Bioequivalence study of a novel orodispersible tablet of meloxicam in a porous matrix after single-dose administration in healthy volunteers.

BACKGROUND: Meloxicam is a non-steroidal anti-inflammatory drug, indicated for osteoarthritis exacerbations, rheumatoid arthritis and ankylosing spondylitis symptomatic treatment. OBJECTIVE: To compare the bioavailability of a 15 mg meloxicam orodispersible tablet (ODT) and a reference 15 mg tablet in healthy volunteers. METHODS: Two randomized, crossover, bioequivalence studies were conducted. In both studies, 28 volunteers were randomly assigned to receive test ODT and reference tablet formulations in single dose under fasting conditions in two study periods, with a 7-day (Study I) or 14-day (Study II) wash-out between administrations. Blood samples were collected at pre-specified times. Pharmacokinetic parameters were obtained by noncompartmental analysis. Bioequivalence was assumed if the 90% confidence interval of the test/reference ratio of the least-squares means for Cmax, AUC0-t and AUC0-∞were within the 80.00 -125.00% range, according to the current guidelines. RESULTS: All 28 subjects in Study I and 26 subjects in study II completed the study and were included in the analysis. The 90% confidence intervals of the geometric means ratios for the logtransformed Cmax, AUC0-t and AUC0-∞were 87 - 96%, 88 - 96% and 87 - 96% in Study I, and 99 - 105%, 98 - 104% and 108 - 120% in Study II. Test product was characterized by a slightly earlier tmax than the reference, i.e., 4.9 ± 1.1 vs. 5.8 ± 2.6 hours in Study I (p = 1.000) and 3.8 ± 2.0 vs. 4.8 ±1.6 hours in Study II (p = 0.0054). The two drugs were well tolerated. CONCLUSIONS: Test and reference formulations met the regulatory criteria for bioequivalence in the fasting healthy volunteers enrolled.

Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study.

BACKGROUND: Intranasal fentanyl spray (INFS, Instanyl®) was developed to treat cancer patients with Breakthrough Pain (BTP). INFS is delivered via a multi-dose delivery system (MDS) that is available in various dose strengths. The aim of this study was to demonstrate the pharmacokinetic bioequivalence of INFS single dose delivery system (SDS) in relation to the currently marketed MDS device. METHODS: In a randomized, single-center, single-dose, open label, comparative, four-period, two-sequence, replicate cross-over study, 48 healthy subjects (24 male and 24 female, mean age of 28.1 years, mean bodyweight 69.8 kg) received 200 µg/100 µl fentanyl administered via SDS and via MDS in one of two alternating treatment sequences. Naltrexone was given to all subjects to prevent potential fentanyl adverse drug reactions. Blood samples were frequently taken up to 72 hours post INFS administration and analyzed by liquid chromatography with tandem mass spectrometric detection. Primary pharmacokinetic parameters were area under the curve extrapolated to infinity (AUC0-∞) and peak plasma concentration (Cmax). Statistical analyses of the primary pharmacokinetic parameters were performed using a linear mixed effect model applied to the natural log-transformed data. RESULTS: Healthy subjects showed very similar plasma concentration over time profiles for both delivery systems. The mean fentanyl Cmax and AUC0-∞ values for SDS and MDS were 948 pg/ml, 949 pg/ml and 4,439 pg×h/ml, 4,489 pg×h/ml. respectively. Point estimates (and 90% confidence intervals) for AUC and Cmax were 0.97 (0.93 - 1.02) and 1.00 (0.92 - 1.09) and therefore in the bioequivalence range of 0.80 - 1.25. CONCLUSIONS: Results of this study show that SDS and MDS met the pre-defined regulatory criteria for bioequivalence. Safety profiles were consistent between both devices and no safety concerns were identified with INFS administered in combination with oral naltrexone.

Lack of a meaningful effect of anacetrapib on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Inhibition of cholesteryl ester transfer protein (CETP) is a potential new mechanism for the treatment of dyslipidaemia. Anacetrapib is a novel CETP inhibitor in development. Warfarin is a commonly prescribed anticoagulant that has a narrow therapeutic index. A drug interaction study for warfarin with a novel CETP inhibitor is expected to be helpful in defining dosing regimens. WHAT THIS STUDY: ADDS • This is the first study to show that there is no clinically meaningful pharmacokinetic interaction between anacetrapib and warfarin. The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib. AIM: Anacetrapib is currently being developed for the treatment of dyslipidaemia. Since warfarin, an anticoagulant with a narrow therapeutic index, is expected to be commonly prescribed in this population, a drug interaction study was conducted. METHODS: In a randomized, open-label, two-period fixed-sequence design, 12 healthy male subjects received two different treatments (treatment A followed by treatment B). In treatment A, a single oral dose of 30 mg warfarin (3 × 10 mg Coumadin(TM) ) was administered on day 1. After a washout interval, subjects began treatment B, where they were given daily 100 mg doses of anacetrapib (1 × 100 mg) beginning on day -14 and continuing through day 7, with concomitant administration of 30 mg warfarin (3 × 10 mg) on day 1. All anacetrapib and warfarin doses were administered with a standard low fat breakfast. After warfarin concentrations and prothrombin time were measured, standard pharmacokinetic, pharmacodynamic and statistical (linear mixed effects model) analyses were applied. RESULTS: Anacetrapib was generally well tolerated when co-administered with warfarin in the healthy males in this study. The geometric mean ratios (GMRs) for warfarin + anacetrapib : warfarin alone and 90% confidence interval (CIs) for warfarin AUC((0-∞)) were 0.94 (0.90, 0.97) for the R(+) warfarin enantiomer and 0.93 (0.87, 0.98) for the S(-) warfarin enantiomer, both being contained in the interval (0.80, 1.25), supporting the primary hypothesis of the study. The GMRs warfarin + anacetrapib : warfarin alone and 90% CIs for the statistical comparison of warfarin C(max) were 1.01 (0.97, 1.05) for both the R(+) warfarin and the S(-) warfarin enantiomers, and were also contained in the interval (0.80, 1.25). The GMR (warfarin + anacetrapib : warfarin alone) and 90% CI for the statistical comparison of INR AUC((0-168 h)) was 0.93 (0.89, 0.96). CONCLUSION: The single dose pharmacokinetics and pharmacodynamics of orally administered warfarin were not meaningfully affected by multiple dose administration of anacetrapib, indicating that anacetrapib does not affect CYP 2C9 clinically. Thus, no dosage adjustment for warfarin is necessary when co-administered with anacetrapib.

Lack of an effect of anacetrapib on the pharmacokinetics of digoxin in healthy subjects.

Anacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co-administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC(0-last) and AUC(0-∞) were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin C(max) were 1.23 (1.14, 1.32). Median T(max) and mean apparent terminal t(½) of digoxin were comparable between the two treatments. The single-dose pharmacokinetics of orally administered digoxin were not meaningfully affected by multiple-dose administration of anacetrapib, indicating that anacetrapib does not meaningfully inhibit P-glycoprotein. Thus, no dosage adjustment for digoxin is necessary when co-administered with anacetrapib.

Techniques for hyaluronidase-facilitated subcutaneous fluid administration with recombinant human hyaluronidase: the increased flow utilizing subcutaneously enabled administration technique (INFUSE AT) study.

INTRODUCTION: Recombinant human hyaluronidase facilitates subcutaneous (SC) fluid delivery, but little is known about how various access sets influence ease of administration, technical challenges (TCs), or adverse events. METHODS: This randomized, open-label, parallel-group trial was performed to assess the impact of catheter size (20- and 24-gauge short peripheral intravenous catheter, 27-gauge SC button), catheter material (Teflon, polyurethane), and securement method (transparent semipermeable membrane dressing [TSM], double chevron with cloth or plastic tape) on hyaluronidase-facilitated SC fluid delivery. Healthy volunteers (N = 100) were randomized to 1 of 9 access groups using a factorial design. To minimize variability, treatment was performed at a single center and standardized to 150 units of SC recombinant human hyaluronidase (HYLENEX, Baxter Healthcare Corporation) followed by 1000 mL of lactated Ringer's solution. RESULTS: The first attempt at needle insertion succeeded in 98% of subjects; the median time for first catheter placement was less than 1 minute. The median infusion time was 6.8 hours. Overall, the incidence of TCs observed (catheter kinking, dislodgment, or pullout or infusion pump alarm) was low and comparable across groups (16.7%-27.3%); however, catheter kinking, dislodgment, and pullout occurred only in groups using double- chevron securement. Infusion-site reactions (pain, 20%-75%; erythema, 17%-36%; swelling, 0%-33%) were the most common adverse events. Pain was less frequent in groups using the 27-gauge SC button (27%) or the 24-gauge catheter (20%-36%) than with the 20-gauge catheter (50%-75%). DISCUSSION: Hyaluronidase-facilitated SC fluid administration with recombinant human hyaluronidase was generally well tolerated and successfully implemented using a range of access sets. Technical challenges were not common but were further minimized with TSM securement. Infusion-site pain was mostly mild and least common with 24-gauge or smaller catheter/needles.

Effects of laropiprant, a selective prostaglandin D2 receptor 1 antagonist, on the steady-state pharmacokinetics of digoxin in healthy adult subjects.

Laropiprant, a prostaglandin D(2) receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful.

An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

Measurement issues related to upper limb interventions in persons who have tetraplegia.

Measurement of upper limb function in persons with tetraplegia poses significant issues for clinicians and researchers. It is crucial that measures detect the small but significant improvements in hand function that may or may not occur as a result of our interventions. Before determining how we measure changes from upper limb interventions, we must establish what outcomes are of greatest interest, and for whom. Many issues have an impact on both the measurement and interpretative process.

Spinal Cord Injury Rehabilitation Evidence: Methods of the SCIRE Systematic Review.

The Spinal Cord Injury Rehabilitation Evidence (SCIRE) is a synthesis of the research evidence underlying rehabilitation interventions to improve the health of people living with SCI. SCIRE covers a comprehensive set of topics and in this issue we present six papers relevant to SCI rehabilitation clinicians (SCI inpatient rehabilitation practices, gait strategies, upper extremity reconstructive surgery, spasticity treatments, cardiovascular health and bone health). The SCIRE used a systematic and well-defined protocol to assess and synthesize the evidence. Each article was scored for its methodological quality using either the Physiotherapy Evidence Database (PEDro) Score for randomized controlled trials or the Downs and Black Tool for other types of studies. Following the individual study assessment, conclusions were drawn about the accumulated studies for each topic of interest based on the levels of evidence, quality of studies and concurring evidence. The SCIRE project was designed for health professionals to inform them of best practices.