. Thirty-six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log-transformed values of AUC0-48 and Cmax were within 90.00% and 111.11%, respectively, for baseline-corrected levothyroxine. Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit-dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. All formulations were well tolerated, with no major side effects.

Modelling the dose-response relationship: the fair share of pharmacokinetic and pharmacodynamic information.

AIMS: The aim of this paper is to investigate the role of drug concentration samplings in the modelling of the dose-response relationship. METHODS: Using an initial PK/PD model, a reference dataset was simulated. PK and PD samples were extracted to create reduced datasets. PK/PD and K-PD models were fitted to theses reduced datasets. Post hoc estimates from both types of models were compared to the initial PK/PD model and performance was assessed. RESULTS: K-PD models were largely biased when the drug has a nonlinear elimination. PK/PD models with 1 PK and 2 PD samples were superior to K-PD models with 3 PD samples. PK/PD models with 1 or 2 PK samples and 3 PD samples proved to be superior to K-PD models with 4 PD samples. CONCLUSIONS: K-PD models should not be used when the drug has nonlinear elimination. K-PD models should not replace PK/PD modelling but are an alternative approach if the PD information is large enough.

Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations.

The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysis. The circadian rhythm of the testosterone was described by a stretched cosine function. Model parameters were estimated using NONMEM(®) 7.3. The effect of different covariates on the testosterone levels was investigated. Model evaluation was performed using non-parametric bootstrap and predictive checks. A stretched cosine function deeply improved the data goodness of fit compared to the standard trigonometric function (p < 0.001; ΔOFV = -204). The effect of the age and the semester, defined as winter and spring versus summer and fall, were significantly associated with the baseline levels of testosterone (p < 0.001, ΔOFV = -15.6, and p < 0.001, ΔOFV = -47.0). Model evaluation procedures such as diagnostic plots, visual predictive check, and non-parametric bootstrap evidenced that the proposed stretched cosine function was able to model the time course of the diurnal testosterone levels in hypogonadal males with accuracy and precision. The circadian rhythm of the testosterone levels was better predicted by the proposed stretched cosine function than a standard cosine function. Testosterone levels decreased by 5.74 ng/dL (2.4%) every 10 years and were 19.3 ng/dL (8.1%) higher during winter and spring compared to summer and fall.

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects.

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Population pharmacokinetic analysis of tesamorelin in HIV-infected patients and healthy subjects.

BACKGROUND AND OBJECTIVES: Tesamorelin is a synthetic analogue of growth hormone-releasing factor (GRF), which increases basal and pulsatile growth hormone (GH) secretion and subsequently increases insulin-like growth factor (IGF)-1. Limited information is available about the pharmacokinetics of this compound. Consequently, the aim of this study was to characterize the population pharmacokinetics of tesamorelin in HIV-infected patients and healthy subjects. METHODS: A total of 38 HIV-infected patients and healthy subjects receiving subcutaneous tesamorelin doses of 1 or 2 mg administered daily during 14 consecutive days were included in the analysis. An open one-compartment model with first- and zero-order absorption and first-order elimination was developed to best describe the data using NONMEM(®) VII. The effect of different covariates on tesamorelin pharmacokinetics was investigated. Model evaluation was performed using predictive checks and non-parametric bootstrap. RESULTS: Plasma clearance and its interindividual variability [% coefficient of variation (CV)] was estimated to be 1,060 L/h (33.6 %). Volume of distribution was calculated to be 200 L (17.7 %). Age, body size measures, race and health status were not related to tesamorelin pharmacokinetic parameters within the range of covariates studied. The fraction of tesamorelin absorbed by a first-order process is 13.1 % higher on day 14 compared with day 1. Predictive checks and non-parametric bootstrap demonstrated that the model is appropriate in describing the time course of tesamorelin plasma concentrations in both HIV-infected patients and healthy subjects. CONCLUSIONS: An open one-compartment model with first and zero order absorption processes and linear elimination is suitable to characterize the pharmacokinetics of tesamorelin. The fraction of tesamorelin absorbed by a first-order process evolves with time. No clinically relevant covariates were identified as predictors of tesamorelin pharmacokinetics.

Pharmacokinetic characterization of baclofen in patients with chronic kidney disease: dose adjustment recommendations.

The pharmacokinetics of baclofen is well delineated in subjects with normal kidney function (KF); however, pharmacokinetics data in patients with chronic kidney disease (CKD) are not and dosage recommendations remain empirical. The effects of CKD on baclofen pharmacokinetics were assessed through a multi-center, open-label, single 5-mg dose, pharmacokinetics study. The KF was measured as the creatinine clearance (CrCL) calculated with the Cockroft-Gault (C-G) equation or as the estimated glomerular filtration rate (eGFR) using subjects' CKD-EPI equation. Subjects were assigned to 1 of 4 groups based on their CrCL (>80 mL/min, 50-80 mL/min; 30-50 mL/min and <30 mL/min). Cmax was not statistically different between the groups, while AUC and T1/2el increased, and CL/F decreased, with increasing severity of CKD. Baclofen's oral clearance and CrCL were statistically significantly correlated, and the trend was the same when classifying subjects either with the CKD-EPI or C-G equations. Linear equations using KF as variable were set to recommend individual dose reduction in CKD patients. Results suggest a mean dose reduction of 1/3, 1/2, and 2/3 in patients with mild, moderate, and severe CKD respectively, in order to achieve baclofen exposure comparable to that observed in healthy subjects.

Single-dose, 2-way crossover, bioequivalence study of two rosuvastatin formulations in normal healthy subjects under fasting conditions.

BACKGROUND: Rosuvastatin, a synthetic lipid-lowering agent acts selectively by competitive inhibition of 3-hydroxy- 3-methylglutaryl-coenzyme A. It is indicated as an adjunct to diet in patients with hypercholesterolemia and mixed dyslipidemia. OBJECTIVE: The purpose of this study was to demonstrate bioequivalence between a generic rosuvastatin 40 mg tablet (Zentiva, Prague, Czech Republic) and a reference product (Crestor, AstraZeneca, Luton, UK), under fasting conditions as required by the European Medicinal Agency. METHODS: A single-oral 40 mg-dose, randomized, open-label, 2-way crossover design study was conducted in 42 healthy volunteers under fasting conditions. Rosuvastatin was administered following an overnight-fast in two occasions with a 14-day washout period in-between. Blood samples were collected in EDTA-K2 tubes prior to dosing and over a 96-hour period. Rosuvastatin was measured in plasma using an automated LC-MS/MS assay (range 81.02 - 40,512.00 pg/ml). Pharmacokinetics were performed using non-compartmental analyses approach to evaluate AUC(last), AUC∞ and C(max). ANOVA was performed on the ln-transformed data and the 90% Confidence Interval (CI) was determined. Bioequivalence will be concluded if the 90% CI falls within 80.00 - 125.00% for AUC(last) and C(max). Safety and tolerability were also evaluated. RESULTS: 39 volunteers completed the study and were considered for the pharmacokinetic and statistical analyses. Descriptive safety data analyses were performed on all subjects. All pharmacokinetic parameters met the acceptance criteria as the 90% CI were within 80.00 - 125.00%. Both formulations were well tolerated and no serious adverse events were reported. CONCLUSION: This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 40 mg oral dose under fasting conditions.

Mycophenolate mofetil 500-mg tablet under fasting conditions: single-dose, randomized-sequence, open-label, four-way replicate crossover, bioequivalence study in healthy subjects.

BACKGROUND: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products. OBJECTIVE: The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA. METHODS: This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (+/-0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C(max) and AUC(0-t) were the primary evaluation criteria, while AUC(0-infinity) was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview). RESULTS: A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C(max), 85.94% to 106.63%; AUC(0-t), 91.94% to 102.20%; and AUC(0-infinity), 93.15% to 105.48%; MPA, C(max), 92.03% to 105.82%; AUC(0-t), 97.42% to 100.59%; and AUC(0-infinity), 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%]). CONCLUSIONS: The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers.

Bioequivalence study of two tablet formulations of sildenafil.

This study was conducted in order to assess the bioequivalence of two tablet formulations containing 100 mg sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-,ethyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulphonyl] -4-methyl piperazine, CAS 139755-83-2). Twenty-eight healthy subjects were enrolled in a single-centre, randomised, single-dose, open-label, 2-way crossover study, with a minimum washout period of 7 days. Plasma samples were collected up to 18.0 h postdosing. Sildenafil levels were determined by reverse liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS). Pharmacokinetic parameters used for bioequivalence assessment [area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(last)) and maximum observed concentration (C(max)) were main evaluation criteria; however, the area under the concentration-time curve from time zero to infinity (AUC(inf)) was also analysed] were determined from the sildenafil concentration data using non-compartmental analysis. The 90% confidence intervals (obtained by analysis of variance, ANOVA) were 86.70-108.19 for C(max), 86.67-99.26 for AUC(last) and 87.19-99.82 for AUC(inf) within the predefined ranges. Bioequivalence between the two formulations was concluded both in terms of rate and extent of absorption.

Comparative bioavailability of two formulations of levofloxacin and effect of sex on bioequivalence analysis. Data from a randomised, 2 x 2 crossover trial in healthy volunteers.

Bioequivalence of levofloxacin (CAS 100986-85-4) 500 mg tablets was assessed in a single dose, open, randomised, crossover trial, with a minimum washout period of 7 days. Serum samples were obtained over 36 h (at baseline, 0.250, 0.500, 0.750, 1.00, 1.25, 1.50, 1.75, 2.00, 2.33, 2.67, 3.00, 4.00, 6.00, 8.00, 12.0, 16.0, 24.0, and 36.0 h post-dose). Levofloxacin serum concentration levels were determined by high-pressure liquid chromatography with fluorescence detection (LOQ 98.31 ng/mL). The 90% confidence intervals (90% Cls; obtained by ANOVA using In-transformed data) for overall bioequivalence analysis were 99.09-115.26% for Cmax, 99.41-105.60% for AUClast and 98.68-104.93% for AUCinf, that is, all within the predefined ranges. Within-gender analysis also produced 90% CIs within the predefined ranges. The use of gender-related model effects showed that sex was a significant factor for AUClast and AUCinf, however, when parameters were normalised by body weight adjusted dose, none of the tested model effects were significant. Comparison between male and female body weight showed significant differences. It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption and that possible differences between male and female pharmacokinetic parameters may be related to differences in body weight.

Bioequivalence study of two different coated tablet formulations of finasteride in healthy volunteers.

This study was conducted in order to assess the bioequivalence of two different coated tablet formulations containing 5 mg finasteride (CAS 98319-26-7). Twenty-six healthy volunteers were enrolled in an open, randomised, crossover single dose study with 2 periods x 2 sequences and a minimum washout period of 7 days. Plasma samples were obtained over 24 h (at baseline, +0.5 h, +1 h, +1.5 h, +2 h, +2.5 h, +3 h, 3.5 h, +4 h, +4.5 h, +5 h, +6 h, +8 h, +10 h, +12 h, +16 h and +24 h after administration). Finasteride levels were determined by high-pressure liquid chromatography with tandem mass detection, HPLC-MS/ MS, (LOQ 0.50 ng/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUClast and Cmax were main evaluation criteria, however, AUCinf was also analysed) were determined from the finasteride concentration data using non-compartmental analysis. The 90 % confidence intervals (obtained by ANOVA) were 86.31-98.69 for Cmax, 95.40-104.88 for AUClast and 96.20-105.81 for AUCinf that is, they were all within the predefined ranges. It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

A pilot study to evaluate the pharmacokinetics of sibutramine in healthy subjects under fasting and fed conditions.

PURPOSE: The purpose of this study was to characterize the food effect on the pharmacokinetics of sibutramine and its pharmacologically active metabolites. METHODS: This was an open label, single dose, crossover study completed by six healthy males. A single dose of sibutramine 15 mg was administered orally under fasting and fed conditions. Plasma concentrations of sibutramine and its metabolites were determined by LC/MS/MS: Non-compartmental pharmacokinetics and statistical analysis were performed using SAS. RESULTS: The food intake increased significantly AUCs and C(max) of sibutramine and its M1 metabolite, but did not affect M2 metabolite. When sibutramine was administered with food, the T(max) was delayed by 2 to 4 hours for sibutramine, M1 and M2 metabolites as stated in the literature. CONCLUSIONS: The results of this study indicate that sibutramine is measurable using a sensitive bioanalytical method. In contrast with what is reported in the product monograph, this study demonstrated that the bioavailability of sibutramine and M1 metabolite was significantly increased with administration with food. The results confirmed lack of food effect on the pharmacokinetics of M2 metabolite. These relatively large food effect observed for sibutramine and M1 metabolite, could have implication for the efficacy and safety of the drug.

Comparative bioavailability of two formulations of terbinafine. Data from a cross-over, randomised, open-label bioequivalence study in healthy volunteers.

An open-label, randomised, cross-over single dose study, using 2 periods x 2 sequences, with a minimum washout period of 21 days, was conducted in order to assess the comparative bioavailability of two formulations of terbinafine (CAS 78628-80-5) 250 mg tablets. Plasma samples were obtained at baseline, +0.333; 0.667; 1.00; 1.33; 1.67; 2.00; 2.33; 2.67; 3.00; 3.50; 4.00; 6.00; 8.00; 12.0; 24.0; 36.0; 48.0 and 72.0 h post-administration. Terbinafine levels were determined by high pressure liquid chromatography with tandem mass detection (HPLC-MS/MS) and the lower limit of quantification was set at 9.99 ng/mL. The pharmacokinetic parameters used for the bioequivalence assessment (AUClast, AUCinf and Cmax) were determined from the terbinafine concentration data using non-compartmental analysis. Classical 90% confidence intervals (90CI) were calculated for the overall sample, and for males and females separately, and gender effects were investigated using an appropriate model. The results showed that overall classical 90CI were 96.08-105.40% for AUCinf, 95.68-105.33 for AUClast and 88.24-112.83 for Cmax, that is, all within the predefined ranges for bioequivalence acceptance. Separate gender analysis showed very similar results for males and females when analysed independently, and no gender effects were detected (p>0.05 for all of the tested model effects). It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.