Fixed-dose combination tablet of repaglinide and metformin is bioequivalent to concomitantly administered individual tablets of repaglinide and metformin : randomized, single-blind, three-period crossover study in healthy subjects.

BACKGROUND AND OBJECTIVE: Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. METHODS: Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. RESULTS: Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. CONCLUSION: An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

Effects of a new antibacterial, telavancin, on cardiac repolarization (QTc interval duration) in healthy subjects.

Telavancin is a rapidly bactericidal antibiotic with multiple mechanisms of action against gram-positive bacteria. Preclinical and early clinical data suggested possible effects on cardiac repolarization requiring the conduct of a definitive evaluation of QT effects in healthy subjects. A total of 160 subjects were randomized into four groups to receive placebo (telavancin vehicle), telavancin at a dose of 7.5 mg/kg or 15 mg/kg, or moxifloxacin 400 mg (positive control). All medications were administered once daily for 3 days as 60-minute IV infusions. Sixteen ECGs were obtained over 24 hours following an infusion of D5W (baseline) and following Day 3 infusions of each medication. ECGs were analyzed digitally in a blinded fashion by a validated core ECG laboratory. The primary endpoint was QT data corrected for heart rate by the Fridericia formula (QTcF). Placebo-corrected mean changes in QTcF values for 7.5 mg/kg telavancin, 15 mg/kg telavancin, and moxifloxacin were 4.1 msec, 4.5 msec, and 9.2 msec, respectively. The mean change from baseline in QTcF for moxifloxacin, which served as the assay-sensitive positive control in the study, helped to establish that telavancin had a minimal effect on QT prolongation. No subject had a QTcF > or = 450 msec, and none experienced clinically significant ECG abnormalities. The telavancin treatment groups were not significantly different from each other. There was no correlation of the magnitude of change in QTc and plasma concentrations of telavancin. Telavancin has a < 5-msec mean effect on cardiac repolarization, with a flat-dose response over a two-fold exposure range.

Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacokinetics in patients with rheumatoid arthritis.

The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.

Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl.

OBJECTIVE: In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects. METHODS: Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose. RESULTS: Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet. CONCLUSION: This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.

The effects of supratherapeutic doses of duloxetine on blood pressure and pulse rate.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of approximately 12 mm Hg and approximately 7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

QT effects of duloxetine at supratherapeutic doses: a placebo and positive controlled study.

BACKGROUND: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential. METHODS: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericia's correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured. RESULTS: Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were <0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values >445 msec with duloxetine, and the change in QT Fridericia's correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method. CONCLUSIONS: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

Interaction of ritonavir-boosted tipranavir with loperamide does not result in loperamide-associated neurologic side effects in healthy volunteers.

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO2 response curves and pupillary response in the presence of TPV and/or RTV.

Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily.

Once-daily administration of 300 mg of lamivudine in combination with other antiretroviral agents has been proposed as a possible way to optimize anti-human immunodeficiency virus (HIV) treatment and to facilitate adherence. A single-center, randomized, two-way, crossover study was conducted in 60 healthy subjects to compare the steady-state pharmacokinetics of lamivudine in plasma and its putative active anabolite, lamivudine 5'-triphosphate (lamivudine-TP), in peripheral blood mononuclear cells (PBMCs) following 7 days of treatment with lamivudine at 300 mg once daily and 7 days of the standard regimen of 150 mg twice daily. Serial blood samples were collected over 24 h for determination of plasma lamivudine concentrations by liquid chromatography-mass spectrometry and intracellular lamivudine-TP concentrations in peripheral blood mononuclear cells by high-performance liquid chromatography/radioimmunoassay methods. Pharmacokinetic parameters were calculated based on lamivudine and lamivudine-TP concentration-time data. Regimens were considered bioequivalent if 90% confidence intervals (CI) for the ratio (once daily/twice daily) of geometric least-squares (GLS) means for lamivudine and lamivudine-TP pharmacokinetic values fell within the acceptance range of 0.8 to 1.25. Steady-state plasma lamivudine pharmacokinetics following the once- and twice-daily regimens were bioequivalent with respect to the area under the drug concentration-time curve from 0 to 24 h at steady state (AUC(24,ss)) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97) and average plasma lamivudine concentration over the dosing interval (C(ave,ss)) (GLS mean ratio, 0.94; 90% CI, 0.92, 0.97). Steady-state intracellular lamivudine-TP pharmacokinetics after the once- and twice-daily regimens were bioequivalent with respect to AUC(24,ss) (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), C(ave,ss) (GLS mean ratio, 0.99; 90% CI, 0.88, 1.11), and maximum lamivudine concentration (C(max,ss)) (GLS mean ratio, 0.93; 90% CI, 0.81, 1.07). Lamivudine-TP trough concentrations were modestly lower (by 18 to 24%) during the once-daily regimen; the clinical importance of this is unclear, given the large intersubject variability in values that was observed (coefficient of variation, 48 to 124%). Once-daily lamivudine was as well tolerated as the twice-daily regimen. Overall, the results of this study suggest that for key AUC-related parameters, lamivudine at 300 mg once daily is pharmacokinetically equivalent to lamivudine at 150 mg twice daily.