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

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 (R2 = 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 (R2 = 0.19) between BZA CL/F and CLcr.

Population pharmacokinetic/pharmacodynamic assessment of pharmacological effect of a selective estrogen receptor ß agonist on total testosterone in healthy men.

BACKGROUND: LY500307 is a highly selective estrogen receptor ß (ERß) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period. A population pharmacokinetics/pharmacodynamics (PK/PD) model that integrated Fourier series in an indirect response model was developed to describe the circadian rhythm of TT and the exposure-response relationship of LY500307 on TT. RESULTS: The maximum TT suppression (Emax ) was approximately 28.6%. The potency (EC50 ) of LY500307 on TT suppression was approximately 1.69 ng/mL with a 95%CI of 0.871 to 4.44 ng/mL. This model could provide inferences on LY500307 dose levels that would result in various magnitudes of TT suppression. CONCLUSIONS: Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT.

Ospemifene: first global approval.

Ospemifene (Osphena™) is an oral selective estrogen receptor modulator (SERM), with tissue-specific estrogenic agonist/antagonist effects. QuatRx Pharmaceuticals conducted the global development of the agent before licensing it to Shionogi for regulatory filing and commercialization worldwide. Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy. The drug is approved in the USA, and application for EU regulatory approval is underway. This article summarizes the milestones in the development of ospemifene leading to this first approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy.

Model-based drug development: the road to quantitative pharmacology.

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies.

Benefit-risk assessment of raloxifene in postmenopausal osteoporosis.

Raloxifene, a nonsteroidal benzothiophene, is a second-generation selective estrogen receptor modulator (SERM) that is an antiresorptive agent. Raloxifene is a non-hormonal agent that binds to the estrogen receptor and results in estrogen agonist effects on bone and the cardiovascular system and estrogen antagonist effects on endometrial and breast tissue. Raloxifene has diverse pharmacodynamic properties due to its differential interactions with the estrogen receptor and tissue selectivity. Raloxifene was the first SERM to be approved for the prevention and treatment of postmenopausal osteoporosis. In this review, we conducted a systematic search of the literature for trials that evaluated the following outcomes: bone density, fractures, quality of life, cardiovascular outcomes, safety and adverse events. Raloxifene at the approved dosage of 60 mg/day increased lumbar spine bone density by 2.5% relative to control after 2 years of therapy. A large fracture prevention trial confirmed that treatment with raloxifene 60 mg/day for 3 years decreased the relative risk of incident vertebral fractures by 30-50% in women with prevalent fractures or osteoporosis. Extraskeletal effects of raloxifene include a reduction in total cholesterol and low density lipoprotein cholesterol levels. Assessment of the safety profile revealed that raloxifene was not associated with endometrial hyperplasia and that there was a 72% reduction in the incidence of invasive breast cancer in raloxifene-treated postmenopausal women with osteoporosis. Adverse events associated with raloxifene included an increase in the absolute risk of venous thromboembolism and an increase in the risk of hot flashes and leg cramps. In comparison to other osteoporosis therapies, raloxifene has a lesser impact on bone mineral density, a similar effect on the occurrence of vertebral fractures, but no effect on the frequency of non-vertebral fractures. Raloxifene can be recommended for the prevention of vertebral fractures in women with osteopenia/osteoporosis who are not at high risk of non-vertebral fractures and who do not have a past history of venous thromboembolism.