NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy.

AimsTwo studies were conduced to assess the effects of ketoconazole, a CYP3A4/5 inhibitor; fluconazole, a CYP2C9 inhibitor; and paroxetine, a CYP2D6 inhibitor, on lasofoxifene pharmacokinetics. MethodsThe first parallel group study was conducted in 45 healthy postmenopausal women (15 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) administered alone and in combination with ketoconazole (400 mg daily × 20 days) or fluconazole (400 mg daily × 20 days). Lasofoxifene was administered on day 2 and blood samples were collected serially for up to 456 h postdose (20 days). The second study enrolled 20 healthy postmenopausal women (10 per group) to compare the pharmacokinetics of a single dose of lasofoxifene (0.25 mg) alone and in combination with paroxetine (30 mg qd × 21 days). Lasofoxifene was given on day 8 of paroxetine treatment and blood samples were collected serially for up to 336 h postdose. ResultsAll subjects completed the study and the treatments were well tolerated. Lasofoxifene C max and AUC ratios [90% confidence interval (CI)] with/without ketoconazole were 111% (98.4, 127) and 120% (105, 136), respectively, and were 91.3% (80.3, 104) and 104% (91.4, 118), respectively, with/without fluconazole. Lasofoxifene C max and AUC ratios (90% CI) with/without paroxetine were 118% (95.4, 146) and 135% (120, 152), respectively. ConclusionsCoadministration of potent inhibitors of CYP3A4/5 and CYP2D6, but not CYP2C9, resulted in a moderate increase in lasofoxifene exposure. No dosage adjustment should be required when lasofoxifene is coadministered with ketoconazole, fluconazole, paroxetine or other agents that inhibit these CYP enzymes.

Quinapril pharmacokinetics were studied in infants and children using a novel study design that allowed substitution of quinapril for one dose of the current chronic angiotensin-converting enzyme (ACE) inhibitor treatment. A total of 24 patients ranging in age from 2.5 to 82 months who were receiving an ACE inhibitor held their usual treatment on the study day and received a 0.2-mg/kg dose of quinapril syrup. Blood samples were collected through 24 hours postdose, and plasma was analyzed for quinapril and its active metabolite, quinaprilat. Quinapril was rapidly converted to quinaprilat. Quinaprilat concentrations generally peaked 1 to 2 hours postdose and declined with a mean half-life of 2.30 hours. Dosing on a mg/kg basis resulted in quinaprilat AUC and Cmax values that were generally comparable across the age range of patients in this study. The overall mean AUC0-infinity was 993 ng.h/mL (range: 533-1523), and mean Cmax was 260 ng/mL (range: 70.0-445.5). Quinaprilat CL/F correlated well with body size (body surface area or weight) and creatinine clearance (mL/min). Pharmacokinetic results after a 0.2-mg/kg dose in infants and children are comparable to those observed following a 10-mg dose in adults.

AimTo investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. MethodsTwelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R-and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. ResultsLasofoxifene had no clinically meaningful effect on R-or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration-time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/ *1, respectively. The mean PT AUC and C max ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar.

Lasofoxifene, a selective estrogen receptor modulator for osteoporosis management, is metabolized primarily by hepatic oxidation and conjugation. This study compared the pharmacokinetics of 0.25 mg lasofoxifene in subjects with mild (Child-Pugh grade A, n = 6) or moderate (Child-Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6). Analysis of variance was used to calculate 90% confidence intervals for the ratios (impaired/healthy) of least squares mean log maximum plasma concentration (C(max)) and area under the curve (AUC) values. Lasofoxifene pharmacokinetics was similar between healthy and mild hepatic impairment subjects: ratios of C(max) and AUC from 0 to infinity (AUC([0-infinity])) were 101% (75.0-138) and 95.5% (77.9-117), respectively. In subjects with moderate hepatic impairment, ratios of C(max) and AUC([0-infinity]) were 121% (89.6-165) and 138% (112-169), respectively; mean terminal half-life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.