The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Tocilizumab is a humanized anti–interleukin‐6 receptor antibody for treating rheumatoid arthritis. Pharmacokinetic/pharmacodynamic analysis was performed on the 24‐week double‐blind parts of 2 randomized, controlled trials: SUMMACTA and BREVACTA. SUMMACTA compared subcutaneous tocilizumab 162 mg every week to intravenous tocilizumab 8 mg/kg every 4 weeks, whereas BREVACTA evaluated 162 mg subcutaneous tocilizumab every 2 weeks versus placebo. In addition to noncompartmental analysis, a 2‐compartment population pharmacokinetic model, with first‐order absorption (for subcutaneous) and linear and Michaelis–Menten elimination was used. Mean observed steady‐state predose tocilizumab concentrations in week 24 were 40 and 7.4 μg/mL for subcutaneous every‐week and every‐2‐week dosing, respectively, and 18 μg/mL for intravenous dosing. In the population PK model, body weight was an important covariate affecting clearance and volume of distribution. Mean ± SD population‐predicted predose concentration for patients ≥100 kg was 23.0 ± 13.5 μg/mL for subcutaneous tocilizumab every week and 1.0 ± 1.6 μg/mL for every 2 weeks. Efficacy was lowest with subcutaneous every‐2‐week dosing in patients > 100 kg, reflecting lower exposure. The subcutaneous every‐2‐week regimen is not recommended for these patients. Pharmacodynamic responses were comparable for the every‐week subcutaneous and every‐4‐week intravenous regimens and less pronounced with the every‐2‐week subcutaneous regimen. No trend was observed for increased adverse events with increasing tocilizumab exposure. The results of this analysis are consistent with the noninferiority of efficacy of the every‐week subcutaneous regimen to the every‐4‐week intravenous regimen and the superiority of the every‐2‐week subcutaneous regimen to placebo. These results support the label recommendations for subcutaneous dosing of tocilizumab in rheumatoid arthritis patients.

Background: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. Objectives: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. Methods: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n 5 26) were conducted. Results: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day

Ranolazine is a novel compound under development as an antianginal agent. The multiple-dose pharmacokinetics of extended-release ranolazine and 3 major metabolites was investigated in healthy subjects (N = 8) and subjects with mild to severe renal impairment (N = 21). The ranolazine AUC(0-12) (area under the concentration-time curve between 0 and 12 hours after dosing) geometric mean ratio versus healthy subjects at steady state was 1.72 (90% confidence interval [CI], 1.07-2.76) in subjects with mild impairment, 1.80 (90% CI, 1.13-2.89) in those with moderate impairment, and 1.97 (90% CI, 1.23-3.16) in those with severe renal impairment. Creatinine clearance was negatively correlated with AUC(0-12) and the maximum observed concentration for ranolazine and the O-dearylated metabolite (P < .05 for all variables), as well as the N-dealkylated metabolite (P < .001), but not for the O-demethylated metabolite. Less than 7% of the administered dose was excreted unchanged in all groups, indicating that factors other than reduced glomerular filtration rate contributed to the increase in ranolazine concentrations in renal impairment. No serious adverse events were observed in the study.

The first-dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured hy enzyme-linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half-life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate postoperative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half-life of FK506, it takes more than 45 hours to reach steady-state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug treatment.FKC506 is a macrolide isolated from the fungus Streptomyces tsukubaensis. 1 It is nearly 100 times more potent than cyclosporine (CsA) in inhibiting lymphocyte proliferation in mixed lymphocyte cultures. 2 FK506 has been shown to prevent or reverse the rejection of heart, liver, kidney, pancreas, lung, intestine, and skin grafts in mice, rats, dogs, monkeys, and baboons.3 FK506 has been in clinical use since March 1989 at the University of Pittsburgh. It was used initially for rescuing livers that have failed under conventional immunosuppression and later as the primary immunosuppressant for liver, kidney, and heart transplantation.4 -6 Current results indicate that FK506 provides better immunosuppression in liver and heart transplant recipients than does CsA. 4,[6][7][8] After transplantation, FK506 is administered intravenously as a continuous infusion at a dose of 0.15 mg/kg/day and then orally at a dose of 0.3 mg/kg/ day twice daily, when the patient can tolerate oral intake. Further dose alterations are normally made based on patient's liver function, episodes of rejection or toxicity, and trough plasma FK506 concentrations. The intravenous dosage form of FK506 is a 10-mg/mL FK506 solution with polyethoxylated hydrogenated castor oil (HCO-60, a nonionic surfactant) and alcohol. This solution is diluted in 100 mL of 5% dextrose and infused at a rate of 4 mL/hour over 24 hours. The Address for reprints: Raman Venkataramanan,