Bioequivalence of cyclobenzaprine hydrochloride extended-release capsule taken intact or sprinkled over applesauce
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OBJECTIVE: Difficulty swallowing pills can compromise pain control in painful musculoskeletal disorders. This open-label, 2-period crossover study assessed pharmacokinetics and safety of cyclobenzaprine extended-release (CER) 30-mg capsule contents sprinkled over applesauce compared with intact capsules in healthy subjects. MATERIALS AND METHODS: 32 subjects were randomized to treatment sequences AB or BA (A = single CER intact capsule; B = single CER capsule contents sprinkled over applesauce (15 mL)). Treatments were separated by a ≥ 14-day washout. Pharmacokinetic assessments included maximum observed plasma drug concentration (Cmax), time to Cmax (tmax), time to first quantifiable plasma drug concentration (tlag), and area under the plasma drug concentration-vs.-time curve from time 0 to the last measurable drug concentration (AUC0-t) and extrapolated to infinity (AUC0-∞). Bioequivalence was established if the 90% confidence intervals (CIs) of the geometric least squares (LS) means ratios of B:A of Cmax, AUC0-t, and AUC0-∞ were 80 - 125%. Safety was also assessed. RESULTS: Mean plasma drug concentration-vs.-time profiles were similar for CER intact and sprinkled over applesauce. The 90% CIs of LS means ratios indicated bioequivalence: Cmax 91.96 - 100.76%, AUC0-t 96.18 - 103.50%, and AUC0-∞ 95.70 - 103.07%. Median tmax was not significantly different (p > 0.05), and median tlag was the same (1 hour). All adverse effects were mild and resolved during the study. No clinically meaningful changes were noted for clinical laboratory values. CONCLUSION: CER capsules intact and sprinkled over applesauce are bioequivalent. Sprinkling CER capsule contents is not expected to affect efficacy or safety and can, therefore, be an option for patients with musculoskeletal pain and difficulty swallowing capsules.
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A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers.

PURPOSE: Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults. The aim of this study was to investigate the pharmacokinetic properties and excretion of prucalopride in healthy individuals, using a microtracer approach with (14)C radioactivity detection using liquid scintillation counting and accelerator mass spectrometry. METHODS: This was a single-period, open-label, nonrandomized absorption, metabolism, and excretion study of [(14)C]prucalopride. Participants were 6 healthy men aged 18 to 50 years. After screening, participants were administered a single dose of [(14)C]prucalopride succinate 2 mg (~200 nCi). Postadministration, urine, feces, and blood samples were collected over a 10-day period. Safety and adverse event data were also collected. FINDINGS: Almost 100% of the administered dose of radioactivity was recovered, with a mean (SD) of 84.2% (8.88%) recovered in urine and 13.3% (1.73%) recovered in feces. The mean blood-to-plasma concentration ratio of 1.9 indicated uptake of prucalopride into blood cells. The renal clearance of prucalopride was 17.0 (2.5) L/h, which is higher than the glomerular filtration rate in healthy individuals, suggesting active renal transport of prucalopride. Prucalopride was well tolerated, with no serious adverse events reported. IMPLICATIONS: Prucalopride was well absorbed and excreted mainly by the kidneys, including both passive and active transporter mechanisms. Quantitative recovery of the radioactive dose was achieved. Consistent with previous studies, prucalopride was generally well tolerated. ClinicalTrials.gov identifier: NCT01807000.

Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study.

BACKGROUND: Lanthanum carbonate and sevelamer carbonate are noncalcium phosphate binders used to treat hyperphosphatemia in patients with chronic kidney disease. This is the first study to compare phosphate absorption from a standardized meal ingested with a typical clinical dose of these binders. STUDY DESIGN: Randomized open-label crossover study. SETTINGS & PARTICIPANTS: Healthy volunteers were confined to a clinical research center during 4 study periods. Of 31 volunteers randomly assigned, 19 completed all treatments and 18 were analyzed in the pharmacodynamic set (1 was excluded because of vomiting). INTERVENTION: Participants were assigned in random order to meal alone, meal plus lanthanum carbonate (1 tablet containing 1,000 mg of elemental lanthanum), and meal plus sevelamer carbonate (three 800-mg tablets). The gastrointestinal tract was cleared, the meal was ingested (± treatment), and rectal effluent was collected. In a fourth period, volunteers repeated the study procedures while fasting. OUTCOMES: The primary end point, net phosphate absorption, was analyzed using a mixed-effect linear model. MEASUREMENTS: Phosphorus content of effluent and duplicate meal samples were measured using inductively coupled plasma-optical emission spectroscopy. RESULTS: The standard meal contained ∼375 mg of phosphate, 75% of which was absorbed (net absorption, 281.7 ± 14.1 mg [adjusted mean ± standard error]). Lanthanum carbonate decreased net phosphate absorption by 45% (net absorption, 156.0 ± 14.2 mg) compared with 21% (net absorption, 221.8 ± 14.1 mg) for sevelamer carbonate (P < 0.001). Lanthanum carbonate bound 135.1 ± 12.3 mg of phosphate, whereas sevelamer carbonate bound 63.2 ± 12.3 mg, a 71.9-mg difference (95% CI, 40.0-103.8; P < 0.001). Per tablet, this equates to 135 mg of phosphate bound with lanthanum carbonate versus 21 mg with sevelamer carbonate. LIMITATIONS: A single-dose study. CONCLUSIONS: In healthy volunteers, 1,000 mg of lanthanum carbonate decreased phosphate absorption by 45% compared with a 21% decrease with 2,400 mg of sevelamer carbonate.

Effect of low-dose omeprazole (20 mg daily) on the pharmacokinetics of multiple-dose atazanavir with ritonavir in healthy subjects.

Atazanavir, a potent protease inhibitor of human immunodeficiency virus (HIV), exhibits pH-dependent solubility. Previous studies have indicated that coadministration with omeprazole 40 mg once daily significantly decreased atazanavir exposure by approximately 75%. Concomitant use of omeprazole and atazanavir is currently not recommended. This study investigated a clinically effective, low dose of omeprazole (20 mg daily) on atazanavir pharmacokinetics in 56 healthy volunteers given atazanavir/ritonavir 300/100 and 400/100 mg once daily. All atazanavir/ritonavir plus omeprazole combinations resulted in atazanavir area under the concentration-time curve (AUC) and trough concentrations (C(min)) comparable to or exceeding those observed with atazanavir 400 mg without omeprazole. Compared with atazanavir/ritonavir 300/100 mg without omeprazole, atazanavir/ritonavir 300/100 mg plus omeprazole reduced atazanavir AUC and C(min) by 42% and 46%, respectively. Increasing the atazanavir/ritonavir dose to 400/100 mg attenuated the effect of omeprazole, resulting in approximately 30% lower atazanavir C(min), with all individual C(min) values exceeded by greater than 10-fold the population mean protein binding-adjusted EC(90) against wild-type HIV. The effect of omeprazole on atazanavir/ritonavir 400/100 mg was similar whether given 1 hour prior to atazanavir/ritonavir or separated by 12 hours. No unexpected adverse events were noted. This study found that omeprazole 20 mg once daily has significantly less profound effects on atazanavir pharmacokinetics than previously observed with omeprazole 40 mg.