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.

Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Sirolimus (Rapamune®) exhibits low bioavailability, high variability and moderate food effect following oral administration. This makes therapeutic blood monitoring of sirolimus concentrations necessary for kidney transplant patients. Furthermore, reaching therapeutic blood sirolimus concentrations in renal cancer patients was found to be challenging when the marketed drug was administered alone. A novel, nano-amorphous formulation of the compound was developed and its pharmacokinetic properties were investigated in a dose escalation study in a first-in-human clinical trial. The effect of food at the highest dose on the pharmacokinetic parameters was also assessed. METHODS: Each group received one of the escalating doses (0.5-2-10-40 mg) of sirolimus as the novel formulation in the fasted state. Following a 2- to 3-week washout period, the 40-mg group then also received another 40 mg dose in the fed state. Sirolimus whole blood concentrations were determined for up to 48 h. To avoid degradation of sirolimus in the acidic environment in the stomach, 40 mg famotidine was administered 3 h pre-dose in all regimens. The main pharmacokinetic parameters were calculated and data were compared with pharmacokinetic data reported for dose escalation studies for Rapamune®. RESULTS: Thirty-two healthy volunteers were divided into 4 cohorts of 8 volunteers. Dose increments resulted in approximately dose-proportional increases of maximal plasma concentrations (Cmax) and area under the concentration-time curve (AUC)0-48 h up to 10 mg, while less than dose-proportional increases were observed when the dose was increased from 10 to 40 mg. Mean AUCinf at the 40 mg dose in the fasted state was 4,300 ± 1,083 ng·h/ml, which is 28% higher than the AUC reported following the administration of 90 (2 × 45) mg Rapamune® and 11% higher than the exposure reported for 25 mg intravenous pro-drug temsirolimus (3,810 ng·h/ml). At the 40 mg dose, food reduced Cmax by 35.5%, but it had no statistically significant effect on AUC. Inter-individual variability of the pharmacokinetic parameters mostly fell in the 20-30% (CV) range showing that sirolimus administered as the nano-amorphous formulation is a low-to-moderate variability drug. CONCLUSION: Based on the pharmacokinetic profiles observed, the nano-amorphous formulation could be a better alternative to Rapamune® for the treatment of mammalian target of rapamycin-responsive malignancies. Therapeutically relevant plasma concentrations and exposures can be achieved by a single 40 mg oral dose. Furthermore, the low variability observed might make therapeutic blood monitoring unnecessary for transplant patients taking sirolimus as an immunosuppressant.

Preparation, Pre-clinical and Clinical Evaluation of a Novel Rapidly Absorbed Celecoxib Formulation.

Celecoxib (Celebrex®) is the only widely used NSAID that selectively inhibits the COX-2 isoenzyme. Celebrex® is absorbed slowly in the fasted state and food intake further delays absorption. In this work, an amorphous water dispersible granule formulation of celecoxib is described with in vitro characterization, preclinical and clinical data. The formulation exhibited very high passive permeability and apparent solubility, significantly outperforming the micronized celecoxib and the drug product Celebrex®. The granule formulation remained stable for at least 1 year in stability tests. In dog studies, tmax was 1 h with over 50% of Cmax reached within 15 min regardless of food intake. A phase 1 clinical trial was conducted with 12 volunteers at 100- and 200-mg doses. Celecoxib plasma concentrations reached 250 ng/ml, the effective therapeutic plasma level, in less than 15 min regardless of food or dose. The novel celecoxib formulation is rapidly absorbed, demonstrating the potential utility as an acute treatment offering advantages over the currently marketed product.

Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate.

Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer. The marketed drug product (Zytiga®) exhibits very low bioavailability in the fasted state and a substantial positive food effect. We recently developed a nano-amorphous formulation of this drug which exhibited higher apparent solubility and dissolution rate, and significantly improved absorption and bioavailability in the fasted state in beagle dogs and in a phase I clinical study. One surprising finding, however, was the very rapid absorption observed both in dogs and in humans with median tmax values in the 0.5-0.75 h range. This could not be explained by the improved dissolution characteristics alone. A recent study showed that following the administration of Zytiga® abiraterone acetate is converted to abiraterone in the intestinal lumen yielding supersaturated abiraterone concentrations, which is believed to be the driving force of the absorption process. In our work we found that the enzymatic hydrolysis of abiraterone acetate profoundly changes the pharmacokinetics of the nano-amorphous formulation in the fasted state and it is the most probable reason for the unexpectedly high absorption rate. Our primary candidate for the isoenzyme involved is pancreatic cholesterol esterase. Furthermore, we identified orlistat as a potent inhibitor of cholesterol esterase and found it to be an ideal compound for the study of the enzymatic process in vivo. The observed inhibition could result in a clinically significant modification of abiraterone pharmacokinetics, which might make a drug interaction warning necessary for abiraterone acetate containing drugs. The mathematical and experimental tools presented in this work might be suitable for the study of the contribution of other intestinal enzymatic processes to the absorption process of other prodrugs as well.