The relative bioavailability of morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®) and an extended release morphine sulfate capsule formulation (KADIAN®) in healthy adults under fasting conditions.

Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, King Pharmaceuticals®, Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a µ-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN®, treatment B). Morphine pharmacokinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of ln-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC0-t) and AUC from time 0 to infinity (AUCinf) and maximum serum concentration (Cmax) for treatments A versus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC0-t (102.2%; 98.6-105.9%), AUCinf (97.4%; 91.2-104.1%), and Cmax (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC0-t and AUCinf fell within the 80%-125% range, but the lower limit for Cmax was 76.9%.

Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus.

Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100-mg dose in patients with diabetes mellitus (n = 9-13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (C(max) and AUC(0-tau)) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2-fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%-50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration-time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high-fat meal was found to significantly increase the C(max) and AUC(0-12 h) of midostaurin by 1.5-fold (P = .04) and 1.8-fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment-related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150-mg/day dose level.

Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years.

BACKGROUND: Guanfacine hydrochloride is an alpha(2a)-adrenoreceptor agonist found to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). Because the available immediate-release formulation requires multiple daily dosing and has been associated with rebound hypertension on abrupt cessation, an extended-release (ER) formulation has been developed for study of efficacy and tolerability parameters in patients with ADHD. OBJECTIVE: This trial was primarily undertaken to determine the effect on blood pressure (BP) of abrupt cessation versus taper-down of guanfacine ER. METHODS: This Phase I, randomized, double-blind, placebo-controlled, dose-escalation trial was conducted at MDS Pharma Services, Lincoln, Nebraska. Male and female healthy young-adult (aged 19-24 years) volunteers were included. Subjects were randomly assigned to receive guanfacine ER as follows. Abrupt-cessation and taper-down groups both received guanfacine ER at forced titration: 1 mg on days 1 to 4, 2 mg on days 5 to 8, 3 mg on days 9 to 12, and 4 mg on days 13 to 16. The abrupt-cessation group then received placebo daily on days 17 to 32. The taper-down group began the following taper-down schedule: 3 mg on days 17 to 20, 2 mg on days 21 to 24, 1 mg on days 25 to 30, and placebo on days 31 to 32. Placebo was administered daily to the subjects in the placebo group (days 1-32). All doses were given in the morning. Tolerability was assessed before (at the 8-hour baseline visit), during (approximately every 4 days and during 48-hour confinements at days 17/18 and 31/32), and 7 days after the study and included assessment of BP and pulse, 12-lead electrocardiography (ECG), and laboratory assays. Adverse events (AEs) were also tracked every 4 days beginning on day 5 and 7, 14, and 30 days poststudy by recording responses and follow-up to a nonleading question about how the patient was feeling that day. RESULTS: Forty-five subjects were enrolled in the study (15 in each group), and 35 subjects completed it. The mean age of study participants was 22 years, 87% were white, and the ratio of women to men was 2:1. There were no marked differences between groups regarding age, sex, or race. Compared with the taperdown group, the abrupt-cessation group did not exhibit a clinically significant elevation of systolic BP (SBP) or diastolic BP (DBP) or other tolerability parameters, including AEs. Significant differences in BP were observed on days 17/18 (first day of abrupt cessation) and 31/32, but the overall means were not statistically different. The SBP decreases were -7.55% (-8.84 mm Hg) in the abrupt-cessation group and -8.33% (-9.69 mm Hg) in the taper-down group. The DBP decreases were -9.14% (-6.17 mm Hg) in the abrupt-cessation group and -9.94% (-6.59 mm Hg) in the taper-down group. There were no statistically significant or clinically important differences in change or percentage change in pulse from baseline to day 31/32 between the taper-down and placebo groups (least squares mean difference, 2.26 bpm). None of the subjects experienced bradycardia. No clinically important treatment related trends were noted in the clinical laboratory, ECG, or physical examination findings, including vital signs. No serious treatment-emergent AEs were reported in this study. Overall, 124 treatment-emergent AEs were reported in 29 (64%) subjects. Treatment-emergent AEs were reported in 14 (93.3%) of 15 subjects in the abrupt-cessation group, 8 (53.3%) of 15 subjects in the taper-down group, and 7 (46.7%) of 15 subjects in the placebo group. Headache was the most common AE reported in the abrupt-cessation (46.7%) and placebo (13.3%) groups. For the taper down group, it was dry mouth (26.7%). All AEs were classified as mild or moderate. CONCLUSION: In this small study group of healthy, young-adult volunteers, guanfacine ER at doses up to 4 mg/d was abruptly discontinued without significant increases in SBP or DBP or other tolerability parameters, including AEs, compared with taper.

Effect of an aluminum- and magnesium-containing antacid on the bioavailability of garenoxacin in healthy volunteers.

STUDY OBJECTIVE: To evaluate the effect of an aluminum- and magnesium-containing antacid (Al-Mg antacid), which contains a high concentration of cations, on the pharmacokinetics of garenoxacin. DESIGN: Prospective, randomized, open-label, control-balanced, residual-effects-design study. SETTING: Pharmaceutical company-affiliated study clinic. SUBJECTS: Twenty healthy volunteers who were garenoxacin naïve. INTERVENTION: Subjects were randomly assigned to receive three of six oral treatments, each separated by a 7-day washout period: garenoxacin 600 mg administered alone, with concomitant Al-Mg antacid, 2 or 4 hours before Al-Mg antacid, or 2 or 4 hours after Al-Mg antacid. The Al-Mg antacid dose was 20 ml, which contained aluminum hydroxide 900 mg and magnesium hydroxide 800 mg. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics and safety of garenoxacin were assessed. For each treatment, serial blood samples for pharmacokinetic analysis of garenoxacin were collected before and up to 72 hours after garenoxacin dosing. Absence of effect of Al-Mg antacid on garenoxacin area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) and maximum observed plasma concentration (C(max)) were concluded if the 90% confidence interval of the adjusted geometric mean ratios with and without the antacid were contained within 0.80-1.25 and 0.70-1.43, respectively. Exposure to garenoxacin measured by AUC(0-infinity), a parameter well correlated with efficacy, was reduced by 58% when coadministered with Al-Mg antacid and reduced by 22% and 16% when administered 2 and 4 hours after the antacid, respectively. Administration of garenoxacin 4 hours before Al-Mg antacid had no effect on AUC(0-infinity) or C(max) of garenoxacin, whereas administration 2 hours before the antacid resulted in a nonclinically relevant (12%) reduction in AUC(0-infinity) of garenoxacin. CONCLUSION: Exposure to garenoxacin was significantly decreased when garenoxacin was coadministered with Al-Mg antacid or within 2 hours after the antacid. The magnitude of the changes in garenoxacin exposure suggests that garenoxacin should be administered at least 2 hours before or 4 hours after administration of Al-Mg antacid or other cation-containing products.

The effect of omeprazole on the bioavailability and safety of garenoxacin in healthy volunteers.

The effect of coadministration of omeprazole on the bioavailability of oral garenoxacin was evaluated in an open-label study in 14 healthy subjects. Single-dose pharmacokinetics of garenoxacin were determined with and without steady-state omeprazole. Following an oral dose of garenoxacin 600 mg on day 1, serial blood samples were obtained over the next 72 hours. Omeprazole 40 mg once daily was administered from days 4 to 10. A second pharmacokinetic assessment of garenoxacin was conducted on day 8. Geometric means for the maximum observed concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 9.6 microg/mL (18.2%) and 132.0 microg.h/mL (18.9%), respectively, for garenoxacin alone and 9.3 microg/mL (21.6%) and 140.4 microg.h/mL (22.1%), respectively, for coadministered garenoxacin and omeprazole. The 90% confidence interval for the ratio of geometric means (with/without omeprazole) for both variables was contained within 0.80 to 1.25, and the bioavailability of garenoxacin was not affected by the concomitant administration of omeprazole.

A pharmacokinetic study to compare two simultaneous 400 microg doses with a single 800 microg dose of oral transmucosal fentanyl citrate.

It is unknown whether two smaller doses of oral transmucosal fentanyl citrate (OTFC) administered simultaneously are pharmacokinetically equivalent to an identical dose administered as a single unit. This issue has important practical implications when patients are attempting to identify the appropriate dosage of OTFC to control their pain. This open-label, randomized, crossover design study compared the pharmacokinetics of two simultaneously consumed 400 microg OTFC doses with one 800 microg OTFC dose in 12 healthy volunteers. The two treatments were pharmacokinetically equivalent. The maximum concentration produced for each dosage group (Cmax) was 1.09 ng/ml for two 400 microg dose and 1.10 ng/ml for one 800 microg dose. Area under the curve (AUC) was 8.2 ng/ml.hr (SE=1.1) and 7.2 ng/ml.hr (SE=1.0). There were no significant differences between the treatment groups in either the time to peak concentration (Tmax) or the mean residence time (MRT). The results demonstrate the bioequivalence of two 400 microg with one 800 microg OTFC units.

Effect of colesevelam on lovastatin pharmacokinetics.

OBJECTIVE: To assess potential interactions of colesevelam hydrochloride and lovastatin in healthy volunteers when lovastatin alone was administered with dinner, both lovastatin and colesevelam were administered with dinner, and colesevelam was administered with dinner and lovastatin was administered 4 hours later with a snack. METHODS: A single-center, open-label, 3-period, crossover drug interaction study was performed with 22 healthy volunteers. Blood samples were collected at specified intervals before and after dosing, and plasma concentrations of lovastatin and lovastatin hydroxyacid were measured using a liquid chromatography/mass spectroscopy/mass spectroscopy method. RESULTS: Maximal concentration (Cmax), AUC from time 0 to the last time point measured (AUC0-t), and AUC0-infinity values for lovastatin were 102%, 94%, and 104%, and for lovastatin hydroxyacid were 102%, 91%, and 92%, respectively, of control values when colesevelam and lovastatin were coadministered with dinner. Administration of colesevelam with dinner and lovastatin 4 hours later with a snack resulted in a decreased Cmax and AUC0-t for lovastatin (63% and 37%, respectively; p < 0.05) and an increased Cmax and AUC0-t for lovastatin hydroxyacid (61% and 50%, respectively; p < 0.05), both compared with lovastatin alone administered with dinner. CONCLUSIONS: Colesevelam had no significant effect on lovastatin pharmacokinetics when coadministered with lovastatin at dinner. A split-dosing regimen resulted in alterations in pharmacokinetic parameters for lovastatin and lovastatin hydroxyacid that are likely due to known differences in the pharmacokinetics of lovastatin when administered to patients with meals or in a fasting state.