ABSTRACT:Bazedoxifene is a selective estrogen receptor modulator under development for the prevention and treatment of osteoporosis. The disposition of [ 14 C]bazedoxifene was determined in six healthy postmenopausal women after administration of a single oral dose of 20 mg (200 Ci). After dosing, blood was collected at frequent intervals, and urine and fecal samples were collected for up to 10 days. Aliquots of plasma, blood, urine, and fecal homogenates were analyzed for concentrations of radioactivity. Bazedoxifene metabolite profiles in plasma and feces were determined by highperformance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Bazedoxifene was rapidly absorbed, exhibiting a mean peak plasma concentration of 3.43 ng/ml at 1.2 h postdose. The total mean recovery of the radioactive dose in excreta was 85.6%, with the majority recovered in feces (84.7%) and only a small fraction (0.81%) in urine. Radiochromatograms of plasma revealed that glucuronidation was the major metabolic pathway; little or no cytochrome P450-mediated metabolism was evident. The majority of circulating radioactivity was constituted by metabolites, with bazedoxifene-5-glucuronide being the predominant metabolite (up to 95%). Bazedoxifene-4-glucuronide was a minor metabolite (up to 20%), and unchanged bazedoxifene represented 0 to 13% of the radioactivity in most plasma samples. Unchanged bazedoxifene was the major radioactive component in feces, however, reflecting unabsorbed drug and/or glucuronides that were hydrolyzed by intestinal bacterial enzymes. [ 14 C]Bazedoxifene was generally well tolerated. These findings demonstrated that, after oral administration in healthy postmenopausal women, bazedoxifene was rapidly absorbed, metabolized via glucuronidation, and excreted predominantly in feces.

Clinical Pharmacology & Therapeutics (2003) 73, P47–P47; doi:

The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, i.v.) and 22 healthy volunteers (10 to 80 mg, i.v. and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after i.v. administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half-lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h-1 and 0.031 h-1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of i.v. and oral pantoprazole on gastric secretion and may be used to predict effects under other dosage regimens.

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Bazedoxifene is a novel selective estrogen receptor modulator in clinical development for the prevention and treatment of postmenopausal osteoporosis. This phase 1, double-blind, randomized, placebo-controlled study (N = 107) of healthy postmenopausal women examined the pharmacokinetics and safety/tolerability profile of multiple doses of bazedoxifene (1, 2.5, 5, 10, 20, 40, and 80 mg) administered orally once daily for 30 days. Bazedoxifene demonstrated a half-life of 25 to 30 hours, reached steady state within 7 days, and exhibited linear pharmacokinetics over a dose range of 5-80 mg. Fibrinogen levels decreased with bazedoxifene doses of 5 mg and greater; these changes were significant for bazedoxifene 20, 40, and 80 mg (P ≤ .05 vs placebo), but were not dose dependent. Bazedoxifene was associated with increased levels of sex hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin (CBG); only increases in the levels of CBG appeared to be dose related. Bazedoxifene was safe and well tolerated within the tested dose range. Bazedoxifene showed no differences from placebo in adverse event reports, vital sign measurements, or electrocardiogram findings.