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PHARMACOKINETICS |
From Pfizer Inc, Ann Arbor, Michigan.
Address for reprints: Candace Bramson, MD, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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]) were 101% (75.0-138) and 95.5% (77.9-117), respectively. In subjects with moderate hepatic impairment, ratios of Cmax and AUC[0-] were 121% (89.6-165) and 138% (112-169), respectively; mean terminal half-life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.
Key Words: Lasofoxifene • osteoporosis • pharmacokinetics • hepatic impairment
Bone remodeling occurs throughout a woman's lifetime, but in an estrogen-deprived environment such as that brought about by menopause, bone resorption outpaces bone formation, causing a net loss in bone. The mechanism by which estrogen affects bone metabolism is complex and not fully elucidated. It is believed that estrogen decreases the rate of bone resorption through a variety of mechanisms including decreasing osteoclastogenesis, in part by inducing apoptosis of osteoclasts, and indirectly through effects on calcium homeostasis.1,2 Thus, in the past, estrogen supplementation, with or without progesterone, was widely recommended to preserve bone mass in postmenopausal women. Results from recent clinical trials, however, have demonstrated that estrogen may have detrimental effects on cardiovascular health that outweigh the positive effects on bone.3
Investigations into alternative treatments that provide beneficial bone effects without the negative effects on breast and uterine tissue are ongoing. One class of agents that has shown the most promise is the selective estrogen receptor modulators (SERMs). The SERMs bind to estrogen receptors in a variety of tissue types but because of differences in transcriptional cofactors in the particular cells, the SERMs have either estrogen agonistic or antagonistic effects, depending on the tissue. The differential effects in various tissues are not fully understood but may involve interaction with transcription coactivators and corepressors.4 Although estrogen has stimulatory properties in the breast and uterus, certain SERMs do not. There are currently 3 members of this class available on the market: tamoxifen and toremifene, which are used in breast cancer therapy, and raloxifene, which is indicated for osteoporosis prevention and treatment in postmenopausal women. Although long-term results with raloxifene have shown that it increases bone mineral density and prevents fractures, its efficacy in bone is not as favorable as that of estrogen.5-7
Lasofoxifene is a new SERM that is being investigated for the prevention and treatment of osteoporosis in clinical studies.8,9 It has demonstrated greater than 100-fold selectivity for estrogen receptors over all other steroid receptors and binds estrogen receptors with affinities similar to estradiol.10,11 In competition binding assays measuring displacement of radiolabeled estradiol from expressed estrogen receptors, lasofoxifene resulted in inhibition constants of 0.27 nM for ER-
and 0.70 nM for ER-ß compared to 0.44 nM and 0.70 nM, respectively, for estradiol.12 Preclinical studies with lasofoxifene have demonstrated positive effects on bone and lipids. In both short-term (4 weeks) and long-term (52 weeks) studies in ovariectomized rats, lasofoxifene completely prevented ovariectomy-induced bone loss and inhibited bone turnover without any adverse effects (AEs) on the uterus.10,13 In addition, total serum cholesterol levels were significantly decreased in rats administered lasofoxifene as compared to controls.10
Hepatic impairment can alter the pharmacokinetics of drugs that are metabolized to a large extent by the liver, resulting in increased exposure in subjects with hepatic impairment. Dosage adjustments of these drugs are often necessary in patients with hepatic impairment. In the elderly, the population most likely to have osteoporosis, it has been shown that increased age alone can affect hepatic oxidative pathways, as can smoking, concurrent disease, and overall frailty. Thus, concomitant liver disease is a critical consideration when choosing treatment for osteoporosis in this population.14
Lasofoxifene is metabolized by hepatic oxidation and conjugation. In humans, it has been found that lasofoxifene as both parent compound and metabolites is recovered primarily in the feces and secondarily in the urine.15 Only 2% of a dose is recovered as unchanged lasofoxifene in the urine. Because the liver is the major route of metabolism and/or elimination, this study was conducted to determine if mild or moderate hepatic impairment would alter the pharmacokinetics of lasofoxifene after administration of the projected therapeutic dose (0.25 mg/d). Although ideally an all-female population would have been preferable, to facilitate enrollment in a timely manner, both men and women were included in this study. The effect of severe hepatic impairment on lasofoxifene pharmacokinetics was not investigated.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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18 years of age with a body weight 50 kg and could be of any race and either gender. Subjects were excluded if they had a history or clinical evidence of significant respiratory, cardiovascular, gastrointestinal, endocrine, hematologic (including thromboembolic disorders), neurologic, immunologic, psychiatric, or other chronic disease, or active alcoholism or drug abuse. Participants were not permitted to take any medication, including any herbal medicine, oral contraceptives, or estrogen replacement therapy, for 14 days before study initiation. Group 1 consisted of healthy subjects as determined by medical history, physical examination, vital sign measurements, electrocardiogram (ECG) findings, and clinical laboratory measurements. Group 1 was recruited after groups 2 and 3 so that the groups were matched with respect to mean age (±5 years), mean weight (±5 kg), and gender. Group 2 included patients with mild hepatic impairment (Child-Pugh grade A), and group 3 consisted of patients with moderate hepatic impairment (Child-Pugh grade B). Patients with hepatic impairment or cirrhosis due to stable chronic hepatic diseases and/or prior alcohol abuse were eligible. Patients in group 2 were required to have confirmation of the diagnosis of cirrhosis made by biopsy or laparoscopy. For group 3, if biopsy or laparoscopy had not been performed, subjects could be included if they had chronic stable liver disease and objective evidence of portal hypertension (ascites diagnosed by imaging or varices). Patients with noncirrhotic causes of portal hypertension, such as portal vein thromboses and mass lesions, were not enrolled, and subjects with encephalopathy other than minimal asterixis or ascites were also excluded.
The study was conducted at 2 sites: Davita Clinical Research Inc (Minneapolis, Minn) and Clinical Pharmacology Associates (Miami, Fla). The institutional review board (IRB) responsible for monitoring this study was Southern IRB from Miami, Florida. Pfizer Inc (Ann Arbor, Mich) ensured IRB or ethics committee approval was received before shipping the drug. The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practices, the Declaration of Helsinki, and in compliance with United States Food and Drug Administration regulations for informed consent and protection of subject rights. Written informed consent was required from each subject who participated in the study, or his/her authorized representative, before the subject's study enrollment.
Subjects stayed at the clinic from the day before (day –1) to 24 hours after receiving the dose of lasofoxifene. They were required to fast for at least 8 hours before receiving the single morning dose of 0.25 mg lasofoxifene as an oral tablet on day 1 and then for an additional 4 hours after administration. Identical lunches and dinners were served to all subjects at 4 and 10 hours, respectively, after the dose on day 1.
For group 1, serial blood samples to determine lasofoxifene plasma concentrations were collected before dosing and at 1, 2, 4, 8, 12, 24 (day 2), 48 (day 3), 72 (day 4), 120 (day 6), 168 (day 8), 216 (day 10), 264 (day 12), and 336 (day 15) hours after lasofoxifene administration. Physical examinations and vital sign and clinical laboratory measurements were performed at screening and on day 15 (closeout). Additional vital sign measurements were performed before administration and at 8 hours after dosing. Electrocardiograms were performed at screening, on day 1 before administration, at 4 and 8 hours after dosing before the scheduled meals, at 12 and 24 hours after dosing (fasting), and at closeout. For groups 2 and 3, serial blood samples to determine lasofoxifene plasma concentrations were collected at the same intervals as for group 1, but additional blood samples were taken at 504 (day 22) and 672 (day 29) hours. An additional blood sample was collected at 8 hours after dosing in all subjects for determination of the fraction of lasofoxifene bound to plasma proteins. Physical examinations and vital sign and clinical laboratory measurements were performed at screening and on day 29 (closeout), with additional vital sign measurements performed before dosing and at 8 and 168 hours after dosing and additional laboratory measurements performed at 168 hours after dosing; ECGs were performed similarly to subjects in group 1.
Lasofoxifene and Protein Binding Analytical Methods
Blood samples were collected in glass tubes containing sodium heparin, centrifuged, plasma separated, frozen, and stored at –20°C until assayed. Plasma concentrations of lasofoxifene were measured by a validated liquid chromatography/mass spectrometry/mass spectrometry method at Cedra Corporation (Austin, Tex). After addition of the internal standard (pentadeuterated lasofoxifene), plasma sample (1.0 mL) was extracted with an organic solvent (MTBE). The organic layer was evaporated and reconstituted before the injection of an aliquot. Detection was by tandem mass spectrometry (MS/MS) using a PE-SCIEX API 3000 mass analyzer. The high-performance liquid chromatography (HPLC) system was coupled to the mass spectrometer using a heated nebulizer. The analysis was by positive ionization MS/MS using the protonated molecular ions as precursors. The mass transition was 414.2 to 98.1. The analytical range was 0.025 to 6.0 ng/mL, with precision (expressed as percentage of coefficient of variation) within 7.03% and accuracy of 96.8% to 106%.
Protein binding was determined using equilibrium dialysis at Cedra Corporation. First, all study samples (0.5 mL) were spiked with 50 ng/mL lasofoxifene to uniformly increase the amount of lasofoxifene so that quantitation would be possible after equilibrium dialysis. After fortification, samples were vortexed, and 1.5 mL was taken from each sample so that 0.750 mL could be transferred into separate dialysis chambers to yield 2 aliquots per sample for analysis. The system used for equilibrium dialysis was a Rotating Disk Dialysis Apparatus (Spectrum Medical Instruments, Los Angeles, Calif) comprising 5 separate chambers containing Spectra/Por-2 Regenerated Cellulose membranes (12 000 14 000 molecular weight cutoff). Each chamber contained a total volume 1.5 mL or 0.75 mL per side. Before performing the dialysis, each membrane was sequentially soaked in HPLC grade water, 30% ethanol, and 100 mM sodium phosphate buffer (pH 7.4) for 15 minutes each. Approximately 0.750 mL of a 100-mmol/L sodium phosphate buffer (pH 7.4) was added to the corresponding opposite chamber (buffer side). These duplicate samples were dialyzed for 6 hours at 37°C and 20 revolutions per minute. After dialysis, plasma and buffer samples were recovered from each of the dialysis cells and weighed. Buffer (0.5 mL) and plasma (0.5 mL) samples were analyzed using a Perkin Elmer SCIEX (Concord, Ontario, Canada) APIIII Plus mass analyzer in positive ionization mode. The mass transition was 414.2 to 98.1. The plasma dynamic range was 0.025 to 6.0 ng/mL, and the buffer side dynamic range was 0.1 to 1.35 ng/mL (0.01-1.5 ng/mL was also used). Precisions of the assay for plasma and buffer samples were within 13.2% and 8.2%, respectively, whereas accuracy ranged from 103% to 105% for plasma samples and from 102% to 105% for buffer samples.
Pharmacokinetic and Statistical Analysis
Pharmacokinetic parameters including maximum plasma concentration (Cmax), time to Cmax (tmax), area under plasma concentration-time curve from time 0 to the time for the last quantifiable concentration (AUC0-tlqc), area under the plasma concentration-time curve from time 0 to infinity (AUC0-), terminal half-life (t
), mean residence time (MRT), total oral clearance (CL/F), volume of distribution (Vd/F), fraction unbound (Fu), and oral clearance of unbound drug (CLu/F) were calculated using standard noncompartmental methods. All pharmacokinetic parameters were summarized using descriptive statistics. Pharmacokinetic parameter values were evaluated by analysis of variance (ANOVA) using a model incorporating hepatic status only. Least squares treatment mean values were also determined for each parameter. Results from ANOVA were used to calculate 90% confidence intervals (CIs) for the ratios (impaired/healthy) of the least squares treatment mean Cmax and area under the curve (AUC) values (based on log transformation). Although the study was not powered to demonstrate bioequivalence, the 90% CI was used to help with the interpretation of the results. Absence of an effect of hepatic function on lasofoxifene pharmacokinetics would be concluded if the 90% CIs for the treatment ratios of log-transformed Cmax and AUC(0-) values were entirely within the 70% to 143% and 80% to 125% ranges, respectively. Secondary pharmacokinetic parameter value comparisons were performed to aid in data interpretation.
Pharmacokinetic and statistical analyses were performed using WinNonlin-Pro Version 2.1 (Pharsight Corp, Mountain View, Calif) software.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics
Lasofoxifene pharmacokinetic profiles are illustrated in Figure 1. Pharmacokinetic parameter values are summarized by group in Table II. Results of the ANOVA on the primary pharmacokinetic parameters are listed in Table III. The Cmax and AUC(0-) values for lasofoxifene were similar between subjects with mild hepatic impairment (group 2) and healthy subjects (group 1), although the CIs for AUC were wide and the lower boundary did not meet the equivalence criteria. Lasofoxifene pharmacokinetic parameters were higher in moderately impaired subjects (group 3) than in healthy subjects.
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For subjects with mild hepatic impairment, the elimination t of lasofoxifene was nearly identical to that of healthy subjects, averaging approximately 194 hours. For subjects with moderate hepatic impairment, the t value was nearly 60 hours longer than in healthy subjects. Oral clearance of lasofoxifene, both total and unbound, was similar between healthy subjects and those with mild hepatic impairment but was approximately 27% and 25% lower, respectively, for subjects with moderate hepatic impairment. The Vd/F of lasofoxifene was similar for all 3 groups. The tmax for subjects with mild or moderate hepatic impairment was approximately half that for healthy subjects. However, variability in tmax values was high in all groups; median tmax was similar between groups, with values of 10, 8, and 8 hours for groups 1, 2, and 3, respectively. Binding of lasofoxifene to plasma proteins was very high and not influenced by the degree of hepatic impairment.
Adverse Events
All AEs were mild or moderate and were generally short in duration (resolved within 1 day). Eleven subjects reported a total of 21 AEs (Table IV), of which 7 were determined to be treatment associated. Seven AEs were experienced by healthy subjects (group 1), of which 5 were treatment associated; 8 AEs were observed in subjects with mild hepatic impairment (group 2), of which only 1 was considered treatment related; 6 AEs were seen in the group with moderate hepatic impairment (group 3), of which only 1 was associated with treatment. There were no deaths or serious AEs reported. The only AE that occurred in more than a single subject within a treatment group was somnolence (2 healthy volunteers; both were considered treatment associated). Headache occurred in 3 subjects (1 in each treatment group), and nausea occurred in 2 subjects. The 4 moderate AEs consisted of headache (n = 1), nausea (n = 1), lymphadenopathy (n = 1), and accidental injury (n = 1). The headache and nausea were considered treatment associated, and both occurred in healthy subjects (group 1).
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A total of 11 subjects had abnormal clinical laboratory assessments after receiving lasofoxifene. In general, clinical laboratory abnormalities were sporadic and transient and appeared unrelated to study drug administration. Only 4 of the 11 subjects had normal values at baseline, and all abnormal clinical laboratory values, after treatment with lasofoxifene, were regarded by the principal investigators to be related to the subjects' hepatic disease or not clinically significant.
No clinically significant changes in physical examination results or vital sign measurements were reported for any subject for the duration of the study. Physical examination results for healthy subjects were normal at all assessments. In subjects with mild or moderate hepatic impairment (groups 2 and 3), incidences of ascites, asterixis, edema, telangiectasia, palmar erythema, and splenomegaly were reported but were considered related to their hepatic diseases and not to study medication.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The present study was designed because lasofoxifene, like other members of this class, is metabolized by hepatic oxidation and conjugation. As the liver appears to be the major route of metabolism and/or elimination, patients with hepatic impairment could display altered lasofoxifene pharmacokinetics.
In this study, the pharmacokinetics of lasofoxifene was not different in subjects with mild hepatic impairment as compared to healthy subjects. Although moderate hepatic impairment resulted in higher plasma concentrations of lasofoxifene, the increase in AUC was moderate (<40%). Because all 6 subjects with moderate hepatic impairment (group 3) were male, the exposure in this group could be biased downward because the males were heavier. Indeed, when CL/F was normalized by body weight, mean values were 1.32, 1.51, and 0.83 mL/min/kg for groups 1, 2, and 3, respectively. Small differences in exposure have been noted in men relative to women after single-dose administration, likely because of differences in body size. In women, lasofoxifene Cmax and AUC were 28% to 30% and 1% to 22% greater than in men, respectively (data on file at Pfizer Inc). The differences observed in moderately impaired subjects are not thought to be clinically relevant because of the large therapeutic index of lasofoxifene, with doses up to 10 mg/d having been well tolerated for up to 1 year in other studies.9 Thus, no dosage adjustment is recommended. The impact of severe hepatic impairment on lasofoxifene exposure was not a part of this investigation.
The observed tmax averaged 6 to 7 hours in subjects with hepatic impairment (both mild and moderate) as compared to 12 hours in healthy subjects. The median value of tmax was similar between groups as described earlier. Thus, the difference in mean values may result from individual variability in that parameter and the small sample size (n = 6 per group). Because the efficacy of lasofoxifene is dependent on overall exposure and not peak concentrations or the time to reach these concentrations, these differences are not considered clinically significant.
Although hepatic impairment did not greatly affect the pharmacokinetics of lasofoxifene, the condition has been shown to affect the pharmacokinetics of toremifene. Investigations showed that the t of toremifene was about double in subjects with impaired liver function as compared to healthy subjects.18-20 Therefore, it is recommended that the dose of toremifene be decreased for patients with impaired liver function. Raloxifene has also been investigated in subjects with hepatic impairment, with plasma concentrations 2.5 times higher in subjects with mild hepatic impairment than controls.21,22 Although no recommendations have been made with respect to raloxifene dosing, caution is warranted. No clinical trial data are available for tamoxifen.
Lasofoxifene was well tolerated in the present study, with only mild and moderate AEs observed. Treatment-associated AEs consisted of headache, somnolence, and nausea. No clinically significant changes in physical examination, vital sign, or laboratory findings were seen. In those subjects with abnormal laboratory results (only groups 2 and 3), the differences were attributed to their hepatic disease and not the study medication.
In conclusion, lasofoxifene was well tolerated and appeared safe in this group of subjects, which consisted of older adults. Lasofoxifene pharmacokinetics was not affected by mild hepatic impairment. Moderate hepatic impairment did alter lasofoxifene pharmacokinetics, but the magnitude of the effect was not clinically relevant. Also, because lasofoxifene displays a large therapeutic index, no dosage adjustment is expected to be necessary for patients with mild or moderate hepatic impairment, a substantial advantage in the elderly.
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REFERENCES |
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