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

Baird-Bellaire²,

Ermer³

et al. 2018

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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.

Section: Methodsmentioning

confidence: 99%

Section: Bioanalytical Assaysmentioning

confidence: 99%

Pharmacokinetic Drug Interaction Study of Bazedoxifene and Ibuprofen

Baird-Bellaire²,

Ermer³

et al. 2018

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“…Plasma bazedoxifene concentrations were measured using a previously described, validated high‐performance liquid chromatography (HPLC) method with fluorescence detection …”

Section: Methodsmentioning

confidence: 99%

“…Plasma bazedoxifene concentrations were measured using a previously described, validated high-performance liquid chromatography (HPLC) method with fluorescence detection. 24 As approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites, the 2 major active metabolites (orthohydroxylated and para-hydroxylated atorvastatin) were assayed in addition to the parent atorvastatin compound using HPLC with mass spectrometric detection. Atorvastatin, para-hydroxyatorvastatin, and orthohydroxyatorvastatin and their respective internal standards (D 5 -atorvastatin, D 5 -para-hydroxyatorvastatin, and D 5 -ortho-hydroxyatorvastatin) were extracted from plasma samples using solid-phase extraction.…”

Section: Assay Methodsmentioning

confidence: 99%

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

Baird-Bellaire

Ermer

et al. 2018

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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.

“…As BZA is conjugated by hepatic and intestinal enzymes, it seems that both hepatic and extrahepatic metabolism play a role in clearance and disposition . A single‐dose study in postmenopausal women with hepatic impairment showed that apparent oral dose clearance (CL/F) was lower and t ½ longer than for those with normal hepatic function …”

mentioning

confidence: 99%

Assessment of the Effects of Age and Renal Function on Pharmacokinetics of Bazedoxifene in Postmenopausal Women

Ermer

Korth‐Bradley

2018

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Bazedoxifene (BZA), a chemically distinct selective estrogen receptor modulator, has demonstrated efficacy and long-term safety in phase 3 placebo-controlled studies for prevention and treatment of osteoporosis. Here, we assessed the potential effects of age and renal function on BZA pharmacokinetics in healthy postmenopausal women (aged 55-84 years; CLcr, 32-109 mL/min). This was an open-label, single-dose, parallel, nonrandomized inpatient study conducted in healthy postmenopausal women and postmenopausal women with impaired renal function. Each subject received a single oral dose of BZA in a 20-mg tablet. Twenty-six subjects were enrolled: 8 in each of 3 age groups (55-64 years, 65-74 years, ≥75 years) and 2 (aged 71 and 75 years) with mild renal impairment; all subjects received treatment and completed the study. Age-related changes in pharmacokinetics were apparent. Although the correlation was modest (R = 0.28), BZA CL/F decreased steadily with age, such that the oldest group (>75 years) had a mean CL/F 60% less than the youngest group (55-64 years). Over the observed range of CLcr, there was a weak positive correlation (R = 0.19) between BZA CL/F and CLcr.