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Claus Christiansen - One of the best experts on this subject based on the ideXlab platform.
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what can be learned from the Levormeloxifene experience
Acta Obstetricia et Gynecologica Scandinavica, 2006Co-Authors: Pernille Ravn, Therese F Nielsen, Claus ChristiansenAbstract:Levormeloxifene is a selective estrogen receptor modulator that was developed as an alternative to estrogen replacement therapy for the treatment and prevention of postmenopausal bone loss. In animal models, Levormeloxifene prevented increased bone turnover and vertebral bone loss following ovariectomy. Studies of healthy postmenopausal women showed that Levormeloxifene 1.25-20 mg/day decreased bone turnover and increased bone mineral density to a comparable extent to that observed during conventional hormone replacement therapy. However, in the phase II and III studies, the effect on bone turnover and bone mineral density was similar for each dose of Levormeloxifene and the minimal effective dose was never established. The development of Levormeloxifene was discontinued during the phase III trial due to a significant incidence of gynecologic adverse events in the Levormeloxifene-treated groups. This article reviews the preclinical and clinical studies of Levormeloxifene and the circumstances for the premature termination of the development of the drug. Other selective estrogen receptor modulators such as tamoxifen and raloxifene and the perspectives for selective estrogen receptor modulators in development are furthermore discussed.
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suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen receptor modulator serm
Menopause, 2004Co-Authors: Stephan Christgau, Szl L B Tank, Paul A C Cloos, Ulrik Mouritzen, Claus Christiansen, Jeanmarie Delaiss, Pernille H EghandersenAbstract:OBJECTIVE Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women. To validate this observation, we investigated the effects of ovariectomy (OVX) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products (CTX-II). Furthermore, we investigated whether estrogen and Levormeloxifene, a selective estrogen-receptor modulator (SERM), can prevent the OVX-induced changes in cartilage degradation. The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with Levormeloxifene versus placebo. DESIGN Sixty 6-month-old rats were divided in five groups. One group was subjected to sham and the others to OVX, followed by treatment with vehicle alone, estradiol or 0.2 mg/kg/day or 5 mg/kg/day of Levormeloxifene. The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover. After study termination, hind knees were removed for histological analysis of erosions. The effect of Levormeloxifene in post-menopausal women was assessed by measuring CTX-II in samples from 301 women who were participating in a phase II study of this SERM. RESULTS OVX rats showed significant increases in the urinary excretion of CTX-II. After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats. Treatment with estrogen or Levormeloxifene prevented the OVX-induced changes. There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 (r = 0.64, P < 0.001). In postmenopausal women treated with Levormeloxifene, the urinary excretion of CTX-II was decreased by approximately 50% and restored CTX-II levels to the premenopausal range. CONCLUSIONS This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans, suggesting potential therapeutical benefits in the prevention of destructive joint diseases such as osteoarthritis.
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associated response in bone mineral density and atherogenic lipid profile during treatment with two different selective estrogen receptor modulators Levormeloxifene and raloxifene
Climacteric, 2003Co-Authors: A Blochthomsen, Claus Christiansen, Sandra Silvestri, N H BjarnasonAbstract:Objective: We recently demonstrated a correlation between the responses in two target areas, bone and lipids, during treatment with hormone replacement therapy. Whether the same association exists during treatment with selective estrogen receptor modulators (SERMs) has not been examined before. Study design: This was an exploratory, post hoc analysis of data from two randomized, double-blind, placebo-controlled trials. Study population: From both studies we examined only the Danish subpopulation. Study 1 included 133 women treated with placebo or Levormeloxifene in four different doses for 12 months, and study 2 included 248 women treated with raloxifene in three different doses or placebo for 24 months. Measurements: Bone mineral density (BMD) of the spine and hip was measured semiannually. Serum lipids and biochemical bone markers were determined at each visit. To eliminate interindividual differences, all values were calculated as individual percentage change from baseline. Results: We found a signific...
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adverse effects of a serm Levormeloxifene safety parameters and bone mineral density 12 months after treatment withdrawal
Maturitas, 2003Co-Authors: L Warming, B J Riis, J A Stakkestad, P D Delmas, C Christoffersen, Claus ChristiansenAbstract:Abstract Objective: Levormeloxifene is a selective estrogen receptor modulator (SERM). The development of the drug was discontinued due to intolerable adverse effects. This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with Levormeloxifene. Methods: Adverse events were recorded at all clinical visits. The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography. Endometrial biopsies were obtained by pipelle. The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance. Bone mineral density of the total body, lumbar spine (L1–L4), hip and forearm was measured by dual-energy X-ray absorptiometry. Results: The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm. No cases of proliferative endometrium were reported. Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner. Hysteroscopic examinations showed that Levormeloxifene was related to increased incidence of edema, vascularization and cysticity. In the Levormeloxifene groups, a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence (including worsening of a previously existing condition). Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment. Conclusion: Endometrial thickening, seen in association with the use of some SERM's, may lead to harmful adverse effects more than 12 months after treatment is initiated. Levormeloxifene prevents the postmenopausal bone loss, but the lowest effective dose is unknown.
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efficacy of Levormeloxifene in the prevention of postmenopausal bone loss and on the lipid profile compared to low dose hormone replacement therapy
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Peter Alexandersen, B J Riis, J A Stakkestad, P D Delmas, Claus ChristiansenAbstract:Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with Levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the Levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the Levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the Levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the Levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between Levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during Levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the Levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the Levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (<0.001) than in all other groups. In conclusion, the study shows that Levormeloxifene, a new selective estrogen receptor modulator, has positive effects on BMD and bone turnover and apparently strong estrogenic effects on the serum concentrations of different cholesterol subfractions. Levormeloxifene at the doses tested had an estrogen-like effect on endometrium and no effect on hot flushes. The study was unable to differentiate between the effects of the different doses of Levormeloxifene.
Benedicte Kiehr - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and allometric scaling of Levormeloxifene a selective oestrogen receptor modulator
Biopharmaceutics & Drug Disposition, 2003Co-Authors: O Osterberg, Benedicte Kiehr, Lars Erichsen, H E Poulsen, Steen H IngwersenAbstract:The pharmacokinetics of a new selective oestrogen receptor modulator Levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(Vss/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(Vc/F) and volume at steady state F(Vss/F) were 28.9 and 57.9 l, respectively. In humans, values of Vc/F and Vss/F were 106 and 587 l, respectively. Predicted CL/F and Vss/F showed a linear relationship when plotted vs BW on a log–log scale; for CL/F, r was 0.95–0.98 and for Vss/F, r was 0.99. Using allometric scaling the predicted human Vss/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21–25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods. Copyright © 2003 John Wiley & Sons, Ltd.
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Levormeloxifene safety pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator
British Journal of Clinical Pharmacology, 2002Co-Authors: Birte K Skrumsager, Benedicte Kiehr, Poul C Pedersen, Mireille Gerrits, Norma Watson, Ketil BjarnasonAbstract:Aims The safety, pharmacodynamics and pharmacokinetics of Levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. Methods The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. Results Levormeloxifene was tolerated well after single doses in the range of 2.5–320 mg and multiple once daily dosing in the range of 20–160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg Levormeloxifene. Five weeks of treatment with 20–160 mg Levormeloxifene and 8 weeks of treatment with 40 or 80 mg Levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLapsTM) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19–25% and 28–35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2–3 h), a slow elimination (mean t½: 4.8–8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3–5). Conclusions Short-term administration of Levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.
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pharmacokinetics of Levormeloxifene in young versus elderly postmenopausal women
Clinical Therapeutics, 2001Co-Authors: Benedicte Kiehr, Birte K Skrumsager, Margarete Muller, Poul C PedersenAbstract:Abstract Background: Physiologic changes of aging may affect processes of drug absorption and distribution, in some cases necessitating age-dependent dose adjustment. Objective: The possibility of age dependence in the pharmacokinetic behavior and tolerability of Levormeloxifene was investigated in a single-center, open-label study. Methods: The study comprised 2 groups of healthy postmenopausal women: group A included younger subjects (50–60 years) and group B included elderly subjects (≥66 years). All subjects received a single 40-mg tablet of Levormeloxifene base. Blood samples were collected immediately before drug intake and at several points after administration, through day 34. Peak plasma concentration, time to maximum plasma concentration, area under the plasma concentration—time curves from zero to the last quantifiable value and to infinity, and terminal half-life were calculated for Levormeloxifene and compared between age groups. Results: Of 29 subjects enrolled, 28 (15 group A, 13 group B) completed the study. The ages of the women in group A ranged from 50 to 58 years and in group B from 66 to 79 years. No serious adverse events were reported. Ten subjects experienced 17 adverse events, of which 2 (abdominal pain and vaginal hemorrhage) were judged to be possibly related to study drug. There was no noticeable difference between age groups in the frequency of adverse events or laboratory abnormalities. The plasma concentration—time curves of Levormeloxifene were indistinguishable between age groups up to 48 hours after dosing. From 72 hours onward, the mean plasma concentration—time curve was ∼20% higher and the area under the curve was ∼19% greater in the older subjects compared with the younger subjects. However, no statistically significant differences were observed between groups in any of the pharmacokinetic parameters, except for the elimination rate constant. The difference in mean elimination half-life was 25 hours (group A, 126 hours; group B, 151 hours).
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metabolism disposition excretion and pharmacokinetics of Levormeloxifene a selective estrogen receptor modulator in the rat
Drug Metabolism and Disposition, 2000Co-Authors: Richard J Mountfield, Benedicte Kiehr, Brian JohnAbstract:The tissue distribution, pharmacokinetics, metabolism, and excretion of the selective estrogen receptor modulator Levormeloxifene have been investigated after oral administration of [14C]-Levormeloxifene to male and female Sprague-Dawley rats. The quantitative distribution of radiolabeled Levormeloxifene and/or metabolites was confirmed by whole body autoradiography. Levormeloxifene was absorbed from the gastrointestinal tract and was widely distributed into tissues, with peak radioactive concentrations generally being observed 4 h after administration in the intestine, liver, lung, kidney, spleen, pancreas, adrenals, and ovary (females). Fecal elimination was the major excretion route of radioactivity. In a separate pharmacokinetic study, plasma C max was generally observed 6 h after dose administration and the half-life of elimination was long (24 h) and a doubling in dose resulted in an approximate doubling in exposure. The majority of the drug was excreted as norLevormeloxifene; the 7-desmethyl metabolite of Levormeloxifene, via the formation of phase II metabolites (glucuronides) and excretion into the bile. Unchanged drug was also excreted, mainly from 0 to 24 h, and accounted for about 6 to 12% of the dose. Together these two components accounted for approximately 50% of the radioactivity excreted. Additional metabolites isolated and identified by liquid chromatography-tandem mass spectrometry, and accounting for 1 to 5% of the excreted radioactivity in rat feces during the first 24 h, included two monohydroxyLevormeloxifene species, a pyrrolidinone ring-opened metabolite of Levormeloxifene, and desmethylnorLevormeloxifene.
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assay for Levormeloxifene a selective estrogen receptor modulator in human and monkey plasma employing high performance liquid chromatography and solid phase extraction
Journal of Chromatography B: Biomedical Sciences and Applications, 1999Co-Authors: Benedicte Kiehr, Michael S ChristensenAbstract:Assays for Levormeloxifene, a new selective estrogen receptor modulator, and its 7-desmethyl metabolite in human and cynomolgus monkey plasma are described. Plasma was extracted on mixed-mode bonded sorbent material (C8/SCX) and the extracts were analysed by high-performance liquid chromatography with fluorescence detection. Recoveries of Levormeloxifene and the metabolite exceeded 70%. Within and total assay precision calculated as a coefficient of variation (C.V.) were <8% for both compounds at all concentration levels, except at the limit of quantitation (LOQ) where the C.V. was 15%. Within and total-assay accuracy calculated as a percentage of the nominal value were between 90 and 114% for both analytes. The LOQ was for Levormeloxifene and 7-desmethylLevormeloxifene, respectively, 1.5 and 2.5 ng/ml (man) and 5.2 and 6.9 ng/ml (monkey). In the monkey plasma assay, human plasma could substitute monkey plasma as blank plasma.
Chingshwun Lin - One of the best experts on this subject based on the ideXlab platform.
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effects of estrogen raloxifene and Levormeloxifene on the expression of rho kinase signaling molecules in urethral smooth muscle cells
Urology, 2010Co-Authors: Nongxiu Ning, Guiting Lin, Tom F Lue, Chingshwun LinAbstract:Objectives To investigate the effects of estrogen, raloxifene, and Levormeloxifene on the expression of Rho-kinase signaling molecules in urethral smooth muscle cells (USMCs). Methods USMCs were isolated from female rats. Expression of calponin and estrogen receptors α (ERα) was detected by immunofluorescence staining. Cells were treated with estrogen, raloxifene, or Levormeloxifene at 0, 1, 10, and 100 nmol/L for 48 h and then processed for Western blotting with antibodies against RhoA, Rho kinase I and II (Rock-I and Rock-II), myosin light chain (MLC), phosphorylated MLC, and β-actin. Protein expression was quantitated by densitometry, followed by statistical analysis with β-actin as control. Results USMCs expressed calponin and ERα. Treatment of USMCs with estrogen, raloxifene or Levormeloxifene resulted in decreased expression of RhoA, Rock-I, Rock-II, and p-MLC in a dosage-dependent manner. Conclusions Estrogen, raloxifene, and Levormeloxifene may affect urinary continence by inhibiting the expression of Rho-kinase signaling molecules.
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effects of estrogen raloxifene and Levormeloxifene on α1a adrenergic receptor expression
The Journal of Urology, 2008Co-Authors: Lia Banie, Guiting Lin, Tom F Lue, Hongxiu Ning, Guifang Wang, Chingshwun LinAbstract:Purpose: We investigated the effect of estrogen, raloxifene and Levormeloxifene on α1A-adrenergic receptor expression.Materials and Methods: Postpartum rats underwent intravaginal balloon injury and ovariectomy, and were then treated with estrogen or placebo for 8 weeks. The urethras were examined for α1A-adrenergic receptor expression by Western blot analysis and immunohistochemistry. Urethral smooth muscle cells were isolated from untreated female rats and examined for the expression of estrogen receptors α and β by immunofluorescence microscopy. Urethral smooth muscle cells were treated with estrogen, raloxifene or Levormeloxifene for 24 hours and examined for α1A-adrenergic receptor expression by real-time polymerase chain reaction. The effects of these drugs on α1A-adrenergic receptor expression were further examined by promoter assays.Results: Estrogen treatment resulted in decreased α1A-adrenergic receptor expression in the urethras. Urethral smooth muscle cells expressed estrogen receptors α and β...
Birte K Skrumsager - One of the best experts on this subject based on the ideXlab platform.
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Levormeloxifene safety pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator
British Journal of Clinical Pharmacology, 2002Co-Authors: Birte K Skrumsager, Benedicte Kiehr, Poul C Pedersen, Mireille Gerrits, Norma Watson, Ketil BjarnasonAbstract:Aims The safety, pharmacodynamics and pharmacokinetics of Levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. Methods The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. Results Levormeloxifene was tolerated well after single doses in the range of 2.5–320 mg and multiple once daily dosing in the range of 20–160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg Levormeloxifene. Five weeks of treatment with 20–160 mg Levormeloxifene and 8 weeks of treatment with 40 or 80 mg Levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLapsTM) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19–25% and 28–35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2–3 h), a slow elimination (mean t½: 4.8–8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3–5). Conclusions Short-term administration of Levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.
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pharmacokinetics of Levormeloxifene in young versus elderly postmenopausal women
Clinical Therapeutics, 2001Co-Authors: Benedicte Kiehr, Birte K Skrumsager, Margarete Muller, Poul C PedersenAbstract:Abstract Background: Physiologic changes of aging may affect processes of drug absorption and distribution, in some cases necessitating age-dependent dose adjustment. Objective: The possibility of age dependence in the pharmacokinetic behavior and tolerability of Levormeloxifene was investigated in a single-center, open-label study. Methods: The study comprised 2 groups of healthy postmenopausal women: group A included younger subjects (50–60 years) and group B included elderly subjects (≥66 years). All subjects received a single 40-mg tablet of Levormeloxifene base. Blood samples were collected immediately before drug intake and at several points after administration, through day 34. Peak plasma concentration, time to maximum plasma concentration, area under the plasma concentration—time curves from zero to the last quantifiable value and to infinity, and terminal half-life were calculated for Levormeloxifene and compared between age groups. Results: Of 29 subjects enrolled, 28 (15 group A, 13 group B) completed the study. The ages of the women in group A ranged from 50 to 58 years and in group B from 66 to 79 years. No serious adverse events were reported. Ten subjects experienced 17 adverse events, of which 2 (abdominal pain and vaginal hemorrhage) were judged to be possibly related to study drug. There was no noticeable difference between age groups in the frequency of adverse events or laboratory abnormalities. The plasma concentration—time curves of Levormeloxifene were indistinguishable between age groups up to 48 hours after dosing. From 72 hours onward, the mean plasma concentration—time curve was ∼20% higher and the area under the curve was ∼19% greater in the older subjects compared with the younger subjects. However, no statistically significant differences were observed between groups in any of the pharmacokinetic parameters, except for the elimination rate constant. The difference in mean elimination half-life was 25 hours (group A, 126 hours; group B, 151 hours).
Poul C Pedersen - One of the best experts on this subject based on the ideXlab platform.
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Levormeloxifene safety pharmacodynamics and pharmacokinetics in healthy postmenopausal women following single and multiple doses of a new selective oestrogen receptor modulator
British Journal of Clinical Pharmacology, 2002Co-Authors: Birte K Skrumsager, Benedicte Kiehr, Poul C Pedersen, Mireille Gerrits, Norma Watson, Ketil BjarnasonAbstract:Aims The safety, pharmacodynamics and pharmacokinetics of Levormeloxifene, a selective oestrogen receptor modulator (SERM), were investigated in postmenopausal women following single doses and multiple dosing once daily up to 56 days. Methods The two randomized, double-blind, placebo controlled studies of six single ascending doses and at four multiple dose levels, respectively, included a total of 104 healthy postmenopausal women. Safety assessments comprised vital signs, ECG, haematology, clinical chemistry and reporting of adverse events. The pharmacodynamic properties were investigated after multiple dosing by assessment of the short-term effects on bone and lipid metabolism and on the hypothalamic-pituitary axis. Blood samples for pharmacokinetic analysis were collected at intervals until 648 h (27 days) after single and multiple dosing. Results Levormeloxifene was tolerated well after single doses in the range of 2.5–320 mg and multiple once daily dosing in the range of 20–160 mg. Adverse events reported were generally mild or moderate. The most frequent adverse events after multiple dosing were headache, abdominal pain and leukorrhea with the highest frequency reported after the highest daily dose of 160 mg Levormeloxifene. Five weeks of treatment with 20–160 mg Levormeloxifene and 8 weeks of treatment with 40 or 80 mg Levormeloxifene reduced the biochemical marker of bone turnover, the collagen I C-terminal telopeptide (CrossLapsTM) by 44.4% [95% CI: 11.3, 65.1] and 35.5% [95% CI: 14.0, 51.6], respectively, without any dose-dependent decrease in the studied dose range. The total cholesterol and LDL-cholesterol concentrations were significantly reduced by 19–25% and 28–35%, respectively, when compared with placebo. HDL-cholesterol and triglyceride concentrations were not affected. An oestrogen-like effect on the hypothalamic-pituitary axis was observed with approximately 50% reductions of FSH and LH after 8 weeks of treatment. No clinically significant changes of other safety variables were observed. The pharmacokinetic analysis demonstrated a rapid absorption (mean tmax: 2–3 h), a slow elimination (mean t½: 4.8–8.4 days) and dose linearity of Cmax and AUC for doses up to 160 mg. As expected for a drug with slow elimination given frequently, the relative fluctuation around the steady state plasma concentration was small and the drug accumulation considerable (RA: 3–5). Conclusions Short-term administration of Levormeloxifene in postmenopausal women was well-tolerated at doses that elicited a favourable pharmacodynamic response suggesting oestrogen-like bone preserving and antiatherogenic effects. Little variation of peak-trough plasma concentrations was observed during daily administration due to a plasma half-life of approximately 1 week.
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pharmacokinetics of Levormeloxifene in young versus elderly postmenopausal women
Clinical Therapeutics, 2001Co-Authors: Benedicte Kiehr, Birte K Skrumsager, Margarete Muller, Poul C PedersenAbstract:Abstract Background: Physiologic changes of aging may affect processes of drug absorption and distribution, in some cases necessitating age-dependent dose adjustment. Objective: The possibility of age dependence in the pharmacokinetic behavior and tolerability of Levormeloxifene was investigated in a single-center, open-label study. Methods: The study comprised 2 groups of healthy postmenopausal women: group A included younger subjects (50–60 years) and group B included elderly subjects (≥66 years). All subjects received a single 40-mg tablet of Levormeloxifene base. Blood samples were collected immediately before drug intake and at several points after administration, through day 34. Peak plasma concentration, time to maximum plasma concentration, area under the plasma concentration—time curves from zero to the last quantifiable value and to infinity, and terminal half-life were calculated for Levormeloxifene and compared between age groups. Results: Of 29 subjects enrolled, 28 (15 group A, 13 group B) completed the study. The ages of the women in group A ranged from 50 to 58 years and in group B from 66 to 79 years. No serious adverse events were reported. Ten subjects experienced 17 adverse events, of which 2 (abdominal pain and vaginal hemorrhage) were judged to be possibly related to study drug. There was no noticeable difference between age groups in the frequency of adverse events or laboratory abnormalities. The plasma concentration—time curves of Levormeloxifene were indistinguishable between age groups up to 48 hours after dosing. From 72 hours onward, the mean plasma concentration—time curve was ∼20% higher and the area under the curve was ∼19% greater in the older subjects compared with the younger subjects. However, no statistically significant differences were observed between groups in any of the pharmacokinetic parameters, except for the elimination rate constant. The difference in mean elimination half-life was 25 hours (group A, 126 hours; group B, 151 hours).