Safety of a Novel Weight Loss Combination Product Containing Orlistat and Acarbose.

The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.

Evaluation of the Bioequivalence of Acarbose in Healthy Chinese People.

The purpose of this study was to determine whether the reference formulation and test formulation of acarbose are bioequivalent among healthy Chinese subjects based on evaluation of the pharmacodynamic end point. Two clinical trials with acarbose were conducted: study A, a pilot study (n = 12; 50 and 100 mg), and study B, a pivotal study (n = 60; 50 mg). In study A, there was a dose-dependent relationship between 50 mg acarbose and 100 mg acarbose and a significant difference compared with sucrose alone. In study B, after logarithmic conversion, a linear mixed-effects model was used to analyze the maximum serum glucose value and area under the serum glucose-time curve from 0 to 2 hours. The geometric mean ratios (test formulation/reference formulation) were 92.68% and 95.70%, with 90% confidence intervals of 84.08%-102.17% and 84.21%-108.76%, respectively, falling between 80.00% and 125.00%. According to the geometric least-squares mean, the test formulation (or reference formulation) was statistically significantly different as a single sucrose (P < .001). The effective dose of acarbose in healthy Chinese volunteers was 50 mg. The reference and test formulations were bioequivalent.

Discovery of novel pyrido-pyrrolidine hybrid compounds as alpha-glucosidase inhibitors and alternative agent for control of type 1 diabetes.

A new library of pyrido-pyrrolidine hybrid compounds were designed, developed and screened for their antidiabetic property with α-glucosidase. The design is based on preliminary screening of key fragments identified from literature reported α-glucosidase inhibitors and antidiabetic compounds. The most active fragments were stitched to provide a pyrido-pyrrolidine hybrid molecule as a new motif. A library of these compounds were synthesized and screened against a series of α-glycosidases. Subsequently, compound 3k was the most efficacious analog with IC50 of 0.56 µM. Photoluminescence study and circular dichroism experiments indicated that compound 3k modulates the primary and secondary structure of the enzyme. It successfully brings down the fasting blood glucose level for streptozotocin (STZ, 70 mg/kg, Intraperitoneal) induced type I diabetic male Sprague-Dawley rats (250-320 g). At lower concentration, compound 3k slightly stimulates proliferation of BRIN-BD11 (α-glucose responsive beta cells from rat pancreas islets that secretes insulin) cells.

Synthesis of sandwich-structured magnetic graphene-Zn-MOFs composites for quantitative determination of acarbose in rat plasma.

In this study, sandwich-structured magnetic graphene composites with Zn metal-organic framework layer coated on both two sides (denoted as magG@Zn-MOFs) were synthesized. The composites have large specific surface of 114 m2 g⁻1, uniform porous structure and rapid magnetic separation within 10 s. The magG@Zn-MOFs composites were used for extraction of acarbose in plasma prior to its quantitative analysis by LC-MS/MS. The established method has good linearity (10-1000 ng mL-1), satisfactory recovery (94.3-107.5%), low detection limit (as low as 2.5 ng mL-1), good intra-day precision (RSD 3.5-5.3%) and inter-day precision (RSD 6.3-8.1%). Finally, the method was successfully applied to pharmacokinetic study of acarbose in rats.

An open-label study to determine the pharmacokinetics and safety of migalastat HCl in subjects with impaired renal function and healthy subjects with normal renal function.

OBJECTIVES: Renal function may progressively decline in patients with Fabry disease. This study assessed pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function. METHODS: Volunteers were enrolled into two cohorts stratified for renal function calculated using the Cockcroft-Gault equation for creatinine clearance. Pharmacokinetic parameters determined were: area under the concentration-time curve (AUC) from time zero to the last measurable concentration postdose (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), maximum observed concentration (Cmax ), time to Cmax (tmax ), concentration at 48 hours postdose (C48h ), terminal elimination half-life (t1/2 ), oral clearance (CL/F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469). RESULTS: Thirty-two subjects enrolled and completed the study (Cohort 1: n = 24; Cohort 2: n = 8). Migalastat clearance decreased with increasing renal impairment, resulting in increases in migalastat HCl plasma t1/2 , AUC0-∞ , and C48h compared with subjects with normal renal function. Incidence of adverse events was comparable across all renal function groups. CONCLUSIONS: Plasma migalastat clearance decreased as degree of renal impairment increased. Data from the migalastat HCl clinical program will guide dosing and intervals for patients with Fabry disease with renal impairment.

Identification of new oral dosing regimens for the neuraminidase inhibitor oseltamivir in patients with moderate and severe renal impairment.

Availability of lower-dose oseltamivir capsules, an increased pharmacokinetic database, and a desire to align drug exposure across the spectrum of renal function prompted reassessment of oral dosing in patients with renal impairment. The data set comprised 128 subjects (71 with varying degrees of renal impairment) from 8 studies, which included single and multiple doses of 20-1000 mg. Pharmacokinetic profiles of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) were modeled simultaneously in NONMEM. Exposure metrics of OP and OC (AUC48 h , Cmax , Cmin ) after administration of various dosing regimens were simulated for renal impairment subgroups and compared with exposures in patients with normal renal function receiving approved regimens. For influenza treatment, 30 mg once-daily and twice-daily regimens were selected for severe and moderate impairment, respectively. These regimens provided OC exposures similar or above those of the approved 75-mg twice-daily treatment regimen in subjects with normal renal function. For influenza prophylaxis, 30 mg once every other day and once-daily regimens were selected for severe and moderate impairment, respectively. No dosing adjustments were required for mild impairment. This analysis supported revised labeling in the United States and Europe for oral oseltamivir dosing in patients with moderate and severe renal impairment.