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BRIEF REPORT/PHARMACOKINETICS |
From Pfizer Global Research and Development, Groton, Connecticut, and Tokyo, Japan.
Address for reprints: R. J. Fountaine, PharmD, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06341; e-mail: Robert.j.fountaine{at}pfizer.com.
Key Words: Lasofoxifene • SERM • menopause • pharmacokinetics • ethnicity
Lasofoxifene is an oral naphthalene derivative selective estrogen receptor modulator (SERM) under investigation for the treatment of osteoporosis. Lasofoxifene has a potency at estrogen receptors that is at least equal to that of estradiol in preventing bone loss and inhibiting bone turnover in ovariectomized rats.1 It is not entirely clear why lasofoxifene possesses such increased in vivo potency relative to other SERMs, but it may be related to its high estrogen receptor alpha (ER
) affinity (concentration required for 50% inhibition of receptor binding [IC50] = 1.5 nM)1, representing at minimum a 10-fold greater binding affinity for the human estrogen receptor than raloxifene, tamoxifen, or droloxifene.2,3
Differences in drug metabolism have been reported between Asian and Western populations, and several studies have shown differences between Asian and white populations with respect to estrogen metabolism.4-9 It is possible that such differences reflect variations in the cytochrome P450 (CYP) system observed between Asian and white populations.6-9 For example, CYP2D6 is functionally absent in less than 1% of Asians but in 8% of whites.10 Polymorphisms of CYP3A4, an important enzyme in the metabolism of many clinically relevant drugs including lasofoxifene, are rare in both Asian and white populations. However, some sequence differences have been noted, which may translate into variations in the metabolism of drugs that rely on CYP3A4 for disposition.8,9 Such racial differences in enzyme activity necessitate investigation of the pharmacokinetics of new chemical entities in different populations. Lasofoxifene is metabolized through both oxidative and conjugative pathways, with CYP450, CYP3A4/3A5, and CYP2D6 as the major oxidative enzymes involved.11 This factor provided the impetus for the current studies.
MATERIALS AND METHODS
Study Design
All studies were conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practices (GCPs) and the Declaration of Helsinki and in compliance with relevant regulations for informed consent and protection of subject rights in the country of conduct. The Institutional Review Board of the participating center approved the protocol, consent documents, and protocol amendments.
Study 1 was a double-blind, placebo-controlled, parallel group, single oral dose evaluation of the clinical pharmacology of lasofoxifene in a population of postmenopausal Japanese and white women and was performed at Radiant Research in Honolulu, Hawaii. It was divided into 2 parts: part 1 evaluated lasofoxifene pharmacokinetics (0.25 mg) in first-generation versus second-generation postmenopausal Japanese women and among all Japanese women versus their white counterparts; part 2 was conducted to compare the pharmacokinetics of single doses of lasofoxifene (0.1 mg and 0.5 mg) across the 2 ethnic groups. Study 2 was a randomized, double-blind, placebo-controlled study of the clinical pharmacology of multiple doses of lasofoxifene in healthy postmenopausal Japanese women and was conducted at the NS Clinic in Tokyo, Japan. Study participants received a loading dose of 4 mg or 8 mg of lasofoxifene on day 1. On days 2 to 14, participants received a single dose of 0.25 or 0.50 mg/d. Subjects were evaluated for pharmacokinetic parameters and safety up to day 28. Study 3 was an open-label, multiple-dose study to bridge lasofoxifene pharmacokinetic results from the Japanese multiple-dose study (study 2) to multiple-dose pharmacokinetics in a white population and was performed at the PRACS Institute in Fargo, North Dakota, and Comprehensive Neurosciences Inc, in Fort Lauderdale, Florida. Study participants received a loading dose of 4 mg or 8 mg of lasofoxifene on day 1. On days 2 to 14, participants received a single dose of 0.25 or 0.50 mg/d. Subjects were evaluated for pharmacokinetic parameters and safety up to day 42.
Study Population
For the purpose of all 3 studies, postmenopausal was defined as the onset of the last menses or bilateral oophorectomy at least 2 years before study start. The term white was used to describe women of European descent. Subjects in all studies were judged to be healthy on the basis of their medical history, full physical examination, clinical laboratory tests, and an electrocardiogram (ECG). Subjects in all studies were required to have a body mass index (BMI) 
30 kg/m2.
Exclusion criteria for all 3 studies were evidence or a history of clinically significant disease, conditions relating to poor drug absorption, drug allergies, and drug or alcohol dependence. Also excluded were patients previously treated with anticoagulants (excluding aspirin), those participating in trials of investigational compounds within the past 4 months, those taking any drug within 2 weeks of study start, those taking hormone therapy or a SERM within 1 month of study start, those taking any agent that may potentially affect the pharmacokinetics of lasofoxifene within 1 month of study start, and those taking any agent that alters serum lipids.
Study 1 enrolled Japanese and white postmenopausal women aged 50 to 80 years. Japanese subjects were further classified as first generation or second generation on the basis of personal or parental birth in Japan, respectively. White participants were age matched ( 5 years) as closely as possible to their Japanese counterparts. Active smokers were excluded from this study. Study 2 enrolled healthy Japanese postmenopausal women aged 45 to 64 years with a serum follicle-stimulating hormone (FSH) 
30 IU/L and serum estradiol 30 pg/mL. Patients smoking 21 cigarettes per day were also excluded. Study 3 enrolled healthy white postmenopausal women aged 45 to 64 years with a serum FSH greater than 30 IU/L that were age matched (±5 years) within each dose level in a 1:1 ratio with the Japanese subjects in study 2. Study 3 subjects were also matched with regard to smoking status (based on positive or negative serum nicotine) with their Japanese counterparts. Additional exclusion criteria included the use of herbal therapies within 30 days of study start and the use of prescription or nonprescription drugs (with the exception of acetaminophen 2 g/d), vitamins, or dietary supplements within 14 days (or 5 half-lives [t
]; whichever was longer) before the first dose of study medication.
Pharmacokinetic and Pharmacodynamic Sampling
Plasma samples were assayed by Cedra Corporation (Austin, Texas) using a validated high-performance liquid chromatography/tandem mass spectrometry method with a dynamic range extending from 0.025 to 6.0 ng/mL.12 Lasofoxifene concentrations below the lower limit of quantification were reported as 0 ng/mL in pharmacokinetic calculations. The following lasofoxifene parameters were estimated at steady state: maximum plasma concentration (Cmax), the time to first Cmax (tmax), area under the plasma concentration-time curve (AUC), terminal phase t, area under the plasma concentration curve from time 0 to the last time (t) with a quantifiable concentration (AUC0-t), AUC from time (t) to infinity (AUCt-
), and percentage of dose eliminated unchanged in the urine at 24 hours (Ae0-24). Terminal phase rate constants (Kel) were estimated using least squares regression analysis of the plasma concentration-time data obtained during the terminal log-linear phase. Half-life was calculated as ln(2)/Kel. AUC0-t was estimated using the linear trapezoidal approximation. AUCt- was estimated as the Cpest/Kel, where Cpest is the estimated plasma concentration at time (t) based on the regression analysis of the terminal log-linear phase. Plasma protein binding was calculated as ([plasma lasofoxifene concentration] - [plasma free lasofoxifene concentration]/[plasma lasofoxifene concentration]) x 100 at 10 hours postdose on day 14.
Analysis of markers of bone metabolism included urinary type I collagen N-terminal telopeptide (NTX), deoxypyridinoline (DPD), bone-specific alkaline phosphatase (BSAP). In addition, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, and the gonadotropins FSH and luteinizing hormone (LH) were evaluated. All pharmacodynamic sample analysis was performed by Esoterix Inc (Calabasas Hills, California) and the Health Sciences Research Institute Inc (Yokohama, Japan).
Study 1 plasma samples were collected at 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 216, 264, 312, 360, 408, and 480 hours after lasofoxifene or placebo administration. Study 2 plasma samples were collected at 0, 1, 2, 4, 8, 10, 12, and 24 hours after drug administration on day 1 and day 14; before drug administration on days 4, 6, 8, 10, and 12 and then at 48, 72, 120, 168, 216, 264, 336, 408, 504, and 672 hours postdose; and 10 hours postdose day 14 to evaluate plasma protein binding. Urine samples were collected on day 1 before dosing and on day 14 over 0- to 6-hour, 6- to 12-hour, and 12- to 24-hour postdose intervals for evaluation of NTX and DPD. Blood samples for pharmacodynamic evaluations of LDL, HDL, FSH, LH, and BSAP were collected just prior to drug administration on days 1, 7, 14, 21, and 28. Study 3 plasma samples were collected predose on days 2, 4, 6, 8, 10, and 12 and at 1, 2, 4, 8, 10, 12, 24, 48, 72, 120, 168, 216, 264, 336, 408, 504, and 672 hours after drug administration on day 14. Samples for the evaluation of LDL and HDL were collected on days 1 and 14.
Statistical Analysis
In study 1, the natural log-transformed AUC0-, AUC0-t, Cmax, tmax, and t were analyzed using an analysis of variance (ANOVA) model for first-generation and second-generation Japanese, white, and Japanese (first generation + second generation) populations and were used as comparison models, respectively, as a fixed effect. SAS procedure Proc Mixed (method = reml) (SAS Institute, Cary, NC) was used for these analyses. The ESTIMATE statement was used to estimate the first-generation and second-generation Japanese differences and standard errors. These findings were then used to calculate the 90% confidence intervals (CIs) of the true first-generation and second-generation Japanese differences. For AUC0-, AUC0-t, and Cmax, the anti-log of the differences and CI was used to estimate the ratio of the first-generation and second-generation Japanese effects and the 90% CI. The pharmacokinetics in the first generation and second generation were considered the same if the 90% CI for the ratios of the logtransformed Cmax and AUC values were contained within 80% to 125%. Part 2 applied the same methods to compare Japanese and white subjects receiving lasofoxifene 0.1 mg, 0.25 mg, or 0.5 mg. At the 0.25-mg dose, the pharmacokinetics in Japanese and white subjects were considered the same if the 90% CI for the ratios of the log-transformed Cmax and AUC values were contained within 70% to 143%. In study 2 and study 3, the pharmacokinetic and pharmacodynamic parameters were analyzed by descriptive statistics, and the calculated arithmetic mean, standard deviation, and coefficient of variation were summarized.
Safety Evaluation
Although these studies were not designed or sufficiently powered to determine safety, all observed and reported adverse events were recorded and monitored throughout the study on the basis of physical examinations, gynecologic examinations, vital signs, ECG readings, clinical laboratory assessments, and premature discontinuations. Adverse events were reported on the basis of nonleading questions, patient self-observations, or by the investigator.
RESULTS
Subjects
Study 1. A total of 60 Japanese and white subjects were enrolled. Two Japanese subjects (0.25-mg dose) completed the protocol but did not meet all entry criteria and were consequently replaced. One white subject was treated with a 0.5-mg dose but could not be appropriately age-matched with a Japanese subject. Safety data from these 3 subjects were included, but pharmacokinetic data were excluded from the analysis.
Studies 2 and 3. Twenty-four Japanese subjects were enrolled in study 2, and 18 matched white subjects were enrolled in study 3. Study participants were generally well matched with respect to age and smoking status between both the studies and the study groups. All 24 subjects in study 2 and 17 of 18 subjects in study 3 completed the study. One of the subjects in study 3 had pharmacokinetic assessments conducted on day 13 versus day 14 (study withdrawal on day 14 because of personal reasons). Trough concentration data for this subject indicated that she had reached steady state by day 13, and the data from this subject were included in the analysis. The interval over which quantifiable plasma concentrations were available was too short relative to the projected t; therefore, these data were excluded.
Pharmacokinetics and Pharmacodynamics
In study 1, part 1, the pharmacokinetic values after a single 0.25-mg dose of lasofoxifene were similar in first-generation and second-generation Japanese subjects. As a result, all Japanese subjects were entered into part 2 of the study without regard to generational status. At the projected clinical dose of 0.25 mg, the AUC and Cmax mean ratios and associated 90% CI fell within the 80% to 125% range. Similarly, the mean ratios for t and tmax values between the 2 groups had 90% CIs that contained zero, indicating no statistically significant difference (Table I). At the 0.1-mg and 0.5-mg doses, the 90% CI for AUC and Cmax fell within the target range of 70% to 143%. However, AUC0- and t could not be consistently estimated at the 0.1-mg dose level (time intervals over which available quantifiable concentrations were insufficient to estimate Kel).
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In studies 2 and 3, lasofoxifene plasma concentrations reached steady state on day 2 (Figure 1). The median tmax was approximately 4 hours and 8 hours in the 0.25- and 0.5-mg dose groups, respectively. At the proposed clinical dose of 0.25 mg/d, the mean Cmax was 1.9 ± 0.5 ng/mL in study 2 and 2.4 ± 0.6 ng/mL in study 3. Mean AUC0-24 and mean Cmax were dose proportional. Lasofoxifene was eliminated slowly, with a mean t of approximately 167 hours. Data from study 2 indicated that the mean lasofoxifene Ae0-24 was 0.53% and 0.49% of the administered dose in the 0.25-mg and 0.5-mg groups, respectively, and that the drug was greater than 99% protein bound. By day 14, in studies 2 and 3, respectively, LDL levels were reduced by approximately 17% and 22% in the 0.25-mg dose groups and by approximately 7% and 14% in the 0.5-mg dose groups versus baseline. There was no consistent change in HDL levels. There was a marked reduction in NTX in the lasofoxifene 0.5-mg group compared with placebo at day 14 (-18.4% vs +12.4%). There was also a reduction in NTX at day 14 in the 0.25-mg group versus placebo (-24.1% vs. +12.4%).
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The levels of BSAP and DPD remained fairly stable in both lasofoxifene dose groups. FSH fell by approximately 14% and 10% in the 0.25-mg and 0.5-mg dose groups, respectively, when compared to baseline. At 14 days after last dose, LH was reduced by 11% and 13% in the 0.25-mg and 0.5-mg dose groups, respectively. Levels of both LH and FSH rose in placebo-treated subjects.
Safety
There were no deaths, serious adverse events, or withdrawals due to adverse events in any of the 3 studies. There were no clinically relevant laboratory abnormalities or significant changes in other safety parameters, including vital signs and ECG.
DISCUSSION
Lasofoxifene exhibited similar pharmacokinetic behavior in white and Asian participants. For all 3 doses investigated in study 1, the ratios for AUC and Cmax were similar in Japanese and white subjects. Cmax and AUC were proportional to dose in both populations. Similar t and tmax values were also observed in the 2 groups for the 0.25-mg and 0.5-mg doses. In studies 2 and 3, at the lower dose of 0.25 mg/d, the mean Cmax (2.4 ng/mL) was similar to that observed for raloxifene, which reaches 1.36 ng/mL after prolonged administration at 60 mg/d.13 At a dose of 0.5 mg/d, the lasofoxifene mean Cmax was substantially higher at 3.6 ng/mL.
Lasofoxifene was eliminated slowly, with a t of approximately 150 hours for both doses in both study 2 and study 3. This finding is consistent with the observed t in study 1 and is similar to other SERMs such as tamoxifen (120-168 hours) and toremifene (120-144 hours) but is substantially longer than raloxifene (16-87 hours).13 The long t of tamoxifen and toremifene is thought to be due to enterohepatic circulation and high plasma protein binding. Both lasofoxifene and raloxifene are also highly protein bound, but unlike lasofoxifene, raloxifene is not metabolized in the liver, which may explain the observed differences in t.
The data from studies 2 and 3 indicate that lasofoxifene, like estrogen, exerts a positive effect on serum lipids. Serum LDL levels fell during the course of the studies in both dosage groups and for both ethnicities, although this result was not dose related. Similar results have been shown for tamoxifen14 and raloxifene15 in postmenopausal women.
The pharmacodynamic data obtained in study 2, relating to bone metabolism, indicate that the short-term effects of lasofoxifene observed in preclinical studies16,17 are also observed in postmenopausal women. A recent 1-year study comparing lasofoxifene 0.25 or 1.0 mg/d with raloxifene 60 mg/d in 410 postmenopausal women showed that after 6 months, both doses of lasofoxifene produced markedly greater mean reductions in NTX, osteocalcin, DPD, and BSAP than did either raloxifene or placebo.18 The trend toward but lack of significant reductions in DPD and BSAP versus baseline observed in study 2 may be attributable to the short duration of treatment, whereas findings from longer term trials have suggested more significant reductions in DPD and BSAP versus baseline.9-11,13,19-22
Lasofoxifene was generally well tolerated at all doses in all 3 studies in both Japanese and white subjects. The majority of adverse events were mild or moderate in intensity, and no relationship was observed between the dose and the number of adverse events. Although these studies lacked sufficient design and power to thoroughly evaluate safety, the nature and frequency of reported adverse events were in keeping with those reported in previous studies.23,24 The safety profile of lasofoxifene is currently being studied more extensively in large comparative clinical studies, which will help define any potential side effects, particularly in comparison with raloxifene.
In conclusion, data from these 3 studies show that single- and multiple-dose administration of lasofoxifene at potential clinical doses is equally well tolerated, with consistent pharmacokinetic and pharmacodynamic parameters in both Japanese and white postmenopausal women. In addition, these results suggest that lasofoxifene has an effect on specific markers of bone formation and resorption and LDL-lowering potential in postmenopausal women of different ethnic backgrounds.
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