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.

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.

Bioequivalence study of two formulations of ibandronic acid 150-mg film-coated tablets in healthy volunteers under fasting conditions: a randomized, open-label, three-way, reference-replicated crossover study.

AIMS: This bioequivalence study aimed to compare rate and extent of absorption of a generic medicinal product of ibandronic acid 150-mg film-coated tablet versus Bonviva(®). METHODS: This was a single-centre, open-label, randomized, three-way, three-sequence, reference-replicated, crossover bioequivalence study, under fasting conditions. A single oral dose of ibandronic acid as one 150-mg film-coated tablet was administered in each study period. Each washout period lasted 14 days. Blood samples were collected according to a predefined sampling schedule and up to 48.0 hours after administraton in each period. Plasma concentrations of ibandronic acid were measured using a liquid chromatograph-mass spectrometry/mass spectrometry method. Bioequivalence between generic and reference medicinal products is acceptable if the 90 % confidence intervals (CI) of ratio of least-squares means between the test and the reference product of ln-transformed area under the serum concentration-time curve from time zero to time of last measurable concentration (AUC0-t ) is within the 80.00-125.00 % interval. Prospectively, a scaled average bioequivalence approach for maximum serum concentration (C max) was established. RESULTS: 153 healthy volunteers were enrolled and randomized. After the test formulation (T) and first and second Bonviva(®) (R) dosing, the C max was 96.71 ± 90.19 ng/mL, 92.67 ± 91.48 ng/mL and 87.94 ± 60.20 ng/mL and the AUC0-t was 390.83 ± 287.27 ng·h/mL, 388.54 ± 356.76 ng·h/mL and 383.53 ± 246.72, respectively. Ratios of T/R and 90 % CI were 100.92 % (94.35-107.94) for AUC0-t , 100.90 % (94.37-107.88) for AUC0-inf and 102.56 % (95.05-110.67) for C max. CONCLUSIONS: Test formulation of ibandronic acid is bioequivalent in rate and extent of absorption to Bonviva(®) following a 150-mg dose, under fasting conditions.