A double‐blind, randomized, ascending, multiple‐dose study of bazedoxifene in healthy postmenopausal women

Baird-Bellaire

Ermer

et al. 2018

Bazedoxifene, a selective estrogen receptor modulator with proestrogenic effects on bone and lipid metabolism and antiestrogenic effects on the breast and endometrium, is a treatment option for osteoporosis in postmenopausal women. It is extensively metabolized by the liver; therefore, a decrease in liver function was expected to decrease bazedoxifene clearance. This single-dose, open-label, inpatient/outpatient, nonrandomized study assessed the pharmacokinetics of bazedoxifene 20 mg in 18 postmenopausal women with hepatic impairment and 18 matched healthy postmenopausal women. Bazedoxifene elimination was slower, and exposure was higher, in hepatically impaired subjects compared with healthy subjects. In subjects with severe (Child-Pugh C) liver impairment, bazedoxifene mean half-life was 50% longer than that of healthy subjects. Area under the concentration-time curve geometric mean ratios (90%CI) for Child-Pugh A, B, and C liver impairment vs healthy subjects were 243% (156-379), 209% (135-326), and 368% (236-572), respectively. Although there were no severe adverse events in this study, bazedoxifene use in patients with hepatic impairment is not recommended.

mentioning

confidence: 99%

“…It reaches steady state within approximately 7 days and exhibits linear pharmacokinetics over a dose range of 5 to 80 mg. The average half‐life is approximately 25 to 33 hours, and protein binding is greater than 99% …”

mentioning

confidence: 99%

Pharmacokinetics and Safety of Bazedoxifene in Hepatically Impaired and Healthy Postmenopausal Women

Baird-Bellaire

Ermer

et al. 2018

“…Pharmacokinetic parameters for bazedoxifene in postmenopausal women have been described previously . After oral administration, bazedoxifene 20 mg is rapidly absorbed, with a time to peak concentration (t max ) of approximately 1 to 2 hours .…”

mentioning

confidence: 99%

Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen

Baird-Bellaire²,

Ermer³

et al. 2018

The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance. The 90% log-transformed confidence intervals (CIs) for bazedoxifene C , 96% to 144%, and AUC, 85% to 134%, were slightly above the bioequivalence limits of 80% to 125%. The 90% log-transformed CIs for ibuprofen pharmacokinetic parameters were within these limits (C , 92%-122%; AUC, 94%-106%). The increase in bazedoxifene plasma concentrations when combined with ibuprofen versus bazedoxifene alone is unlikely to be clinically significant. The lack of interaction between bazedoxifene and ibuprofen suggests that they may be coadministered without dose adjustment.

“…The pharmacokinetics of bazedoxifene have been characterized in studies in healthy postmenopausal women. It reaches maximum plasma concentrations 2 to 3 hours after multiple‐dose oral administration and is eliminated with a half‐life of approximately 25 to 30 hours . Glucuronidation is the main metabolic pathway for bazedoxifene, and there is little or no cytochrome P450‐mediated metabolism .…”

mentioning

confidence: 99%

A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women

Baird-Bellaire

Ermer

et al. 2018

An open-label, 3-period study was conducted in 30 healthy postmenopausal women (mean age, 58.4 years) who received a single oral dose of atorvastatin 20 mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40 mg on days 4-11 (period 2), and coadministration of atorvastatin 20 mg + bazedoxifene 40 mg on day 12 (period 3). Serial blood samples were collected (24 hours after bazedoxifene and 72 hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho-hydroxy and para-hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20 mg (C and AUC were within bioequivalence limits). Similarly, atorvastatin and ortho-hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para-hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. C for atorvastatin and ortho-hydroxyatorvastatin was 14% and 18% lower, respectively, and T was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.