Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects

Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

Tacrolimus Dose-Conversion Ratios Based on Switching of Formulations for Patients with Solid Organ Transplants

Background: Tacrolimus may be administered during hospitalization as an IV formulation or oral suspension. However, literature suggesting appropriate ratios for conversion from these formulations to capsules is limited. Objective: To evaluate conversion ratios after a switch in formulation of tacrolimus for solid-organ transplant recipients. Methods: This single-centre observational longitudinal study involved hospitalized patients who underwent a switch in formulation of tacrolimus according to 1 of 3 possible scenarios: IV to oral suspension, IV to capsule, or oral suspension to capsule. Data were collected from the earliest accessible electronic file (January 2009) to January 1, 2019. Conversion ratios were calculated for each of the 3 groups using data for blood concentrations and doses before and after the switch. The calculated ratios were then compared with recommended conversion ratios: 1:5 (i.e., 1 mg of IV tacrolimus is converted to 5 mg of oral tacrolimus, expressed as “5”) for either of the switches involving an IV formulation and 1:1 (i.e., same amount, expressed as “1”) for the switch from oral formulation to capsules. Results: For the group who underwent switching from the IV formulation to oral suspension, the mean calculated conversion ratio was 3.04, which was significantly different from the recommended ratio of 5. For the group who underwent switching from the IV formulation to capsules, the calculated conversion ratio was 5.18, which was not significantly different from the recommended ratio of 5. For the group who underwent switching from oral suspension to capsules, the calculated conversion ratio was 1.17, which was not significantly different from the recommended ratio of 1. Conclusion: In this small retrospective study of tacrolimus therapy, the calculated conversion ratio was significantly different from the recommended ratio for patients who were switched from IV administration to oral suspension, but not for those switched from IV administration or oral suspension to capsules. Therapeutic drug monitoring therefore appears indispensable, regardless of conversion ratios. RÉSUMÉ Contexte : Le tacrolimus peut être administré par IV ou sous forme de suspension orale pendant une hospitalisation. Cependant, il existe peu de documents qui proposent des ratios appropriés pour convertir ces formulations en capsules. Objectif : Évaluer les ratios de conversion après un changement de formulation du tacrolimus pour les bénéficiaires de greffes d’organes solides. Méthodes : Cette étude observationnelle longitudinale unicentrique impliquait des patients hospitalisés, pour qui la formulation de tacrolimus changeait en fonction de chacun des trois scénarios possibles : passage de l’administration par IV à la suspension orale, passage de l’administration par IV aux capsules ou passage de l’administration par suspension aux capsules. Le recueil des données a été effectué à partir du plus ancien dossier électronique accessible (janvier 2009) jusqu’au 1er janvier 2019. Les ratios de conversion ont été calculés pour chacun des trois groupes à l’aide de données pour les concentrations de sang et des doses avant et après le changement. Les ratios calculés ont ensuite été comparés avec les ratios de conversion recommandés : 1:5 (c.-à-d., 1 mg de tacrolimus administré par IV est converti en 5 mg de tacrolimus par voie orale, conversion exprimée par le nombre « 5 ») pour chacun des changements impliquant une formulation IV et 1:1 (c.-à-d. même quantité, conversion exprimée par le nombre « 1 ») pour le passage de la formulation orale aux capsules. Résultats : Dans le groupe dont l’administration par IV est passée à une suspension orale, le ratio de conversion moyen calculé était de 3,04, ce qui était significativement différent par rapport au ratio recommandé de 5. Pour le groupe dont l’administration par IV est passée à des capsules, le ratio de conversion moyen calculé était de 5,18, ce qui n’était pas significativement différent par rapport au ratio recommandé de 5. Pour le groupe dont l’administration est passée de la suspension orale aux capsules, le ratio de conversion moyen calculé était de 1,17, ce qui n’était pas significativement différent par rapport au ratio recommandé de 1. Conclusion : Dans cette petite étude rétrospective de la thérapie à l’aide du tacrolimus, le ratio de conversion calculé était significativement différent du ratio recommandé pour les patients qui passaient d’une administration IV à une suspension orale, mais pas pour ceux qui passaient d’une administration par IV ou d’une suspension orale à des capsules. La surveillance thérapeutique des médicaments semble donc indispensable, quels que soient les ratios de conversion.

DEVELOPMENT SODIUM ALGINATE SODIUM BICARBONATE CALCIUM CARBONATE ORAL SUSPENSION USING TURBISCAN TOWER AND ZETA POTENTIAL

Sodium Alginate Sodium Bicarbonate Calcium Carbonate combination reduces heartburn, heartburn or stomach complaints caused by reflux. The aim of this study is to create sodium alginate sodium bicarbonate calcium carbonate combination formulation using pre-development devices such as Turbiscan Tower and Zeta Potential. In order to obtain a homogeneous mixture during production and pilot study using two different boiler 5 trial production, samples will be pre-feasibility devices (Turbiscan Tower and Zeta Potential) stress conditions using physical behaviors have been observed.