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Rivipansel is a pan-selectin inhibitor in phase 3 development for the treatment of vaso-occlusive crises in patients with sickle cell disease. This single-dose, randomized, 3-period, 3-treatment (400 mg moxifloxacin open-label, 4 g rivipansel-blinded, and placebo-blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21-53 years; weight, 60-115 kg). Time-matched, placebo-adjusted change from baseline QT interval using Fridericia's correction method (QTcF) was determined using a repeated-measures mixed-effects model. The highest upper bound of the 2-sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2-sided 90%CI was less than 10 milliseconds at all times. Exposure-response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.

Safety, tolerability, and pharmacokinetics of tigecycline in 76 healthy Japanese subjects were determined in three randomized, double-blind, placebo-controlled studies. Subjects in an ascending single-dose study (n = 40) received 25-150 mg intravenously, whereas subjects in two multiple-dose studies received every 12-hour (q12h) dosing with 25 mg (n = 10) or 25, 50, or 100 then 50 mg (n = 30). Serial blood samples and urine were collected, drug concentrations determined, and pharmacokinetic parameters calculated. Fecal samples were also collected in the second multiple-dose study. After 10 days of tigecycline 50 mg q12h, mean ± standard deviation pharmacokinetics in 8/10 subjects were: maximum concentration 1,118 ± 127 ng/mL, area under the concentration-time curve 0-12 hours 3,261 ± 937 ng h/mL, clearance 0.25 ± 0.05 L/h/kg, half-life 60.7 ± 23.4 hours, and volume of distribution 11.9 ± 2.3 L/kg. The most common adverse events were nausea and vomiting. Changes in total bilirubin were also observed. Enterococci in the intestinal microflora were reduced, whereas the number of Enterobacteriaceae and Bacteroides remained relatively constant. Several strains of Bacteroides spp. resistant to tigecycline treatment were found in fecal samples on days 30 and 31. The pharmacokinetic profile of tigecycline was similar to non-Japanese subjects; tolerability and change in intestinal microflora were also similar.

Thegoalofthethisstudywastore‐evaluatetigecyclineboneconcentrationsinsubjectsundergoingelectiveorthopedicsurgery,usingmultipledosesand a more robust bone assay than was used in a previous study. Each subject received three intravenous doses of tigecycline (one 100‐mg infusion followed

Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.

Tigecycline, a novel glycylcycline, possesses broad-spectrum antimicrobial activity. A structural population pharmacokinetic model for tigecycline was developed based on data pooled from 5 phase I studies. Intravenous tigecycline was administered as single (12.5-300 mg) or multiple (25-100 mg) doses every 12 hours for up to 10 days. Three-compartment models with zero-order input and first-order elimination separately described the single- or multiple-dose full-profile data. Additional models were evaluated using a subset of the phase I data mimicking the phase II/III trial sparse-sampling scheme and dosage. A 2-compartment model best described the reduced phase I data following single or multiple doses and provided reliably accurate estimates of tigecycline AUC(0-12). This modeling supported phase II/III population pharmacokinetic model development to further determine individual patient tigecycline exposures for safety and efficacy analyses.

Thirty Japanese (J) and 32 American (A) healthy subjects received single doses of etanercept by subcutaneous injection, in 3 separate trials. Serum samples were collected for 480 hours after dosing. Concentrations were determined using enzyme-linked immunosorbent assay methods. Pharmacokinetic parameters were calculated using both non-compartmental and compartmental methods. Etanercept was slowly absorbed, with mean+/-SD time to maximum serum concentration of 47+/-15 hours (J), and 51+/-20 hours (A). The maximum serum concentration and area under the concentration time curve increased for doses 10 mg, 25 mg, and 50 mg, in a linear relationship. Etanercept was slowly eliminated, with observed mean+/-SD half-life of 80+/-25 hours (J) and 75+/-15 hours (A) and mean+/-SD apparent clearance of 144+/-65 mL/h (J) and 132+/-74 mL/h (A). Very low concentrations of etanercept were observed in the urine samples collected in the Japanese subjects. All adverse reactions observed resolved without issue, and none required discontinuation from the study.

Etanercept. a soluble recombinant human tumor necrosis factor receptor (TNFr), is effective and well tolerated in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between digoxin and etanercept at steady state. In a crossover, open-label, nonrandomized, 3-period study, 12 healthy male subjects received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days. Etanercept was administered as a twice-weekly 25-mg subcutaneous dose beginning on day 9 and continuing up to day 37 for a total of 9 doses. All ratios of maximum plasma concentration (C m a x ) and area under the plasma concentration versus time curve (AUC) for pharmacokinetics of digoxin fell within the confidence interval of 0.8 to 1.25. Although not considered clinically relevant. the mean C m a x and AUC of etanercept were 4.2% and 12.5% lower, respectively, when etanercept was given with digoxin than when administered alone. There were no clinically relevant changes in the electrocardiogram (ECG) parameters, and adverse events did not increase when both drugs were combined. In conclusion, there is no clinically relevant interaction between etanercept and digoxin, and both drugs can be safely coadministered without the need for a dosage adjustment.

Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr) fusion protein, is effective and well tolerated in the treatment of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between a single dose of R- and S-enantiomers of warfarin and multiple doses of etanercept after administration of warfarin and etanercept alone and together. In a nonrandomized, three-period study, 12 healthy male subjects received a single oral 25-mg dose of warfarin after an overnight fast, followed by twice-weekly 25-mg subcutaneous doses of etanercept for seven doses. The last dose of etanercept was administered concurrently with a second dose of warfarin. Serial blood samples for plasma warfarin concentration measurement and international normalized ratio (INR) assessment were collected before and up to 144 hours after dose administration. Serial blood samples for serum etanercept concentration measurement were collected before and up to 60 hours after the sixth dose and 264 hours after the seventh dose. Etanercept did not affect the pharmacokinetics and pharmacodynamics of warfarin. All ratios of maximum serum concentration (C(max)) and area under the serum concentration versus time curve (AUC) for pharmacokinetics (R- and S-enantiomers of warfarin) and INR fell within the confidence interval of 0.8 to 1.25. Warfarin also did not cause a clinically significant alteration in the pharmacokinetics of etanercept. In conclusion, coadministration of etanercept and warfarin would not be expected to change the pharmacokinetics of either medication; therefore, no dosage adjustment is needed in cases in which warfarin and etanercept are coadministered.

A study was performed to further investigate the apparent instability of tobramycin when coadministered with piperacillin/tazobactam in subjects with renal impairment. Twenty-six otherwise healthy volunteers between 23 and 74 years of age were studied. Eight subjects had moderate renal impairment, 10 had mild renal impairment, and 8 had normal renal function. Each subject received single doses of piperacillin/tazobactam and tobramycin alone as well as combined doses in a randomized, three-way crossover design. The subjects with normal renal function also received combined doses of piperacillin and tobramycin. Considerable care was taken to protect against in vitro inactivation of plasma and urine samples after collection. No systematic changes in pharmacokinetic parameters were observed. It is concluded that piperacillin, either alone or with tazobactam, did not change the pharmacokinetics of tobramycin in subjects with renal impairment. The apparent in vivo inactivation of tobramycin in the presence of piperacillin or piperacillin/tazobactam reported by others may be an artifact of ex vivo inactivation.

The objective of this double-blind, randomized, parallel-group study was to evaluate the pharmacokinetics of etodolac and the pharmacodynamic response of pain in patients following oral surgery who had received 200 or 400 mg of etodolac immediate release (IR), 400 or 1200 mg of etodolac extended release (ER), or a placebo. Etodolac concentrations in 441 plasma samples from 187 patients were analyzed for population pharmacokinetics using the NONMEM program. A one-compartment pharmacokinetic model with first-order absorption described the observed data. For etodolac IR, the population mean (%CV) estimates were 3.01 L/h (5.3%) for clearance, 13.6 L (6.8%) for volume of distribution, and 2.31 h-1 (33%) for ka. Respective values for etodolac ER were 3.68 L/h (11%) for clearance, 24.3 L (22%) for volume of distribution, and 0.172 h-1 (24%) for ka. These values generally agreed with previously reported values in healthy adults. Pharmacodynamic assessments included collection of a four-level categorical rating of pain intensity for up to 24 hours after treatment. Pain intensity difference scores were temporally related to etodolac concentrations and were described using an indirect response model. Mean (%CV) pharmacodynamic parameters were IC50 of 14.0 mg/L (9.5%), kout of 1.62 h-1 (13%), FR of 0.56 (8.2%), and Hill coefficients that ranged from 1.26 to 3.34 units. A single 1200 mg dose of etodolac ER given once daily was shown to provide substantial efficacy for 13 hours after dose, modest effect through 24 hours, and a more sustained duration of action than the IR dosage form.