Odanacatib Pharmacokinetics Comparison Between Chinese and Non-Chinese Postmenopausal Women
Clinical Pharmacology in Drug Development 2018, 00(0) 1–7
⃝C 2018, The American College of Clinical Pharmacology
DOI: 10.1002/cpdd.434
Xia Chen1,2, Ji Jiang1,2, Pei Hu1,2, Stefan Zajic3, Wen Liu3, Jacqueline McCrea3, Fang Liu3, Rose Witter3, Eric Mangin3, and S. Aubrey Stoch3
Abstract
Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this phase 1 open-label study, 12 healthy Chinese postmenopausal women re- ceived single-dose ODN 50 mg on day 1 and multiple-dose ODN 50 mg once weekly on days 15, 22, 29, and 36 under fasted conditions. Pharmacokinetic (PK) parameters were evaluated on days 1 and 36. Multiple-dose area under the concentration–time profile (AUC0–168h) and maximum plasma concentration (Cmax) were compared with historical data from 9 non-Chinese postmenopausal women who also received ODN 50 mg once weekly for 4 weeks. Median time to Cmax (tmax) was 3 and 4 hours following single- and multiple-dose administration, respectively. The arithmetic mean ± SD terminal half-life was 81.0 ± 14.0 and 106.7 ± 14.4 hours following single- and multiple-dose administration, re- spectively. Comparison of multiple-dose PK parameters showed that the geometric mean ratios (Chinese/non-Chinese) and 95%CIs for AUC0–168h and Cmax were 0.81 (0.55–1.19) and 0.87 (0.69–1.11), respectively. All adverse events were mild, none were serious, and none led to discontinuation. Single- and multiple-dose PKs of ODN 50 mg in Chinese postmenopausal women were generally similar to those previously reported in non-Chinese postmenopausal women.
Keywords: Cathepsin K inhibitor, China, odanacatib, pharmacokinetics, postmenopausal women
Odanacatib (ODN), an oral selective inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. Based on data from a phase 2b dose-ranging study, dose- dependent increases in bone mineral density (BMD) at the lumbar spine and hip sites have been observed with once-weekly administration of ODN at doses ranging from 10 to 50 mg.1–3 ODN has been evaluated in different populations, including Japanese subjects in a separate dose-ranging phase 2b study,4 which also demonstrated dose-dependent increases in BMD and further supported the selection of the 50-mg dose for the global phase 3 Long-term Odanacatib Fracture Trial (LOFT; NCT00529373). In LOFT, ODN 50 mg significantly reduced the risk of osteoporotic fractures in women with postmenopausal osteoporosis com- pared with placebo, but this was associated with an observed increase in the risk of stroke in the study, and further clinical development was stopped.5 ODN is a Biopharmaceutics Classification System class II drug with high permeability (consistent with absorption via passive diffusion) and low solubility (below 0.001 mg/mL in water).6 The pharmacokinetics (PK) and pharmacodynamics of ODN have been char- acterized in phase 1 single-dose7 and multiple-dose8,9 studies conducted in healthy men and postmenopausal women. The absorption, distribution, metabolism, and excretion of ODN were investigated in both animals10 and humans.11 ODN exhibited a monophasic decline in plasma concentration, with an apparent terminal half- life (t½) of ~40–80 hours,7 which is consistent with its low metabolic intrinsic clearance and warranted a once-weekly dosing regimen. Less than dose- proportional increases were observed for area under the plasma concentration–time profile from time 0 to 24 hours (AUC0–24h), concentration at 24 hours (C24h), and maximum plasma concentration (Cmax) from 2 to 600 mg.7 The metabolism of ODN (mainly mediated by cytochrome P450 [CYP]3A) and biliary and/or intestinal excretion of intact parent compound account for approximately 70% and 30%, respectively, of elimination of ODN in humans.11 The studies also showed comparable PK and pharmacodynamics in older men (aged 50–75 years) and postmenopausal women (aged 45–75 years).7–9,11
The present study was designed to characterize the PK of ODN after administration of single and mul- tiple doses to Chinese postmenopausal women. The multiple-dose PK data obtained in this study were compared with multiple-dose PK in non-Chinese post- menopausal women from a previous multiple-dose study.8 This study was also performed to assess the safety and tolerability of single and multiple oral doses of ODN in Chinese postmenopausal women.
Methods
Subjects
Eligible subjects were healthy postmenopausal women of Chinese descent (ie, all 4 biological grandparents born in China and of Chinese descent) between 45 and 75 years of age who had a body mass index of 17–30 kg/m2 and weighed > 50 kg. Subjects were not permitted to use any prescription medications, nonpre- scription medications, or herbal remedies within the 2 weeks prior to the study start. Concomitant therapy during the course of the study had to be discussed be- tween the investigator and sponsor.
Study Design
This was an open-label study to investigate the single- and multiple-dose PK of ODN in 12 healthy Chinese postmenopausal women (protocol 034 [P034]). The primary objective was to assess the PK parameters (eg, AUC from time 0 extrapolated to infinite time [AUC0–∞], AUC from time 0 to 168 hours [AUC0–168h], Cmax, time to Cmax [tmax], and t½) of ODN after admin- istration of single and multiple 50-mg doses of ODN to Chinese postmenopausal women. The secondary objective was to assess the safety and tolerability of single and multiple oral doses of ODN in Chinese postmenopausal women.
Subjects received a single oral dose of ODN 50 mg on day 1, followed by a 14-day washout, and then mul- tiple oral doses of ODN 50 mg once weekly on days 15, 22, 29, and 36. ODN was administered with 240 mL of water under fasted conditions (ie, no food or drink, except water, for at least an 8-hour overnight fast prior to dosing) with water restricted for 1 hour prior to and after dosing. Subjects were admitted to the clinical re- search unit (CRU) the day prior to dosing on days 1 and 36 and remained in the CRU until 24 hours post- dose on days 1 and 36. Subjects were admitted the day prior to dosing on days 15, 22, and 29 and were dis- charged after study-drug administration on days 15, 22, and 29.
The protocol and applicable amendments were reviewed and approved by the Independent Ethics Committee of Peking Union Medical College Hospi- tal, Beijing. The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and applica- ble local regulations. All subjects provided written informed consent.
Study Assessments
The plasma concentration profile of ODN was mea- sured for 336 hours (14 days) following dosing on days 1 (single dose) and 36 (multiple doses). Blood samples for ODN assay were taken predose and 1, 2, 4, 6, 9, 12, 16, 24, 32, 48, 72, 96, 120, 168, 240, and 336 hours post-
dose on days 1 and 36, and predose on days 22 and 29. PK parameters evaluated include AUC0–∞, AUC0–168h (as appropriate), Cmax, tmax, and t½.Plasma samples were analyzed for ODN by WuXi AppTec Co., Ltd. (Shanghai, China). The analyti- cal method used liquid–liquid extraction with methyl tert-butyl ether for analyte isolation, followed by liq- uid chromatographic–tandem mass spectrometric de- tection under positive ion mode via a turbo ion-spray source.12 The lower limit of reliable quantitation was 0.5 ng/mL (~1 nM); concentrations below this limit were set to 0.
PK parameters were calculated using the software Pharsight Phoenix WinNonlin (version 6.3). AUC0–∞ was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations (linear up/log down). AUC0–∞ was calculated as the sum of AUC from 0 hours to the time of the last measurable concen- tration (AUC0–last) and Ct/λ, where λ is the apparent terminal rate constant and Ct is the last observed quantifiable concentration. For each subject, λ was cal-
culated by regression of the terminal log-linear portion of the plasma concentration–time profile, and t½ was calculated as the quotient of the natural log of 2 (ln [2]) and λ. At least 3 data points (excluding the Cmax) in the terminal phase were used for λ calculations. Onset of the terminal log-linear phase was determined using sample times ? 96 hours with at least 1 time collected at ? 240 hours. Cmax and tmax were generated by WinNonlin from each subject’s plasma concentration–study (P059).8 The P059 study, in which a total of 44 subjects (ie, 32 men and 12 women) were randomized, was chosen for the Chinese/non-Chinese comparison because it used the same dosing regimen (50 mg once weekly for 4 weeks).
Plasma concentrations for ODN can be converted into mass units using the molecular weight of 525.57 g/mol for ODN.AUC, area under the plasma concentration–time profile; AUC0–∞, AUC from time 0 extrapolated to infinite time; AUC0–168h, AUC from time 0 to 168 hours; Cmax, maximum plasma concentration; CV, coefficient of variation; GM, geometric mean; NA, not applicable; ODN, odanacatib; PK, pharmacokinetic; SD, standard deviation; t½, apparent terminal half-life; tmax, time to Cmax.
The safety and tolerability of ODN were assessed by the clinical assessment of adverse events (AEs) and other safety measurements, including vital signs, physical examinations, laboratory safety assessments (eg, hematology, chemistry, and urinalysis), and electro- cardiograms (ECGs).
Statistical Analysis
Descriptive statistics of PK parameters (AUC0–∞ [sin- gle dose], AUC0–168h [multiple doses], Cmax, tmax, and t½) were provided by treatment. Minimum, median, maximum, arithmetic mean, and standard deviation (SD) were provided for all PK parameters. In addition, the percent between-subject coefficient of variation was calculated according to the following formula: 100 × sqrt(exp[s2] – 1), where s2 is the observed variance on the natural log scale. Harmonic mean and jackknife SD were provided for t½.
Figure 1. Mean ± SE ODN plasma concentration–time pro- files following 50-mg single and multiple doses of ODN to Chi- nese postmenopausal women: (a) linear and (b) semilogarithmic scale. Plasma concentrations for ODN can be converted into mass units using the molecular weight of 525.57 g/mol for ODN. ODN, odanacatib; SE, standard error.
A 1-way analysis of variance model with a factor of ethnic group (Chinese, non-Chinese) was used to compare the multiple-dose AUC0–168h with the Cmax of ODN in Chinese patients with the historical non- Chinese data. A log transformation was applied prior to model fitting. Point estimates and 95% confidence in- tervals (CIs) of the geometric mean were generated. A 95%CI was also generated from the model for the geo- metric mean ratio (GMR; Chinese/non-Chinese).
The incidence of subjects with AEs was summarized descriptively by treatment. Because individual changes were not deemed clinically important, summary statistics for laboratory safety tests, ECGs, and vital signs were not provided.
Results
Subjects
Twelve Chinese postmenopausal women were enrolled and completed the study between June and August 2011; all subjects completed the study per protocol and were included in the PK and safety evaluations. One subject received concomitant Chinese herbal ther- apy (Huoxiang Zhengqi soft capsule) during the study; however, based on the subjects’ PK data, this was considered unlikely to have affected the PK or safety results of this study. The mean age of the subjects was 51.8 years (range, 48 to 57 years), the mean height was 159.4 cm (range, 153 to 176 cm), the mean weight was 62.8 kg (range, 55.0 to 68.7 kg), and mean body mass index was 24.9 kg/m2 (range, 18.1 to 28.9 kg/m2).
Pharmacokinetics
PK parameters for ODN following single and mul- tiple doses in Chinese postmenopausal women are shown in Table 1. ODN was absorbed in Chinese post- menopausal women with a median tmax of 3 hours fol- lowing single dosing and 4 hours after multiple dosing. Mean ODN plasma concentration–time profiles fol- lowing 50-mg single and multiple dosing of ODN are shown in Figure 1. Secondary peaks were observed, as have been previously reported in studies in non-Chinese subjects.7 The arithmetic mean ± SD t½ was 81.0 ± 14.0 hours following single dosing and 106.7 ± 14.4 hours following multiple dosing.
AUC0–168h and Cmax were compared between Chinese postmenopausal women in this study and non-Chinese postmenopausal women in P059 follow- ing multiple dosing. The results of this comparison are shown in Table 2. The GMR (Chinese/non-Chinese) and corresponding 95%CI for multiple-dose AUC0–168h was 0.81 (0.55–1.19). The corresponding GMR and 95%CI for multiple-dose Cmax was 0.87 (0.69–1.11). Individual values, arithmetic means with SD, and geometric means with 95%CIs of AUC0–168h and Cmax following 50-mg multiple doses of ODN in Chinese and non-Chinese postmenopausal subjects from P059 are shown in Figure 2. Mean ODN plasma concentration– time profiles in Chinese postmenopausal women in this study, compared with those in non-Chinese post- menopausal women in P059, are shown in Figure 3.
Safety
No serious clinical AEs were reported, and no subjects were discontinued from the study because of an AE. No laboratory AEs were reported.
Figure 3. Mean ± SE ODN plasma concentration–time profiles following multiple doses of ODN 50 mg between Chinese and non-Chinese postmenopausal women. Plasma concentrations for ODN can be converted into mass units using the molecular weight of 525.57 g/mol for ODN. ODN, odanacatib; SE, standard error.
Discussion
The primary objective of this study was to character- ize the PK of ODN in Chinese postmenopausal women following single and multiple oral doses to help to sup- port that the dose of ODN (50 mg once weekly) that has been administered to non-Chinese postmenopausal women with osteoporosis is appropriate from a PK per- spective in Chinese subjects. Because the study did not include a comparable group of non-Chinese women, multiple-dose PK parameters from this study were com- pared with multiple-dose PK in non-Chinese post- menopausal women from a previous study.8
Figure 2. Individual values, arithmetic means with SDs, and ge- ometric means with 95%CIs of (a) AUC0–168h and (b) Cmax, fol- lowing multiple doses of ODN 50 mg between Chinese (on day 36) and non-Chinese (on day 22) postmenopausal women. Plasma concentrations for ODN can be converted into mass units using the molecular weight of 525.57 g/mol for ODN. AUC0–168h, area under the plasma concentration–time profile from time 0 to 168 hours; CI, confidence interval; Cmax,maximum plasma concentration; ODN, odanacatib; SD, standard deviation.
A total of 41 nonserious AEs, 37 possibly or probably related to the study drug, were reported in 11 subjects. All were rated mild in intensity by the investigator and resolved without intervention. The most common AEs were diarrhea (5 subjects, 42%), dizziness (4 subjects, 33%), and bradyphrenia (4 sub- jects, 33%). Bradyphrenia is the preferred term for the verbatim term “slow thinking” (this verbatim term was translated from the source). The investigator provided summaries for these events and explained the AE as “misty head and brain unclear”; this AE occurred only at this study site.
The single- and multiple-dose PK of ODN 50 mg in Chinese postmenopausal women in this study were generally similar to those previously observed in non- Chinese postmenopausal women.7–9 A comparison of multiple-dose PK parameters between Chinese and non-Chinese postmenopausal women showed that the GMR (95%CI) for AUC0–168h and Cmax was 0.81 (0.55–1.19) and 0.87 (0.69–1.11), respectively, suggest- ing that the multiple-dose PK observed in Chinese women were slightly lower than those observed in non- Chinese women, with no evidence of ethnic sensitiv- ity. There are no major metabolic pathways likely to result in a difference in PK between the 2 popula- tions: the metabolism of ODN is principally medi- ated by CYP3A4,11 and the major CYP3A4 polymor- phisms in the Chinese population are of low allelic frequency.13 In the phase 2 dose-ranging study eval- uating ODN doses of 3, 10, 25, and 50 mg, lumbar spine BMD gains were observed throughout 5 years in patients on continuous treatment with combinations of 10 to 50 mg.3 In addition, ODN at 50 mg once weekly appears to be at or near the plateau of the exposure–response relationship for BMD efficacy. Therefore, the small reduction observed in multiple- dose PK is not anticipated to be clinically meaningful. AEs were mild, and there was no serious AE or dis- continuation because of an AE. The AE profile in this study in Chinese subjects is consistent with that seen in other studies, with the exception of bradyphrenia (slow thinking), which has not been reported in any other studies.1,4,14–16 The bradyphrenia was self-limiting and not of clinical concern.
In conclusion, the single- and multiple-dose PK of ODN 50 mg in Chinese postmenopausal women were generally similar to those observed in non-Chinese postmenopausal women, and single and multiple doses of ODN 50 mg were generally well tolerated in healthy Chinese postmenopausal women.
Acknowledgments
Medical writing was provided by Annette Smith, PhD, of Complete Medical Communications, Macclesfield, UK. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Declaration of Conflicting Interests
Xia Chen, Ji Jiang, and Pei Hu have no conflicts of interest to declare. Wen Liu, Jacqueline McCrea, Fang Liu, Rose Wit- ter, Eric Mangin, and Aubrey Stoch are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., who may hold stock and/or hold stock options in the com- pany. Stefan Zajic was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA at the time the study was conducted.
Funding
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
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