Effect of Food Intake and Body Position on the Pharmacokinetics of Swallowed APT-1011, a Fluticasone Orally Disintegrating Tablet, in Healthy Adult Volunteers.

Eosinophilic esophagitis is a common atopic disease of the esophagus. APT-1011 is an orally disintegrating tablet formulation of fluticasone propionate under development for the treatment of eosinophilic esophagitis. The objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of APT-1011 under fed or fasted conditions in the morning (am) or at bedtime (hs) in the supine position. The study was a randomized, single-dose, 3-way, crossover design in healthy adult volunteers. In each study period participants received 2 3-mg orally disintegrating APT-1011 tablets. Serial plasma samples were collected before dosing and up to 72 hours after each dose. Twenty-two participants completed the study. The fluticasone propionate peak concentration (Cmax ) ranged from 5.97 to 200 pg/mL. Compared with am-fasted dosing, am-fed dosing was associated with a modestly higher Cmax (∼21%) but lower net exposure (area under the concentration-time curve ∼56% difference) and shorter time to reach Cmax (Tmax ) (Tmax fasted = 10 hours, fed = 5 hours). Dosing at hs resulted in an 18% and 32% decrease in Cmax relative to am-fasted and am-fed conditions, respectively. Dosing at hs led to an exposure that was higher than am-fed but lower than am-fasted dosing. Tmax with hs dosing (14 hours) was later than that with am dosing (Tmax fasted = 10 hours, fed = 5 hours). Adverse events were mild. There is low systemic exposure of fluticasone propionate with APT-1011. The rate of absorption was increased with a high-fat meal but decreased with hs dosing, suggesting the potential for longer dwell times in the esophagus.

Association between the North Carolina Medical Board opioid guideline update and opioid prescriptions in Medicare Part D beneficiaries.

OBJECTIVE: To examine if North Carolina (NC) opioid prescribing guidelines were associated with changes in opioid prescribing. METHOD: Retrospective secondary analysis of the Medicare Provider Utilization and Payment Data: Part D Prescriber datasets from 2013 to 2015. PARTICIPANTS: Providers who prescribed at least one opioid from 2013 to 2015 and paid by Medicare Part D. MAIN OUTCOME MEASURE: Per-prescriber Medicare-population adjusted number of analgesic opioid claims and per-prescriber average day supply. Generalized estimating equations (GEE) were used to analyze the data. RESULTS: There were significantly higher per-prescriber Medicare adjusted opioid claims in 2014 compared to 2015 (p < 0.001) but no difference between 2013 and 2015 (p = 0.584). GEE results also indicated that there was a significant increase in 2015 in per-prescriber average day supply, compared to 2013 and 2014 (both p < 0.0001). CONCLUSIONS: State opioid prescribing guidelines published in mid-2014 may have slowed the escalation of numbers of opioid prescriptions in NC. Future research should examine whether the guidelines were associated with changes in morphine equivalent dosing in NC during the same timeframe.

Exercise is medicine: student pharmacists' perceptions and knowledge of exercise prescription.

With healthcare costs on the rise, a global initiative was launched in 2007, called Exercise is Medicine, to prescribe and counsel patients on exercise to aid in the prevention and treatment of chronic diseases. Since community pharmacists are one of the most accessible healthcare providers, this is an opportunity for pharmacists to also engage in this initiative. This study aimed to assess pharmacy student perceptions and knowledge on exercise to determine whether they are adequately prepared to counsel patients on exercise prescription. Third and fourth year pharmacy students were surveyed to test their basic knowledge of exercise prescription. Results show that 93.5% of students agreed or strongly agreed that it is important for pharmacists to counsel patients about exercise. The mean (SD) score for the 11 basic knowledge quiz questions on exercise prescription was 28.9% (SD 16.8), with no significant difference between third and fourth year pharmacy students. While students deemed exercise counseling as important, students proved deficient in exercise prescription knowledge. Schools of pharmacy may consider increasing curricular content to be congruent with this initiative.

Evaluation of the use of intra-operative radiology for open placement of lag screws for the stabilization of sacroiliac luxation in cats.

OBJECTIVES: To assess the effect of intra-operative radiology on the quality of lag screw insertion for the management of sacroiliac joint luxations in cats. METHODS: In this retrospective single-centre study, the surgical, anaesthetic and imaging records of 40 screws (32 cats) placed with lag effect for management of sacroiliac luxation were reviewed. Postoperative radiographs were assessed for sacroiliac joint reduction, screw position, and sacral width purchased by each screw. Cases were divided into two groups according to the use of (IOR) or the absence of intra-operative radiology (NIOR). RESULTS: A total of 23 lag screws were placed with the aid of intra-operative radiology and 17 without. Three of the 23 screws placed in the IOR group exited the sacrum as opposed to eight of 17 screws in the NIOR group (p = 0.03). Mean sacral width purchased by the screws in the IOR group (70.8%) was also significantly higher (p = 0.002) than in the NIOR group (54.6%). Mean general anaesthetic times for unilateral and bilateral screw placement for the IOR group and NIOR group were not significantly different. CLINICAL SIGNIFICANCE: The use of intra-operative radiology can significantly improve the quality of lag screw insertion for the stabilization of sacroiliac luxations in cats, which should lead to a reduced incidence of postoperative screw loosening.

Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.

UNLABELLED: GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides. TRIAL REGISTRATION: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Inverse dynamics analysis evaluation of tibial tuberosity advancement for cranial cruciate ligament failure in dogs.

OBJECTIVE: To evaluate, using inverse dynamic analysis, the biomechanical outcome from tibial tuberosity advancement (TTA) surgery in dogs affected by unilateral cranial cruciate ligament failure (CCLF). STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 13) 11-20 months after surgery. METHODS: Kinematic and force data were collected from 13 dogs 11-20 months after TTA and inverse dynamics analysis of the dogs' pelvic limb mechanical function performed. Angle, moment, and power were calculated for each joint. Total support moment (TSM) was calculated. RESULTS: Six dogs were affected on the right side (Raff) and 7 on the left (Laff). Peak stifle flexor moment was significantly larger for the right stifle compared with the left in Laff dogs, but similar in Raff dogs. Peak stifle extensor moment was significantly larger for the left stifle compared with the right in Raff dogs, and was also larger for the left stifle compared with the right in Laff dogs. Stifle power in early stance was larger on the left in Raff dogs and significantly larger on the right in Laff dogs. TSM was larger on the right in Raff dogs and significantly larger on the right in Laff dogs. CONCLUSIONS: Affected limbs had a reduction in power of the stifle flexors. Irrespective of the side of CCLF, TSM was larger on the right side and the stifle extensor moment in late stance was larger on the left, perhaps indicating a mechanical limb dominance effect.

Opioid receptor modulation of hedonic taste preference and food intake: a single-dose safety, pharmacokinetic, and pharmacodynamic investigation with GSK1521498, a novel µ-opioid receptor inverse agonist.

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

Pharmacokinetics of modified slow-release oral testosterone over 9 days in normal men with experimental hypogonadism.

Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 µg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P < .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency.

Multiple-dose safety, pharmacokinetics, and pharmacodynamics of the µ-opioid receptor inverse agonist GSK1521498.

The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.

Oral testosterone with and without concomitant inhibition of 5α-reductase by dutasteride in hypogonadal men for 28 days.

PURPOSE: Co-administration of the 5α-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days. MATERIALS AND METHODS: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures. RESULTS: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group. CONCLUSIONS: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency.

Pharmacokinetics of 2 novel formulations of modified-release oral testosterone alone and with finasteride in normal men with experimental hypogonadism.

Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency.

Safety, tolerability, pharmacokinetics and pharmacodynamics of albiglutide, a long-acting GLP-1-receptor agonist, in Japanese subjects with type 2 diabetes mellitus.

OBJECTIVE: To investigate safety, pharmacokinetics and pharmacodynamics of albiglutide in Japanese subjects with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: This randomized, single-blind, placebo-controlled study examined four doses/dose schedules of subcutaneously (sc) administered albiglutide: 15 mg weekly, 30 mg weekly, 50 mg biweekly, and 100 mg monthly (cohorts A-D, respectively) in 40 subjects (mean age 54.5 years, mean range of glycosylated hemoglobin [HbA(1c)] 7.1-8.3%), over a 4-week treatment period. MAIN OUTCOME MEASURES: Safety parameters, including adverse events, clinical laboratory tests, vital signs, and 12-lead electrocardiogram; plasma concentrations of albiglutide; and pharmacodynamic parameters, including change from baseline and weighted mean AUC(0-4) in plasma glucose, glucagon, insulin, and C-peptide levels. CLINICAL TRIAL REGISTRATION: NCT00530309. RESULTS: At day 29, mean changes from baseline (vs. placebo) in fasting plasma glucose (FPG) were: cohort A, -1.92 mmol/L; B, -1.98 mmol/L; C, -1.74 mmol/L; D, -0.73 mmol/L; changes in weighted mean glucose AUC(0-4) were: cohort A, -2.86 mmol/L; B, -3.58 mmol/L; C, -2.51 mmol/L; D, -1.44 mmol/L (for FPG and AUC(0-4), all p < or = 0.002 except 100 mg sc monthly, p = NS); changes from baseline HbA(1c) were: cohort A, -0.58%; B, -0.57%; C, -0.63%; and D, -0.51% (all p < 0.03). Albiglutide sc had a median half-life of 5.3 days, plasma apparent systemic clearance of 68.7 mL/h, and apparent volume of distribution of 12.6 L. Incidence of adverse events was low and comparable to sc placebo in all albiglutide treatment arms except 100 mg sc monthly, where gastrointestinal (GI) adverse events were most common. Limitations of this study include the small sample size, short treatment duration, and enrollment of predominantly male subjects. CONCLUSIONS: Weekly and biweekly albiglutide improved glycemic control and were well-tolerated in Japanese subjects with type 2 diabetes mellitus.

Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes.

CONTEXT: Native glucagon-like peptide-1 increases insulin secretion, decreases glucagon secretion, and reduces appetite but is rapidly inactivated by dipeptidyl peptidase-4. Albiglutide is a novel dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to human albumin designed to have sustained efficacy in vivo. OBJECTIVES: The objectives were to investigate pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide in type 2 diabetes subjects. METHODS: In a single-blind dose-escalation study, 54 subjects were randomized to receive placebo or 9-, 16-, or 32-mg albiglutide on d 1 and 8. In a complementary study, 46 subjects were randomized to a single dose (16 or 64 mg) of albiglutide to the arm, leg, or abdomen. RESULTS: Significant dose-dependent reductions in 24-h mean weighted glucose [area under the curve((0-24 h))] were observed, with placebo-adjusted least squares means difference values in the 32-mg cohort of -34.8 and -56.4 mg/dl [95% confidence interval (-54.1, -15.5) and (-82.2, -30.5)] for d 2 and 9, respectively. Placebo-adjusted fasting plasma glucose decreased by -26.7 and -50.7 mg/dl [95% confidence interval (-46.3, -7.06) and (-75.4, -26.0)] on d 2 and 9, respectively. Postprandial glucose was also reduced. No hypoglycemic episodes were detected in the albiglutide cohorts. The frequency and severity of the most common adverse events, headache and nausea, were comparable with placebo controls. Albiglutide half-life ranged between 6 and 7 d. The pharmacokinetics or pharmacodynamic of albiglutide was unaffected by injection site. CONCLUSIONS: Albiglutide improved fasting plasma glucose and postprandial glucose with a favorable safety profile in subjects with type 2 diabetes. Albiglutide's long half-life may allow for once-weekly or less frequent dosing.

Nanomilled oral testosterone plus dutasteride effectively normalizes serum testosterone in normal men with induced hypogonadism.

Oral androgen development has been hampered by the rapid metabolism of orally administered testosterone (T) and low bioavailibility. The addition of the 5alpha-reductase inhibitor dutasteride (D) to oral T in oil dramatically improves concentrations of serum T. In this study we evaluate the absorption of oral T+D, comparing nanomilled T (NmT+D) vs T dissolved in oil (Capmul; CpT+D), as nanomilling might offer a simpler, more practical means of oral T administration, given the limited solubility of T in oil. Twelve healthy men were administered leuprolide on Day -14 to suppress endogenous T biosynthesis and were pretreated with D to block 5alpha-reductase. Once hypogonadal, subjects were sequentially administered 200- and 400-mg doses of CpT+D and NmT+D in the fasted and fed states. Serum T and dihydrotestosterone (DHT) were measured: before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each dose. Two weeks after leuprolide administration, T levels were below the normal range. A 400-mg dose of either formulation of oral T+D increased mean serum T above the lower limit of the normal range for 8-10 hours. Food had a minimal effect on the pharmacokinetic parameters of the NmT+D formulation but decreased the maximum observed concentration after dosing (C(max)) for CpT+D. Serum DHT remained below the normal range throughout the study period with both formulations. No significant changes in liver function tests or other adverse events were observed. A 400-mg dose of either oral T+D formulation normalized serum T for 8-10 hours and suppressed DHT. NmT allows for tablet formulation, and its pharmacokinetics were not affected by food, demonstrating the feasibility of oral nanomilled T as a promising and practical twice-daily therapy for the treatment of male hypogonadism.