Clinical Therapeutics/Volume ], Number ], 2014

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Parathyroid Hormone (1–34) in Healthy Chinese Subjects Yani Liu, MS1; Chunxiao Yang, BS1; Zhongfang Li, BS1; Jiali Zhou, BS1; Yongning Lv, MD1; Yu Zhang, MD1; Fandian Zeng, MD1,2; and Shaojun Shi, MD1 1

Clinical Research Organization for Pharmaceutical Products, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; and 2Institute of Clinical Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

ABSTRACT Background: The recombinant human parathyroid hormone (1–34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China. Objective: The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1–34) after single and multiple subcutaneous doses in healthy Chinese subjects. Methods: Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1–34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1–34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1–34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1–34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters. Results: Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1–34) was well tolerated during the investigated single (10–60 μg) and multiple (10–20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1–34), the drug was

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rapidly absorbed, with a Tmax of 20 to 30 minutes, and rapidly cleared from the plasma, with a t½ of 47.2 to 60.6 minutes. The mean Cmax, AUC0–t, and AUC0–1 increased in proportion to the doses, whereas the t½, total clearance, and Tmax values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for Tmax in the 10-μg and 20-μg singledose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels. Conclusions: All rhPTH(1–34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874. (Clin Ther. 2014;]:]]]– ]]]) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: pharmacodynamic parameters, pharmacokinetic parameters, recombinant human parathyroid hormone (1–34), safety profile, tolerability.

INTRODUCTION Osteoporosis is defined as a skeletal disease characterized by compromised bone strength that predisposes patients to an increased risk of fracture, typically of the spine, hip, and wrist.1 Because of increase in the elderly population and the effects of Accepted for publication March 27, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.03.015 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics more sedentary lifestyles, the prevalence rate of osteoporosis has been increasing rapidly in China,2 and osteoporotic fractures have become a major public health problem, affecting an estimated 69.4 million Chinese people.3,4 Currently, 2 categories of agents are available for the treatment of osteoporosis: antiresorptive agents (such as bisphosphonates and raloxifene) and anabolic agents.5,6 The recombinant human parathyroid hormone (1–34) (rhPTH[1–34]) teriparatide was approved by the US Food and Drug Administration as the first anabolic agent for the treatment of osteoporosis in men and women. Unlike antiresorptive agents that act by inhibiting bone resorption, rhPTH(1–34) has a different mechanism of action.7 It can reduce fracture rates significantly by directly stimulating bone formation and improving bone mass and quality.8,9 As the first anabolic agent, rhPTH(1–34) is manufactured by recombinant DNA technology with an identical sequence to the 34 Nterminal amino acids of the full-length rhPTH. In various clinical trials, such as the Fracture Prevention Trial, rhPTH(1–34) had been reported to increase bone mineral density and reduce vertebral and nonvertebral fracture risk.10–14 In addition, it had been found to increase trabecular connectivity and thickness, as assessed by microcomputed tomography of iliac crest bone biopsy specimens.15 Clinical trials have also found that teriparatide produces larger gains in bone mass and bone strength (using modeling techniques) than alendronate.16–18 Recently, a direct secretagogue effect of teriparatide on adrenals in osteoporotic postmenopausal women was found.19 For the treatment of glucocorticoid-induced osteoporosis, rhPTH(1–34) appears to be more effective than alendronate.20 Furthermore, rhPTH(1–34) administration in the morning has been reported to be more effective than evening application.21 The preclinical pharmacokinetic parameters of rhPTH(1–34) have been previously extensively studied in rats, monkeys, and dogs.22–24 After single-dose subcutaneous administration in healthy rats, rhPTH(1–34) was rapidly absorbed and eliminated with high absolute bioavailability.23 Despite the widespread clinical use of rhPTH(1–34) for 410 years, the clinical safety, pharmacodynamic, and pharmacokinetic parameter data were extremely limited in the Chinese population. To our best knowledge, only one study investigated the pharmacokinetic parameters of rhPTH (1–34) (teriparatide) after single-dose subcutaneous

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administration in healthy Chinese subjects.25 rhPTH(1– 34) (teriparatide) was absorbed rapidly after dosing, reached Cmax within approximately 30 minutes, and cleared with a t½ of approximately 1 hour. The test drug of rhPTH(1–34) is a biological medical product developed to be biosimilar to teriparatide. However, because biotech medicines cannot be fully copied, the test drug is not exactly the same as teriparatide. According to the European Medicines Agency guideline,26 such minor differences can result in different effects on safety, pharmacokinetic, and pharmacodynamic parameters. Therefore, to gain market authorization for the biosimilar product in China, it is necessary to evaluate the safety, pharmacokinetic, and pharmacodynamic parameters of this drug. To determine the optimal dose, frequency, and duration of treatment with rhPTH(1–34) for the Phase II clinical trial in China, we evaluated the maximum tolerated dose of rhPTH(1–34) in healthy Chinese subjects. The primary purposes of this present study were to investigate the maximum tolerated dose and safety profile of rhPTH(1–34), to evaluate the pharmacokinetic properties of rhPTH(1–34), to assess the effect of sex on the pharmacokinetic properties of rhPTH(1–34), and to analyze the serum calcium and phosphate responses to single- and multiple-dose subcutaneous administration of rhPTH(1–34) in healthy Chinese subjects.

METHODS All study-related procedures were performed in accordance with the principles of the Declaration of Helsinki and its amendments for biomedical research involving human subjects,27 as well with the principles of the International Conference on Harmonization, Good Clinical Practice guidelines.28 This clinical trial protocol was approved by the State Food and Drug Administration of China (approval No. 2003L01454) and by the independent ethics committee of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China (approval No. [2010] 090). The investigational drug (lot No. 20100901) was provided without cost by Chengdu Bofa Biological Technology Co Ltd, Chengdu, Sichuan, China. All subjects were informed of the investigational nature of this study and signed written informed consent forms before any screening procedures.

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Study Population All subjects enrolled in this study were healthy Chinese adults who met the following criteria: (1) half of them were men and the other half were women; (2) age ranged from 18 to 45 years; (3) the range of body mass index was 19 to 24 kg/m2, with a weight of Z50 kg; (4) they were in good health based on complete physical examination, vital signs, 12-lead ECGs, chest radiography, and clinical standard laboratory tests, including hematologic testing (red blood cell count, white blood cell with differential cell count, platelet count, hemoglobin, and hematocrit), blood chemical analysis (blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase, albumin, total protein glucose, serum total calcium, and serum total phosphate), urinalysis (pH, specific gravity, protein, glucose, ketones, bilirubin, urobilinogen, nitrites, blood, and leukocytes); (5) they tested negative for hepatitis B surface antigen, hepatitis C virus, and HIV; (6) female subjects were required to have a negative pregnancy test result at the time of screening; and (7) they voluntarily signed the informed consent forms. Subjects were excluded for the following criteria: (1) any clinically significant abnormality of physical findings, ECG results, or laboratory values; (2) for female subjects, pregnancy and in the breastfeeding and menstrual phase; (3) history or evidence of hepatic, renal, gastrointestinal, endocrine, pulmonary, hematologic, cardiovascular, vascular, or collagen disease; (4) history of muscle disease, nervous system disease, or psychiatric disorder; (5) history of alcohol, tobacco, or drug abuse; (6) history of allergy or hypersensitivity to any chemicals; (7) participation in any clinical investigation or blood donation within 12 weeks before initial dosing; (8) urinary tract stones; or (9) any drug treatment within 2 weeks before the study.

Study Design Study 1 had an open-label, randomized, singlecenter, dose-escalation design to assess the safety parameters and tolerability of rhPTH(1–34) after single- and multiple-dose subcutaneous administration into the thigh in subjects. In the single-dose phase, 30 subjects (15 men and 15 women) were randomly allocated to 1 of 6 dosage groups of 10, 20, 30, 40, 50, and 60 μg; each group contained 4 or 6 subjects ] 2014

(half of them were male and the other half were female). Subjects were admitted to the Phase I Clinical Research Unit of Union Hospital at 10:00 PM the night before the study and fasted 10 hours before drug administration. At approximately 8:00 AM the next day, all subjects were subcutaneously administered the assigned dose of rhPTH(1–34) into the thigh after a standardized breakfast that consisted of a cup of milk (200 mL), 1 egg (40 g), 1 sausage (40 g), and 3 slices of bread (45 g). This study was designed to begin with the 10-μg dosage group and would not proceed to the subsequent higher-dose group until the tolerability and safety parameters of the previous lower dose were confirmed. Within each group, the trial was terminated immediately if any of the following conditions occurred: (1) any severe adverse event (AE); (2) mild AEs (except for erythema at the injection site) that were attributed to the study medication; and (3) moderate erythema at the injection site (415 mm). In the multiple-dose phase, 12 healthy subjects (6 men and 6 women) were randomly assigned to 1 of 2 dose groups of 10 and 20 μg (n ¼ 6; 3 men and 3 women in each group). These subjects were subcutaneously administered 10 and 20 μg of rhPTH(1–34) once daily for 7 consecutive days to assess the safety and tolerability parameters. Intake of water and food was identical to those of the single-dose phase. Study 2 had an open-label, randomized, singlecenter design to evaluate the pharmacodynamic and pharmacokinetic properties of rhPTH(1–34) after single- and multiple-dose subcutaneous administration into the thigh in healthy Chinese subjects. In the single-dose phase, 30 subjects (15 men and 15 women) were randomly allocated to 1 of 3 dose groups of 10, 20, and 40 μg (n ¼ 10; 5 men and 5 women in each group). Subjects were hospitalized at 10:00 PM the night before the study and fasted 10 hours before drug administration. At approximately 8:00 AM the next day, all subjects were subcutaneously administered the assigned dose of rhPTH(1–34) into the front of the thigh after they were given a standardized breakfast. A standard lunch (consisting of 200 g of cooked rice, 200 g of vegetables, 50 g of pork, and 50 mL of tomato soup) was provided at 4 hours after dosing. No other food was permitted during the study period. Vigorous physical activity, smoking, and alcohol- and caffeine-containing beverages were prohibited during the study. Sequential blood samples (3 mL each) were obtained before dosing (2, 1,

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Clinical Therapeutics and 0 hours) and at 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, and 240 minutes after dosing. Blood samples were drawn from an indwelling venous catheter placed in the arm after 1 mL of blood retained in the catheter was discarded. After blood sampling, 1 mL of normal saline was flushed into the catheter to prevent coagulation. The blood samples were collected in EDTAtreated Vacutainer tubes (Becton, Dickinson and Company, Franklin Lakes, New Jersey), and the tubes were inverted several times immediately after blood collection and placed promptly on ice. Within 30 minutes after collection, plasma was separated by centrifugation at 1000g for 10 minutes at 41C. Then 1 mL of plasma was mixed with 40 μL of protease inhibitors work solution and stored at 801C until analysis. The pharmacodynamic parameters analyzed were serum calcium and phosphate concentrations, which were measured by an automated clinical chemistry analyzer at the time points of 0 (predose), 1, 2, 4, and 24 hours after dosing. After the single-dose phase, subjects assigned to the 20-μg dose group in the single-dose phase continued into the multiple-dose phase, during which they were confined to the Phase I Clinical Research Unit. These subjects were subcutaneously administered 20 μg of rhPTH(1–34) once daily (at approximately 8:00 AM) for 7 consecutive days. This dose was selected for the multiple-dose phase because it was likely to be commonly used in clinical practice. Blood samples (3 mL each) were collected before daily dosing on days 5, 6, and 7 to determine the Cmin and Css. On day 7, blood samples were also drawn at 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, and 240 minutes after dosing the last dose of rhPTH(1–34). In addition, serum calcium and phosphate concentrations were analyzed at 96, 120, 144, and 168 hours after dosing. All other investigational conditions were identical to those of the single-dose phase.

Safety and Tolerability Assessments During the whole treatment period, all subjects were confined to the study unit and continuously monitored by the qualified physicians. Assessment of safety and tolerability parameters included vital signs, physical examination, routine laboratory examinations (urinalysis, hematologic tests, and biochemical analyses), and ECGs, which were performed before and after the study. Throughout the study, details of adverse experiences, such as dizziness, nausea,

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vomiting, upset stomach, somnolence, fatigue, skin hives, rash, itchy or swollen skin, and other unpleasant effects, were collected by nondirective questioning and/or spontaneous reporting and recorded by the study physicians. Particular attention was paid to observing the injection site reactions, which were evaluated at the time points of 0 (predose), 0.5, 1, 1.5, 2, 4, and 24 hours after dosing. In addition, vital signs (including blood pressure, heart rate, body temperature, and breathing rate) were assessed at 0.5, 1, 2, 4, 8, 12, and 24 hours after administration in the single-dose phase and daily before and after administration in the multiple-dose phase. ECG was also assessed at 0 (predose), 1, 4, 12, and 24 hours, respectively, after administration in the single-dose phase and before administration daily in the multipledose phase. The intensities of the AEs were categorized as mild, moderate, or severe, and the levels of the AE correlations to the investigational drug were rated as unrelated, suspected, possible, probable or likely, or certain, according to the criteria developed by the World Health Organization.

Measurement of Plasma rhPTH(1–34) Concentration Plasma concentrations of rhPTH(1–34) were specifically analyzed in Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China, using the radioimmunoassay method with a commercial kit (Rat PTH IRMA Kit; Immutopics Inc, San Clemente, California), which was a 2site immunoradiometric assay kit. Two different goat antibodies of the N-terminal region (1–34) of PTH were purified by affinity chromatography. One of the antibodies was immobilized onto plastic beads to capture the PTH molecules; the other one was radiolabeled for detection. Samples were incubated simultaneously with antibody-coated beads and the 125 I-labeled antibodies. N-terminal PTH(1–34) contained in the samples were immunologically bound by the immobilized antibodies and the radiolabeled antibodies to form sandwich complexes. The radioactivity of the antibody complex bound to the bead was directly proportional to the amount of PTH in the sample. The radioactivity bound to the bead was measured in an automatic gamma counter (1470 Wizard Gamma Counter; Pharmacia, Wallac Oy, Finland). Procedures were performed completely according to the instructions of the kit and the manufacturers.

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BMI ¼ body mass index. *Values are presented as mean (SD) unless otherwise indicated.

20 10 50 40 30 20 10

Sex, male/ 2/2 3/3 3/3 3/3 2/2 2/2 3/3 3/3 5/5 5/5 5/5 female, No. Age, y 23.3 (1.0) 23.3 (1.4) 23.5 (1.2) 23.8 (2.3) 23.5 (0.6) 23.0 (2.2) 23.3 (3.1) 23.7 (1.5) 23.2 (1.8) 23.9 (1.7) 23.2 (1.1) Height, cm 167.9 (5.2) 167.4 (10.4) 163.4 (5.5) 167.3 (8.8) 165.5 (6.6) 168.7 (11.1) 166.3 (7.8) 165.5 (4.4) 167.4 (8.6) 165.9 (9.9) 164.0 (7.9) Weight, kg 57.4 (3.4) 58.9 (9.7) 56.1 (4.9) 61.5 (8.5) 56.8 (4.9) 60.0 (9.7) 58.1 (7.3) 57.7 (3.6) 57.4 (6.3) 57.0 (8.2) 56.5 (7.9) 20.3 (0.1) 20.9 (1.1) 21.0 (1.4) 21.9 (1.4) 20.7 (0.9) 21.0 (1.4) 20.9 (1.2) 21.1 (1.1) 20.5 (1.1) 20.6 (0.8) 20.9 (1.4) BMI, kg/m2

A total of 72 healthy subjects (36 men and 36 women) were enrolled in this trial. All the subjects

Characteristic

RESULTS Study Population

Single Dose, μg

All statistical analyses were conducted using the SPSS software package, version 11.5 (SPSS Inc, Chicago, Illinois). The difference in pharmacokinetic parameters was defined as significant if P o 0.05. Analyses of tolerability and safety parameters included descriptive summaries of baseline characteristics, procedural data, and all other safety variables, including vital signs, AEs, ECGs, and clinical laboratory results. AE data were presented using percentages and frequencies. Pharmacokinetic parameters were summarized by dose group using descriptive statistics (arithmetic mean [SD] and median [range]). In the pharmacokinetic study, the characteristics of the linear pharmacokinetic parameters were evaluated by examining the AUC, Cmax, total clearance, and t½ as a function of the single dose. The values, which were obtained before and after dosing, were evaluated using the paired t test, and the variances among different groups were assessed using ANOVA.

Table I. Demographic characteristics of the study population.*

Statistical Analysis

Safety and Tolerability Study

60

The following pharmacokinetic parameters were calculated for each individual plasma concentration versus time data using noncompartmental methods with Drug and Statistics Software, version 2.1.1 (Mathematical Pharmacology Professional Committee of China, Shanghai, China): Cmax, Tmax, ke, AUC0–t, AUC0–1, t½, total clearance, and Vd. Individual pharmacokinetic parameters were calculated and then averaged.

20

Pharmacokinetic Analysis

10

Multiple Dose, μg

Pharmacokinetic Study Dose, μg

According to international guidelines,29 the analytic method for determining the concentration of rhPTH(1– 34) in human plasma was validated for the range of 13.1 to 3350 pg/mL with a lower limit of quantitation of 13.1 pg/mL. Intraday and interday precisions ranged from 6.8% to 11.5% and 13.3% to 14.4%, respectively. The accuracy, as expressed by the bias, ranged from 3.82% to 14.80%. The mean absolute recovery varied from 92.1% to 102.3%. In addition, rhPTH(1–34) in plasma was stable under different storage conditions (4 hours at room temperature and 90 days at 801C after 3 freeze-thaw cycles).

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Y. Liu et al.

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Clinical Therapeutics findings, hematologic findings, clinical chemical analysis results, and urinalysis results after administration of rhPTH(1–34) did not reveal any clinically relevant differences from the baseline values.

completed the study. The characteristics of the study population are summarized in Table I. There were no apparent differences in demographic characteristics (age, height, weight, and BMI) among different groups.

Pharmacokinetic Parameters Plasma concentration-time profiles of rhPTH(1–34) after single and multiple subcutaneous dosing are displayed in Figure 1 and Figure 2. The arithmetic means of the pharmacokinetic parameters of rhPTH (1–34) after single- and multiple-dose subcutaneous administrations are summarized in Table III and Table IV, respectively. In the single-dose phase, rhPTH(1–34) was rapidly absorbed, and the median Tmax values were 30, 20, and 30 minutes for the 10-, 20-, and 40-μg doses, respectively. The mean t½ values of rhPTH(1–34) ranged from 47.2 to 60.6 minutes. The median Tmax and mean t½ values were independent of the rhPTH (1–34) dose. The total clearance values were 0.86, 1.06, and 1.10 L/min for the 10-, 20-, and 40-μg doses, respectively. The mean Vd values were 56.8, 80.4, and 95.0 L for the 3 doses, respectively. No significant differences were found in t½, total clearance, or Vd among groups. When normalized to the 10-μg dose, the Cmax (134.0, 95.0, and 74.4 pg/mL, respectively), AUC0–240 (9345.5, 7873.8, and 8345.2 pg  min/mL, respectively), and AUC0–1 (11,770.4, 9651.4, and 9179.6 pg  min/mL, respectively) had

Tolerability and Safety Parameters In general, rhPTH(1–34) was well tolerated in the tested dose range (single subcutaneous doses of rhPTH[1–34] up to 60 μg and multiple subcutaneous doses of rhPTH[1–34] up to 20 μg once daily for 7 consecutive days). There were no serious AEs or study withdrawals. All AEs that occurred throughout the study are summarized in Table II. A total of 29 AEs were reported in 24 of the 72 subjects. The most commonly reported AEs were erythema at the injection site (in 83.3% of affected subjects) and gastrointestinal reactions (including nausea, inappetence, and vomiting in 33.3% of affected subjects). Except for one case of moderate erythema, which occurred in the 60-μg single-dose group of study 1, all the AEs were judged to be mild in intensity and resolved spontaneously without any medical intervention. The incidence of reported AEs appeared to be dose dependent. The injection site reactions of AEs, including erythema and soreness, were considered to be certainly related to rhPTH(1–34), whereas the other AEs were considered possibly related to the study drug. Assessments of physical examination findings, vital signs, ECG

Table II. Number of possible treatment-related adverse events at each dose level. Safety and Tolerability Study Multiple Dose, μg

Single Dose, μg Treatment

10 20

Subjects treated, No. Subjects with any event, No. (%) Events, No. (%) Injection site erythema Injection site soreness Nausea Inappetence Vomiting

4 6 0 0

6 6 4 4 6 6 10 10 10 3 (50.0) 5 (83.3) 4 (100.0) 3 (75.0) 0 1 (16.7) 0 1 (10.0) 7 (70.0)

0 0 0 0 0

2 (33.3) 4 (66.6) 4 (100.0) 3 (75.0) 0 0 0 0 1 (16.7) 1 (16.7) 1 (25.0) 0 1 (16.7) 0 0 0 0 1 (16.7) 1 (25.0) 0

6

0 0 0 0 0

30

40

50

60

10

20

Pharmacokinetic Study Dose, μg

0 0 0 1 (16.7) 0 1 (16.7) 0 0 0 0

10

20

40

0 0 7 (70.0) 0 0 0 0 0 0 0 1 (10.0) 0 0 0 0

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Y. Liu et al. good consistency across the dose range. Exposure to rhPTH(1–34) (Cmax and AUC0–1) was proportional to the dose in the range of 10 to 40 μg (r2 ¼ 0.9999 and 0.9988) (Figure 3). Pharmacokinetic parameters for rhPTH(1–34) after the multiple-dose phase were consistent with those derived from the single-dose phase. There were no significant differences in pharmacokinetic parameters after single and multiple doses. After single and multiple subcutaneous dosing, rhPTH(1–34) was quickly cleared from the plasma. Mean (SD) t½ values were 51.4 (13.8) minutes and 49.1 (12.6) minutes for the single and multiple dose, respectively, with no dose or time dependency. Because of its short t½, the concentrations of rhPTH(1–34) in plasma on days 5, 6, and 7 before dosing were undetectable. These findings indicated that there was no accumulation of rhPTH(1–34) with repeated doses.

350

Concentration (pg/mL)

300 10 μg 250

20 μg (Day 1)

200

40 μg 20 μg (Day 7)

150 100 50 0

0

40

80

120 160 Time (min)

200

240

Figure 1. Mean (SD) plasma concentration-time profile of recombinant human parathyroid hormone (1–34) (rhPTH[1–34]) after administration of single and multiple subcutaneous doses of rhPTH (1–34) (n ¼ 10).

300 Concentration (pg/mL)

Concentration (pg/mL)

250 200 150 100 50 0

0

40

80

120 160 Time (min)

200

150 100 50 0

40

80

0

40

80

120 160 Time (min)

200

240

250

350

Concentration (pg/mL)

Concentration (pg/mL)

200

0

240

400 300 250 200 150 100 50 0

250

0

40

80

120 160 Time (min)

200

240

200 150 100 50 0

120 160 Time (min)

200

240

Figure 2. Individual plasma concentration-time curves of recombinant human parathyroid hormone (1–34) (rhPTH[1–34]) after administration of single and multiple subcutaneous doses of rhPTH(1–34) (n ¼ 10). (A) Single-dose group of 10 μg; (B) single-dose group of 20 μg; (C) single-dose group of 40 μg; and (D) multiple-dose group of 20 μg.

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8

30 (20–45) 30 (20–45) 30 (20–45) 30.0 (15–60)

rhPTH(1–34) ¼ recombinant human parathyroid hormone (1–34). *Values are presented as mean (SD) except for Tmax, which is presented as median (range). † P o 0.05 versus women.

20 (15–20)† 30 (20–60) 20 (15–60) 20 (15–45)† 45 (30–60)

11,770.4 (1596.0) 11,327.7 (1337.9) 12,213.1 (1857.7) 19,302.7 (3099.3) 18,351.3 (3531.8) 20,074.1 (2766.2) 36,718.3 (3594.8) 35,610.6 (3057.2) 37,826.0 (4081.9)

80.4 (13.5) 76.6 (13.0) 84.1 (14.4) 95.0 (24.0) 97.5 (33.8) 92.6 (11.7) 15,747.6 (1880.0) 15,648.0 (2549.5) 15,847.2 (1194.9) 33,380.8 (2977.7) 32,332.2 (2519.9) 34,429.4 (3294.2) 60.7 (13.9) 8876.4 (664.5) 56.8 (13.6) 9345.5 (817.6)

52.9 (13.6) 9814.7 (715.6)

301.5 (36.5) 60.5 (8.8) 1.07 (0.11) 293.2 (34.1) 60.7 (21.5) 1.13 (0.10) 297.4 (33.6) 60.6 (15.5) 1.10 (0.11) 184.2 (54.7) 48.8 (10.2) 1.11 (0.20) 114.8 (11.7) 48.5 (17.1) 0.89 (0.10) 134.0 (32.9) 47.2 (16.6) 0.86 (0.12)

Cmax, pg/mL t½, min Total clearance, L/min Vd, L AUC0–240, pg  min/mL AUC0–1, pg  min/mL Tmax, min

153.1 (37.2) 46.0 (17.9) 0.83 (0.13)

190.0 (39.6) 51.4 (13.8) 1.06 (0.18)

195.9 (21.3) 59.4 (15.9) 1.02 (0.17)

Women All Subjects Women All Subjects

Women

The effects of sex on the pharmacokinetic parameters of rhPTH(1–34) were evaluated by pooling the data of single and multiple doses from all subjects. As indicated in Table III and Table IV, no significant differences between female and male subjects were observed in the pharmacokinetic parameters except for Tmax in the groups that received the 10- and 20-μg single dose. The mean Tmax values in females were slightly longer than the values obtained in males (45 vs 20 minutes in the 10-μg single-dose group, P ¼ 0.040; 30 vs 20 minutes in 20-μg single-dose group, P ¼ 0.049). Hence, no dose adjustment appears to be necessary according to the sex.

Pharmacodynamic Parameters

Parameter

Men

All Subjects

Men

40-μg Dose (n ¼ 10) 20-μg Dose (n ¼ 10) 10-μg Dose (n ¼ 10)

Table III. Pharmacokinetic parameters of rhPTH(1–34) after a single subcutaneous dose in healthy Chinese subjects.*

Men

Clinical Therapeutics

The mean values in serum calcium and phosphate concentrations after single- and multiple-dose subcutaneous administration of rhPTH(1–34) are given in Table V. None of the doses of rhPTH(1–34) administered in the single- and multiple-dose studies resulted in a significant increase of serum calcium level and an evident reduction of serum phosphate level. Furthermore, no apparent dose-dependent changes in the serum calcium and phosphate levels were observed.

DISCUSSION Unlike bisphosphonates and other approved antiresorptive agents, PTH, an 84–amino acid polypeptide, represents the first new class of anabolic agents.30,31 All of the in vivo biological actions of PTH are believed to reside in the N-terminal 34 amino acids.30 rhPTH(1–34) is identical to the N-terminal portion of the endogenous PTH with the similar pharmacologic activity.8 Various studies have reported that rhPTH (1–34) can improve bone mass and quality and directly stimulate bone formation, thereby significantly reducing fracture rates.8,10,32 To our knowledge, our studies are the first attempt to systematically investigate the tolerability, safety, pharmacodynamic, and pharmacokinetic parameters of rhPTH(1–34) after single and multiple subcutaneous doses in healthy Chinese male and female subjects. In these 2 studies, rhPTH(1–34) had an acceptable safety profile and was well tolerated in healthy male and female Chinese subjects at all the investigated dose levels. In the single-dose study, AEs did not limit dose escalation up to 60 μg. The maximum tolerated dose of rhPTH(1–34) was not

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Table IV. Pharmacokinetic parameters of rhPTH(1–34) after multiple subcutaneous dose administrations in healthy Chinese subjects.* 20-μg Dose (n ¼ 10) Parameter Cmax, pg/mL t½, min CL, L/min Vd, L AUC0–240, pg  min/mL AUC0–1, pg  min/mL Tmax, min

All Subjects 203.7 49.1 1.04 72.8 16,659.1 19,506.6 30

Women

(30.4) (12.6) (0.13) (15.6) (1715.1) (2220.9) (20–45)

214.9 53.9 0.97 74.3 17,182.5 20,741.1 30

Men

(12.8) (16.8) (0.08) (19.1) (1198.0) (1598.6) (20–45)

192.5 44.4 1.11 71.2 16,135.8 18,272.0 30

(40.1) (4.2) (0.14) (13.2) (2121.0) (2175.3) (20–45)

rhPTH(1–34) ¼ recombinant human parathyroid hormone (1–34). *Values are presented as mean (SD) except for Tmax, which is presented as median (range).

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A

45,000

AUC0–∞ = 837.19×Dose + 3062.6 r 2 = 0.9988

AUC0–∞ (pg•min/mL)

40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0

B

0

400

10

20 30 Dose (μg)

40

50

Cmax = 5.4356×Dose + 80.29 r 2 = 0.9999

350 300 Cmax (pg/mL)

reached after the subcutaneous administration of single doses of up to 60 μg or multiple doses of up to 20 μg once daily for 7 consecutive days. The most frequent AEs that might have been related to the study drug were mild gastrointestinal symptoms (nausea, inappetence, and vomiting) and mild erythema at the injection site, which had also been reported in the previously published studies.33–35 However, the incidence of erythema (27.8%) was higher than that in the previous studies (4.9%),35 which might be due to the different manufacturing techniques and excipients of rhPH(1–34) injection, as well as the different subcutaneous injection site. In addition, the test drug of rhPTH(1–34), an agent biosimilar to teriparatide, is not exactly the same as teriparatide, which might be another reason for the higher incidence of the erythema. The differences, which might make a significant difference to injection site erythema and would be of concern in the clinical practice, were likely to be as follows. The test drug was a sterile lyophilized powder supplied in a clear, colorless, glass vial, which contained 20 μg of rhPTH (1–34), whereas teriparatide used in previous research was supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge, which contained 250 μg/mL of rhPTH(1–34). The test drug needs to be dissolved in 0.5 mL of sterile water for injection before the subcutaneous administration,

250 200 150 100 50 0

0

10

20 30 Dose (μg)

40

50

Figure 3. Linear correlation between AUC0–1 (A) and Cmax (B) versus increasing doses of recombinant human parathyroid hormone (1–34) (n ¼ 10).

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Clinical Therapeutics

Table V. Mean (SD) serum calcium and phosphate concentrations after single- and multiple-dose subcutaneous administration of rhPTH(1–34).* Serum Total Calcium Concentration, mmol/L

Serum Total Phosphate Concentration, mmol/L

Time, h

10-μg Dose

20-μg Dose

40-μg Dose

10-μg Dose

20-μg Dose

40-μg Dose

0 0.5 1 2 4 24 96 120 144 168

2.27 2.28 2.16 2.20 2.22 2.42

2.31 2.29 2.18 2.21 2.22 2.24 2.32 2.31 2.26 2.26

2.30 2.23 2.22 2.25 2.25 2.25

1.20 1.09 1.00 0.92 0.98 1.19

1.12 0.98 0.98 1.09 0.97 1.10 1.20 1.33 1.30 1.11

1.09 1.09 1.07 1.13 1.04 1.09

(0.05) (0.04) (0.05) (0.08) (0.07) (0.06)

(0.07) (0.09) (0.06) (0.15) (0.07) (0.08) (0.09) (0.09) (0.06) (0.06)

(0.07) (0.07) (0.08) (0.11) (0.06) (0.06)

(0.16) (0.50) (0.16) (0.18) (0.16) (0.15)

(0.15) (0.15) (0.11) (0.11) (0.16) (0.13) (0.14) (0.13) (0.17) (0.08)

(0.12) (0.16) (0.13) (0.07) (0.12) (0.08)

*rhPTH(1–34) ¼ recombinant human parathyroid hormone (1–34).

whereas teriparatide could be administered directly. In addition, the dosing concentration of rhPTH(1–34) was lower in the present study than in the previous ones, which means the higher volume for injection was administered in our study. Thigh or abdomen was selected as the injection site in the previous studies, whereas only the thigh was chosen in the present study. Vital signs (including heart rate, body temperature, blood pressure, and respiratory rate) and ECG readings were not affected by rhPTH(1–34). During the studies, there were no serious or severe AEs, treatment-related withdrawal, or important medical events, suggesting that administration of rhPTH(1–34) at or below a once-daily dose of 20 μg might be appropriate for long-term treatment of patients with osteoporosis. These results were driven from healthy subjects; thus, further clinical studies for actual patients in various clinical settings are still required. In the single ascending dose study, concentrationtime profiles were similarly shaped regardless of dose, and plasma rhPTH(1–34) concentrations increased in a dose-dependent manner throughout the dose range studied. The pharmacokinetic parameters of rhPTH (1–34) behaved in a predictable manner, with Cmax and AUC increasing approximately dose proportionally with increasing dose; Tmax and t½ did not vary

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significantly with the different doses. These results suggest that none of the disposition processes were saturable in this tested dose range. Therefore, rhPTH (1–34) exhibited linear pharmacokinetic properties after single subcutaneous doses of 10, 20, and 40 μg, consistent with those reported for rhPTH(1–34) in white subjects.35,36 In a multiple-dose study, the pharmacokinetic properties were similar to those observed in the single-dose study. Because of its short t½ of approximately 1 hour, rhPTH(1–34) is not likely to accumulate over time with a typical once-daily subcutaneous dosage regimen. A double-peak phenomenon in the rhPTH(1–34) plasma concentration-time profile after subcutaneous administration was observed in nearly twothirds of the subjects at all treatment dose levels, with the first peak appearing approximately 5 to 20 minutes after dosing and the second peak appearing approximately 30 to 60 minutes after dosing. The same phenomenon was not reported in the previous pharmacokinetic studies,25,37 which may be attributable to the different injection sites or the different adjuvants and techniques of the formulation. However, the double-peak phenomenon was found in the pharmacokinetic parameters of rhPTH(1–84), as well as observed in its active metabolite rhPTH(1– 34).31,38 According to the published studies,31,38 this double-peak phenomenon in the plasma rhPTH

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Y. Liu et al. (1–84) concentrations probably indicated that the subcutaneously administered rhPTH(1–84) was released from the injection site into the systemic circulation at different rates. rhPTH(1–84) was also speculated to rapidly metabolized into various fragments and to maintain an equilibrium between rhPTH(1–84) and its metabolite rhPTH(1–34), which might result in the double peak. In the present study, Tmax and t½ were in good agreement with those values previously reported in white subjects.35–39 After subcutaneous injection, rhPTH(1–34) was rapidly absorbed and eliminated, with the maximum observed plasma concentration reached at approximately 30 minutes. The t½ was approximately 1 hour, whereas the true t½ of rhPTH (1–34) after intravenous injection was approximately 5 minutes, which reflected the time required for absorption from the injection site.40 The pharmacokinetic parameters, total clearance, and Vd were comparable to those of white healthy adult subjects.41,42 Comparison of overall exposure of the 20-μg single dose with white healthy subjects revealed that Cmax and AUC were 25.8% and 59.1% higher than the values in white subjects. These differences were likely due to different injection sites, assay methods, sample collection periods, and weights. Compared with the previous study,42 the mean (SD) weight of Chinese healthy subjects in the present study (57.0 [8.2] kg) was lower than that of white healthy subjects (68.0 [7.6] kg), which might result in the observed higher exposure in Chinese healthy subjects. Furthermore, the effects of sex on the pharmacokinetic parameters of rhPTH(1–34) were also evaluated. No significant difference was found in AUC, Cmax, t½, Vd, and total clearance between male and female subjects for all doses. The only exception was Tmax in the 10-μg and 20-μg single-dose groups. However, the P values, which were 0.040 and 0.049 for the 10-μg and 20-μg single-dose groups, respectively, were slightly o0.05. These significant differences might be due to the relatively small sample size. Accordingly, in clinical practice, dose adjustment of rhPTH(1–34) might be unnecessary for sex. As an essential regulator of calcium and phosphate metabolism, the roles of rhPTH(1–34) in mineral homeostasis are to increase serum calcium levels and decrease serum phosphate levels. The expected reduction

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in serum phosphate levels and increment in serum calcium levels were not observed in these studies, which may be due to methodologic issues, such as the limited number of subjects, healthy studied population, open-label design, inadequate treatment, or too few collection points. A 2-year prospective study indicated that endogenous intact PTH levels were suppressed rapidly and persistently by the exogenously administered rhPTH(1–34), which may be another important reason for such unexpected observations. In addition, serum calcium and phosphate levels also remained within the reference range without significant changes throughout this previous study.43 The lack of a study arm with teriparatide was a limitation of the present study. In future Phase II and Phase III clinical trials, researchers would need to compare the test drug with teriparatide in a larger Chinese patient population. This study was performed in healthy adults with normal weight. This limitation should be considered when extrapolating the results to an elderly population, children, or actual patients.

CONCLUSIONS The results of the present study indicated that rhPTH (1–34) was well tolerated in healthy Chinese female and male subjects in the evaluated single- and multiple-dose ranges with no serious AEs observed. After single subcutaneous dosing, rhPTH(1–34) exhibited predictable and linear pharmacokinetic parameters in the dose range of 10 to 40 μg. The main pharmacokinetic parameters did not differ between single and multiple subcutaneous doses. rhPTH(1–34) was rapidly eliminated from the plasma without accumulation after multiple doses. Sex appeared to have no significant effect on the pharmacokinetic characteristics of rhPTH(1–34). In healthy Chinese subjects, rhPTH(1–34) did not significantly change the serum calcium and phosphate levels.

ACKNOWLEDGEMENTS The authors would like to thank Dr. Ju Ming, Dr. Minghui Wu, and Dr. Qian Chen for their valuable suggestions. The authors would also like to thank the reviewers for their constructive comments. Yani Liu and Chunxiao Yang contributed to study design, data acquisition and analysis, manuscript draft. Yu Zhang and Yongning Lv conducted the literature search and

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Clinical Therapeutics assisted with the study design. Fandian Zeng contributed to data interpretation and writing assistance. Zhongfang Li and Jiali Zhou were involved in sample collection and provided bioanalysis monitoring and pharmacokinetic analysis. Shaojun Shi contributed to the conception and design of the study and proof reading of this article. All authors approved the final version of the manuscript.

CONFLICTS OF INTEREST This research was funded by Shanghai Shenjiu Medpharm Biotech Co, Ltd, Shanghai, China. The sponsor had no influence in the study design, conduct, monitoring, analysis, presentation, or publication of the results. There were no benefits from commercial sources for the work reported in this article. The authors would like to thank the subjects who participated in the study. The authors declare that they have no conflicts of interest.

REFERENCES 1. NHI Consensus Development Panel. Osteoporosis prevention, diagnosis and therapy. JAMA. 2001;285:785–795. 2. Xia WB, He SL, Xu L, et al. Rapidly increasing rates of hip fracture in Beijing, China. J Bone Miner Res. 2012;27:125– 129. 3. Nabanita S. Datta. Osteoporotic fracture and parathyroid hormone. World J Orthop. 2011;2:67–74. 4. Wang Y, Tao Y, Hyman ME, et al. Osteoporosis in China. Osteoporos Int. 2009;20:1651–1662. 5. Papapoulos S, Makras P. Selection of antiresorptive or anabolic treatments for postmenopausal osteoporosis. Nat Clin Pract Endocrinol Metab. 2008;4:514–523. 6. Cusano NE, Bilezikian JP. Combination anabolic and antiresorptive therapy for osteoporosis. Endocrinol Metab Clin North Am. 2012;41:643–654. 7. File E, Deal C. Clinical update on teriparatide. Curr Rheumatol Rep. 2009;11:169–176. 8. Cheng ML, Gupta V. Teriparatide: indications beyond osteoporosis. Indian J Endocrinol Metab. 2012;16:343–348. 9. Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol. 2011;8:81–91. 10. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–1441. 11. Prevrhal S, Krege JH, Chen P, et al. Teriparatide vertebral fracture risk reduction determined by quantitative and qualitative radiographic assessment. Curr Med Res Opin. 2009;25:921–928.

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12. Marcus R, Wang O, Satterwhite J, et al. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. J Bone Miner Res. 2003;18:18–23. 13. Cosman F, Lane NE, Bolognese MA, et al. Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 2010;95:151–158. 14. Sethi BK, Chadha M, Modi KD, et al. Efficacy of teriparatide in increasing bone mineral density in postmenopausal women with osteoporosis-an Indian experience. J Assoc Physicians India. 2008;56:418–424. 15. Jiang Y, Zhao JJ, Mitlak BH, et al. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18:1932–1941. 16. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357:2028–2039. 17. McClung MR, San Martin J, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med. 2005;165:1762– 1768. 18. Keaveny TM, Donley DW, Hoffmann PF, et al. Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis. J Bone Miner Res. 2007;22:149–157. 19. Lasco A, Catalano A, Morabito N, et al. Adrenal effects of teriparatide in the treatment of severe postmenopausal osteoporosis. Osteoporos Int. 2011;22:299–303. 20. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus alendronate for treating glucocorticoidinduced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 2009;60:3346–3355. 21. Michalska D, Luchavova M, Zikan V, et al. Effects of morning vs. evening teriparatide injection on bone mineral density and bone turnover markers in postmenopausal osteoporosis. Osteoporos Int. 2012;23:2885–2891. 22. Jones KO, Owusu-Ababio G, Vick AM, et al. Pharmacokinetics and hepatic extraction of recombinant human parathyroid hormone, hPTH (1–34), in rat, dog, and monkey. J Pharm Sci. 2006;95:2499–2506. 23. Hu Z, Niu H, Yang X, et al. Recombinant human parathyroid hormone 1–34: pharmacokinetics, tissue distribution and excretion in rats. Int J Pharm. 2006;317:144–154. 24. Serada M, Sakurai-Tanikawa A, Igarashi M, et al. The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatid eacetate in rats. Xenobiotica. 2012;42:398–407. 25. Chu NN, Li XN, Chen WL, et al. Pharmacokinetics and safety of recombinant human parathyroid hormone

Volume ] Number ]

Y. Liu et al.

26.

27.

28.

29.

30.

31.

32.

(1-34) (teriparatide) after single ascending doses in Chinese healthy volunteers. Pharmazie. 2007;62:869– 871. European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (49348/ 2005). London, UK: European Medicines Agency, Committee for Medicinal Products for Human Use; 2006. World Medical Association Declaration of Helsinki-ethical principles for medical research involving human subjects. http://www.wma.net/en/ 30publications/10policies/b3/index.html. Accessed May 4, 2013. European Medicine Agency. ICH Topic E 6 (R1): Guideline for Good Clinical practice. http://www.emea. europa.eu/pdfs/human/ich/ 013595en.pdf. Accessed May 4, 2013. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: bioanalytical method validation. May 2001. http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui dances/ucm070107.pdf. Accessed May 4, 2013. Bogado CE, Massari FE, Zanchetta JR. Parathyroid hormone (1–84) and teriparatide in the treatment of postmenopausal osteoporosis. Womens Health (Lond Engl). 2006;2: 447–457. Liu Y, Shi S, Wu J, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of recombinant human parathyroid hormone after single- and multiple-dose subcutaneous administration in healthy Chinese volunteers. Basic Clin Pharmacol Toxicol. 2012;110:154–161. Stroup J, Kane MP, Abu-Baker AM. Teriparatide in the treatment of osteoporosis. Am J Health Syst Pharm. 2008;65:532–539.

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33. Tashjian AH Jr, Gagel RF. Teriparatide [human PTH(1–34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res. 2006;21:354–365. 34. Shiraki M, Sugimoto T, Nakamura T. Effects of a single injection of teriparatide on bone turnover markers in postmenopausal women. Osteoporos Int. 2013;24:219–226. 35. Forteo (teriparatide) [package insert]. Indianapolis, IN: Eli Lilly and Co; 2004. 36. Cappuzzo KA, Delafuente JC. Teriparatide for severe osteoporosis. Ann Pharmacother. 2004;38:294–302. 37. Satterwhite J, Heathman M, Miller PD, et al. Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis. Calcif Tissue Int. 2010;87:485–492. 38. Schwietert HR, Groen EW, Sollie FA, Jonkman JH. Single-dose subcutaneous administration of recombinant human parathyroid hormone [rhPTH (1-84)] in healthy postmenopausal volunteers. Clin Pharmacol Ther. 1997;61:360–376.

39. Lindsay R, Nieves J, Henneman E, et al. Subcutaneous administration of the amino-terminal fragment of human parathyroid hormone-(1– 34): kinetics and biochemical response in estrogenized osteoporotic patients. J Clin Endocrinol Metab. 1993;77:1535–1539. 40. Fraher LJ, Klein K, Marier R, et al. Comparison of the pharmacokinetics of parenteral parathyroid hormone-(1–34) [PTH-(1–34)] and PTH-related peptide-(1–34) in healthy young humans. J Clin Endocrinol Metab. 1995;80:60–64. 41. Blick SK, Dhillon S, Keam SJ. Teriparatide: a review of its use in osteoporosis. Drugs. 2008;68:2709– 2737. 42. Tsujimoto M, Uenaka K, Iwata A, et al. Effects of teriparatide in Japanese and non-Japanese populations: bridging findings on pharmacokinetics and efficacy. J Bone Miner Metab. 2012;30:326–337. 43. Anastasilakis AD, Polyzos SA, Goulis DG, et al. Endogenous intact PTH is suppressed during teriparatide (rhPTH 1–34) administration in postmenopausal women with established osteoporosis. Endocr J. 2008;55:613–616.

Address correspondence to: Shaojun Shi, MD, Clinical Research Organization for Pharmaceutical Products, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, People’s Republic of China. E-mail: sjshicn@163. com

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