Pharmacokinetics of penicillin G in plasma and interstitial fluid
RESuLtS...RESuLtS Pharmacokinetics: • The mean plasma BA058 concentrations-time profilefollowing...
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PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUSLY (SC) ADMINISTERED DOSES OF BA058, A BONE MASS DENSITY RESTORING AGENT IN HEALTHY POSTMENOPAUSAL WOMEN M. Obaidi, PhD 1 , R. E. Chavira, MA 1 , L. Reinbolt, MS 1 , E. Offman, B.Sc. Pharm, MSc 2 , K. McKay 3 , and L. St. L. O’Dea, MB BCh BAO. FRCP(C) 3 1,2 Celerion, Lincoln, NE and Montreal, Canada, respectively 3 Radius Health Inc., Cambridge, MA OBJECTIVE • Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue which leads to enhanced fragility and increased risk of fractures. 1 • Normally, the process of bone turnover is a dynamic process consisting of bone mineralization and resorption. In addition to age, a number of underlying pathological mechanisms result in an imbalance in this process leading to the clinical sequelae of osteoporosis. • Current therapeutic options used in the treatment of osteoporosis include: - Estrogens - Selective estrogen receptor modulators (SERMs) - Calcitonin (salmon) - Bisphosphonates - Monoclonal Antibodies (e.g. denosumab) • A relatively new pharmacologic approach is the use of human parathyroid hormone (hPTH) and related analogues and peptides: - The 34-amino acid terminal fragment of hPTH, known as hPTH(1-34), appears to contain the full biological activity of native PTH(1-84) with regard to restoration of bone. 2 Teriparatide (Forteo ® ; Eli Lilly and Co., Indianapolis, Indiana), a recombinant human PTH (rhPTH(1-34)), was approved by the FDA in 2002 as a new therapy for osteoporosis. Teriparatide can stimulate bone formation, increase bone mass and reduce the risk of fractures. 3 - Human PTH-related peptide (hPTHrP) is related to the PTH family, is secreted endogenously, and is partially homologous with the sequence of hPTH at the amino-terminus, where 8 of the first 13 amino acids are identical in both peptides. 4 - hPTHrP has also been shown to have an important role in calcium homeostasis 4 , normal skeletal development 5 and to restore bone mass in people when administered in an intermittent pattern. 6 - BA058 is a 34-amino acid analog of hPTHrP (1-34) with molecular modifications of specific amino acids. - BA058 is expected to have similar or greater efficacy in restoring bone mineral density in individuals with osteoporosis than hPTH(1-34), but with less risk of causing hypercalcemia. Initial in vitro and in vivo studies identified BA058 as displaying such properties. 7-10 • The objective of the present investigation was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) of multiple doses of BA058 when given by sc injection to healthy postmenopausal women. METHODOLOGY • This was a randomized, double-blind, placebo-controlled, multiple-dose safety, tolerability, and PK/PD study of sc administered BA058 in healthy postmenopausal women, conducted at 2 sites. • A total of 39 eligible subjects were sequentially enrolled into 1 of 4 study groups (receiving 5, 20, 40, and 80 µg of BA058) consisting of 10 subjects each, with the exception of Group 2 which had only 9 subjects. Within each study group of 10 subjects, 8 were randomly assigned to receive BA058 and 2 were randomly assigned to receive placebo (Group 2 had only 1 placebo). All subjects received a single sc dose of study medication (BA058 or placebo) for 7 days. After a dose level had been determined to be well tolerated, subsequent cohorts of subjects were enrolled in the next study groups. • The demographic information of the subjects who were enrolled in the study is presented in Table 1. • Pharmacokinetic parameters (AUC 0-t , AUC 0-t ,C max ,T max ,T last , CL/F, k el ,t 1/2 , and accumulation index [AI]) were calculated from plasma BA058 data on Days 1 and 7 using WinNonlin ® Version.5.01 (Pharsight Corporation, Mountain View, CA). Moreover, AUC 0-∞ and ratio of AUC 0-t to AUC 0-∞ (AUCR) were computed for Day 1 and AI was computed for Day 7. • Dose proportionality of BA058 PK parameters (C max , AUC 0-∞ , AUC 0-t , and AUC 0-t ) was evaluated using the power model using PROC MIXED of SAS ® . Version 8.2 (SAS Institute Inc., Cary, NC). • Descriptive statistics for BA058 plasma concentrations and PK parameters and PD concentration data in serum (total and ionized calcium, phosphorus: PTH(1-84),1, 25-dihydroxyvitamin D [vitamin D], procollagen type 1 N-propeptide [P1NP-marker of bone formation], and C-telopeptide type 1 collagen [CTX- marker of bone resorption], and anti-BA058 antibody) and urine (calcium, phosphorus, cyclic AMP [c-AMP], and creatinine) were calculated using SAS ® . RESULTS Pharmacokinetics: • The mean plasma BA058 concentrations-time profile following BA058 doses are presented in Figure 1. • Plasma BA058 PK parameters following BA058 doses for Days 1 and 7 are summarized in Tables 2 and 3. • BA058 was characterized by a rapid absorption following sc administration with a mean C max occurring within approximately 1 hour postdose. • BA058 exhibited a short half-life with mean t 1/2 values of 1.05 to 2.59 hours. • Apparent clearance was 28.56 L/hr following the lowest dose (5 μg) and ranged from 82.74 L/hr to 103.9 L/hr following the 20, 40, and 80 μg doses. • The results indicated that exposure to BA058 was relatively comparable between Days 1 and 7 for each BA058 dose. • Mean AI values ranged from 0.844 to 1.12 following multiple dosing of BA058. Moreover, mean PK parameters values of T max ,t 1/2 , and CL/F were comparable between Days 1 and 7. • Dose proportionality was concluded for C max and AUC following the BA058 doses investigated (Table 4 and Figures 2 and 3. Note: AUC 0-∞ and AUC 0-t are presented as AUC 0-inf and AUC 0-tau , respectively in the figures). Pharmacodynamics: • Themeanbaseline-adjustedtotalandionizedcalcium,phosphorus:PTH(184),vitamin D, P1NP, and CTX following BA058 doses and placebo are presented in Figures 4 and 5. • The mean urinary excretion rate of calcium, phosphorus, c-AMP, and creatinine following BA058 doses and placebo are presented Figure 6. • Compared to placebo and predose levels, repeated sc administration of BA058 doses resulted in a small transient increase in serum calcium that remained within the normal laboratory ranges (normal range for total calcium: 8.4 to 10.4 mg/dL, normal range for ionized calcium: 1.11 to 1.37 mmol/L). • Serum phosphorus levels temporarily decreased following the sc administration of BA058 doses compared to placebo and predose levels (normal range: 2.6 to 4.7 mg/dL). • Consistent with physiological expectations, serum PTH (1-84) concentrations marginally and briefly decreased and vitamin D concentrations slightly increased following BA058 doses compared to placebo and predose levels. • Serum P1NP concentrations rose above baseline for all dose groups by Day 8 in an apparent but non-significant dose-dependent manner. • Serum CTX fluctuated around baseline values without any apparent dose- proportionality. • While mean urinary excretion rates of c-AMP increased immediately following BA058 administration; those of calcium, phosphorus, and creatinine generally stayed at the predose levels. • The majority of observed changes in the levels of PD markers in serum and urine were small in magnitude and remained within 1 SD of the mean. • No antibodies to BA058 were detected prior to or following the administration of BA058 or placebo doses. Figure 5:Mean Baseline-Adjusted PTH(1-84), P1NP, and CTX Following BA058 Doses and Placebo Figure 6: Mean Urinary Excretion Rate of Calcium, Phosphorus, c-AMP, and Creatinine Following BA058 and Placebo Figure 4: Mean Baseline-Adjusted Total and Ionized Calcium, Phosphorus and Vitamin D Following BA058 Doses and Placebo Table 4: Dose Proportionality Analysis of Plasma BA058 Following 5 μg Though 80 μg BA058 Doses Figure 3: Dose Proportionality Assessments of BA058 Doses –Day 7 Table 3: Summary of Plasma BA058 Pharmacokinetic Parameters Following 5 μg Through 80 μg BA058 Doses - Day 7 Figure 2: Dose Proportionality Assessments of BA058 Doses –Day 1 Table 2: Summary of Plasma BA058 Pharmacokinetic Parameters Following 5 μg Through 80 μg BA058 Doses - Day 1 Figure 1: Mean Plasma BA058 Concentrations Following BA058 Doses Table 1: Demographic Summary of Subjects Enrolled in the Current Investigation REFERENCES 1. Rizzoli R, Bonjour JP, and Ferrari SL. Osteoporosis, genetics and hormones. J Mol Endocrinol 2001; 26:79-94. 2. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, and Mitlak BH. 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. 3. Reeve J. Recombinant human parathyroid hormone. BMJ 2002; 324:435-436. 4. Strewler GJ, Nissenson RA. Parathyroid Hormone-Related Protein. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism . Chapter 14, Fourth Edition. Philadelphia: Lippincott, Williams and Wilkins, 1999. 5. Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, and Karaplis AC. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 2005; 115:2402-2411. 6. Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, and Stewart AF. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2003; 88:569-575. 7. Culler MD, Dong J, Shen Y, Taylor JE, Carlile L, Sullivan T, Batista I, Bonin P, Carlson M, Lauer J, Savola A, Kasprzyk P, Morgan BA, Fisch C, Becret A, Legrand J, and Woon CW. BIM44058, a novel analog of PTHrP with enhanced bone building activity, but decreased calcium mobilization potential. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S540. 8. Legrand J, Guillaumat P, Forster R, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, does not increase total plasma calcium in cynomolgus monkeys at an effective pharmacological dose. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S539. 9. Legrand J, Becret A, Fisch C, Attia M, de Jouffrey S, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, increases bone formation but not bone resorption histomorphometric parameters in old ovariectomized osteopenic cynomolgus monkeys. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S539. 10. Legrand J, Fisch C, Guillaumat P, de Jouffrey S, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, restores in vivo spinal bone mineral density in old ovariectomized osteopenic cynomolgus monkeys. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 Treat 5 μg 20 μg 40 μg 80 μg Pooled Active Pooled Placebo Total Gender Female 8 8 8 8 32 7 39 Race Black 1 3 0 0 4 0 4 Caucasian 4 3 8 8 23 7 30 Hispanic 3 2 0 0 5 0 5 Frame Size Small 2 1 1 0 4 0 4 Medium 5 7 4 8 24 5 29 Large 1 0 3 0 4 2 6 Treatment A Treatment B Treatment C Treatment D Pharmacokinetic Parameters Mean± SD (N) Mean± SD (N) Mean± SD (N) Mean± SD (N) C max (pg/mL) 43.1 ± 10.7 115 ± 53.9 223 ± 99.0 310 ± 54.3 (7) (8) (8) (8) T max (hr) # 0.566 (0.531, 1.00) 0.296 (0.250, 0.624) 0.494 (0.262, 0.579) 0.752 (0.251, 1.01) (7) (8) (8) (8) T last (hr) # 2.01 (1.50, 4.00) 2.01 (1.00, 4.00) 4.00 (1.51, 6.01) 7.00 (4.00, 12.0) (7) (8) (8) (8) AUC 0-t (pg*hr/mL) 78.439 ± 45.472 160.52 ± 110.83 419.89 ± 275.15 949.89 ± 493.58 (7) (8) (8) (8) AUC 0- ∞ (pg*hr/mL) 187.36 ± 54.536 257.17 ± 119.05 592.94 ± 281.40 1055.6 ± 513.61 (4) (5) (6) (8) AUC 0- τ (pg*hr/mL) 186.92 ± 54.397 257.16 ± 119.02 592.90 ± 281.37 1053.2 ± 511.27 (4) (5) (6) (8) t 1/2 (hr) 2.59 ± 0.690 1.05 ± 0.314 1.65 ± 0.254 2.30 ± 0.715 (4) (5) (6) (8) k el (1/hr) 0.282 ± 0.0722 0.713 ± 0.229 0.428 ± 0.0603 0.335 ± 0.127 (4) (5) (6) (8) AUCR 0.521 ± 0.111 0.828 ±0.0449 0.838 ± 0.0703 0.892 ± 0.0369 (4) (5) (6) (8) CL/F (L/hr) 28.56 ± 8.727 94.20 ± 46.04 84.15 ± 46.04 94.61 ± 51.09 #= T max and T last are presented as Median(Minimum,Maximum) Treatment A Treatment B Treatment C Treatment D Pharmacokinetic Parameters Mean± SD (N) Mean± SD (N) Mean± SD (N) Mean± SD (N) C max (pg/mL) 40.8 ± 7.63 109 ± 19.2 207 ± 77.7 436 ± 68 .8 (6) (8) (8) (8) T max (hr) # 1.05 (0.514, 1.53) 0.512 (0.250, 3.05) 0.492 (0.349, 1.00) 0.507 (0.500, 1.00) (6) (8) (8) (8) T last (hr) # 2.53 (1.50, 4.08) 3.00 (1.11, 4.00) 3.49 (2.00, 8.02) 6.00 (4.00, 8.02) (6) (8) (8) (8) AUC 0-t (pg*hr/mL) 80.704 ± 30.441 171.58 ± 82.031 407.98 ± 219.70 1003.0 ± 383.45 (6) (8) (8) (8) AUC 0- τ (pg*hr/mL) NC 228.20 ± 95.154 481.88 ± 226.19 1080.3 ± 408.57 (0) (6) (8) (8) t 1/2 (hr) NC 1.05 ± 0.244 1.43 ± 0.397 1.69 ± 0.425 (0) (6) (8) (8) k el (1/hr) NC 0.694 ± 0.165 0.527 ± 0.192 0.437 ± 0.124 (0) (6) (8) (8) CL/F (L/hr) NC 103.9 ± 53.01 102.0 ± 53.34 82.74 ± 26.95 (0) (6) (8) (8) AI NC 1.10 ± 0.369 0.844 ± 0.0673 1.12± 0.353 (0) (5) (6) (8) # =T max and T last are presented as Median (Minimum,Maximum) NC= Not calculable Day Pharmacokinetic Parameters Slope Standard Error 95% CI 1 C max 0.77861 0.1375 (0.4935, 1.0637) AUC 0-t 0.90714 0.1237 (0.6542, 1.1600) AUC 0-∞ 0.99565 0.2024 (0.5685, 1.4228) 7 C max 0.99804 0.0985 (0.7938, 1.2023) AUC 0- τ 1.14127 0.1649 (0.7974, 1.4852) A: 5 ug BA058 B: 20 ug BA058 C: 40 ug BA058 D: 80 ug BA058 Day 1 Day 7 Plasma BA058 Concentration (pg/mL) 0 50 100 150 200 250 300 350 400 450 500 550 Time (hr) 0 4 8 12 16 20 24 48 72 96 120 144 148 152 156 160 164 168 172 Plasma BA058 Pharmacokinetic Parameter ln(Cmax) Versus ln(Dose) - Day 1 ln(Cmax) = ( 0.732 * ln(Dose) ) + 2.537 ln(Cmax) 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 ln(Dose) 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Plasma BA058 Pharmacokinetic Parameter ln[AUC(0-t)] Versus ln(Dose) - Day 1 ln[AUC(0-t)] = ( 0.907 * ln(Dose) ) + 2.529 ln[AUC(0-t)] 3 4 5 6 7 8 ln(Dose) 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Plasma BA058 Pharmacokinetic Parameter ln[AUC(0-inf)] Versus ln(Dose) - Day 1 ln[AUC(0-inf)] = ( 0.64 * ln(Dose) ) + 3.925 ln[AUC(0-inf)] 4 5 6 7 8 ln(Dose) 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Plasma BA058 Pharmacokinetic Parameter ln(Cmax) Versus ln(Dose) - Day 7 ln(Cmax) = ( 0.847 * ln(Dose) ) + 2.238 ln(Cmax) 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 ln(Dose) 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Plasma BA058 Pharmacokinetic Parameter ln[AUC(0-tau)] Versus ln(Dose) - Day 7 ln[AUC(0-tau)] = ( 1.141 * ln(Dose) ) + 1.906 ln[AUC(0-tau)] 4 5 6 7 8 ln(Dose) 1.5 2.0 2.5 3.0 3.5 4.0 4.5 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo Total Serum Calcium Baseline-Adjusted Total Serum Calcium Concentration (mg/dL) Day 1 Day 7 Hours Hours -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Serum Ionized Calcium Baseline-Adjusted Serum Ionized Calcium Concentration (mmol/L) Day 1 Day 7 Hours Hours -0.05 -0.03 -0.01 0.01 0.03 0.05 0.07 0.09 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Serum Phosphorus Baseline-Adjusted Serum Phosphorus Concentration (mg/dL) Day 1 Day 7 Hours Hours -0.8 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Serum 1,25 dihydroxyvitamin D Baseline-Adjusted Serum 1,25 dihydroxyvitamin D Concentration (pg/mL) Day 1 Day 7 Hours Hours -20 -10 0 10 20 30 40 50 0 4 8 12 16 20 24 0 4 8 12 16 20 24 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo Serum PTH1-84 Baseline-Adjusted Serum PTH1-84 Concentration (pg/mL) Day 1 Day 7 Hours Hours -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Serum Procollagen type 1 N-propeptide (P1NP) Baseline-Adjusted Serum Procollagen type 1 N-propeptide (P1NP) Concentration (ng/mL) Days -10 -5 0 5 10 15 20 25 30 -2 3 8 14 Serum C-telopeptide type 1 collagen (CTX) Baseline-Adjusted Serum C-telopeptide type 1 collagen (CTX) Concentration (ng/mL) Days -0.20 -0.15 -0.10 -0.05 0.00 0.05 0.10 0.15 0.20 0.25 -2 3 8 14 -21 -15 -6 3 9 18 3 9 18 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo -21 -15 -6 3 9 18 3 9 18 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo -21 -15 -6 3 9 18 3 9 18 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo -21 -15 -6 3 9 18 3 9 18 A: Administration of a Single SC Dose of 5 ug BA058 for Seven Days B: Administration of a Single SC Dose of 20 ug BA058 for Seven Days C: Administration of a Single SC Dose of 40 ug BA058 for Seven Days D: Administration of a Single SC Dose of 80 ug BA058 for Seven Days P: Placebo Calcium Urinary Excretion of Calcium (mg/hr) Day 1 Day 7 Time (hr)# # Time presented as midpoint of collection interval using nominal elapsed time from most recent dose. 2 4 6 8 10 12 14 Phosphorus Urinary Excretion of Phosphorus (mg/hr) Day 1 Day 7 Time (hr)# # Time presented as midpoint of collection interval using nominal elapsed time from most recent dose. 10 20 30 40 50 60 70 Cyclic AMP Urinary Excretion of Cyclic AMP (μmol/hr) Day 1 Day 7 Time (hr)# # Time presented as midpoint of collection interval using nominal elapsed time from most recent dose. 0.05 0.10 0.15 0.20 0.25 Creatinine Urinary Excretion of Creatinine (mg/hr) Day 1 Day 7 Time (hr)# # Time presented as midpoint of collection interval using nominal elapsed time from most recent dose. 30 40 50 60
Transcript of RESuLtS...RESuLtS Pharmacokinetics: • The mean plasma BA058 concentrations-time profilefollowing...
Pharmacokinetics and Pharmacodynamics of subcutaneously (sc) administered doses of ba058, a bone mass density restoring agent in healthy PostmenoPausal Women
M. Obaidi, PhD1, R. E. Chavira, MA1, L. Reinbolt, MS1, E. Offman, B.Sc. Pharm, MSc2 , K. McKay3, and L. St. L. O’Dea, MB BCh BAO. FRCP(C)3 1,2Celerion, Lincoln, NE and Montreal, Canada, respectively 3Radius Health Inc., Cambridge, MA
OBjECtIvE • Osteoporosisisasystemicskeletaldiseasecharacterizedbylowbonemass
andmicroarchitecturaldeteriorationofbonetissuewhichleadstoenhancedfragilityandincreasedriskoffractures.1
• Normally, the process of bone turnover is a dynamic process consisting ofbonemineralizationandresorption.Inadditiontoage,anumberofunderlyingpathological mechanisms result in an imbalance in this process leading to the clinical sequelae of osteoporosis.
• Currenttherapeuticoptionsusedinthetreatmentofosteoporosisinclude:- Estrogens- Selective estrogen receptor modulators (SERMs)- Calcitonin (salmon)- Bisphosphonates- Monoclonal Antibodies (e.g. denosumab)
• A relatively new pharmacologic approach is the use of human parathyroidhormone(hPTH)andrelatedanaloguesandpeptides:- The 34-amino acid terminal fragment of hPTH, known as hPTH(1-34),
appearstocontainthefullbiologicalactivityofnativePTH(1-84)withregardto restoration of bone.2 teriparatide (Forteo®; Eli Lilly and Co., Indianapolis, Indiana),arecombinanthumanPTH(rhPTH(1-34)),wasapprovedbytheFDAin2002asanewtherapyforosteoporosis.Teriparatidecanstimulateboneformation,increasebonemassandreducetheriskoffractures.3
- Human PtH-related peptide (hPtHrP) is related to the PtH family, is secreted endogenously,and ispartiallyhomologouswiththesequenceofhPTHattheamino-terminus,where8ofthefirst13aminoacidsareidenticalinbothpeptides.4
- hPTHrPhasalsobeenshowntohaveanimportantroleincalciumhomeostasis4, normal skeletal development5 and to restore bonemass in peoplewhenadministered in an intermittent pattern.6
- BA058isa34-aminoacidanalogofhPTHrP(1-34)withmolecularmodificationsofspecificaminoacids.
- BA058isexpectedtohavesimilarorgreaterefficacyinrestoringbonemineraldensityinindividualswithosteoporosisthanhPTH(1-34),butwithlessrisk of causing hypercalcemia. Initial in vitro and in vivo studies identified BA058 as displaying such properties.7-10
• Theobjectiveofthepresentinvestigationwastoevaluatethepharmacokinetic(PK)andpharmacodynamic(PD)ofmultipledosesofBA058whengivenbyscinjectiontohealthypostmenopausalwomen.
MEtHODOLOGY• Thiswas a randomized, double-blind, placebo-controlled,multiple-dose safety,
tolerability,andPK/PDstudyofscadministeredBA058inhealthypostmenopausalwomen,conductedat2sites.
• Atotalof39eligiblesubjectsweresequentiallyenrolledinto1of4studygroups(receiving 5, 20, 40, and 80 µg ofBA058) consisting of 10 subjects each,withtheexceptionofGroup2whichhadonly9subjects.Withineachstudygroupof10subjects,8were randomlyassigned to receiveBA058and2were randomlyassignedtoreceiveplacebo(Group2hadonly1placebo).Allsubjectsreceivedasinglescdoseofstudymedication(BA058orplacebo)for7days.Afteradoselevelhadbeendeterminedtobewelltolerated,subsequentcohortsofsubjectswereenrolledinthenextstudygroups.
• Thedemographic informationof the subjectswhowereenrolled in the study ispresentedinTable1.
• Pharmacokinetic parameters (AUC0-t, AUC0-t, Cmax, Tmax, Tlast, CL/F, kel, t1/2, andaccumulationindex[AI])werecalculatedfromplasmaBA058dataonDays1and7 using WinNonlin® Version.5.01 (Pharsight Corporation, Mountain View, CA).Moreover,AUC0-∞andratioofAUC0-ttoAUC0-∞(AUCR)werecomputedforDay1andAIwascomputedforDay7.
• DoseproportionalityofBA058PKparameters (Cmax,AUC0-∞,AUC0-t,andAUC0-t)wasevaluatedusingthepowermodelusingPROCMIXEDofSAS®.Version8.2(SASInstituteInc.,Cary,NC).
• Descriptive statistics for BA058 plasma concentrations and PK parametersand PD concentration data in serum (total and ionized calcium, phosphorus:PTH(1-84),1,25-dihydroxyvitaminD[vitaminD],procollagentype1N-propeptide[P1NP-markerofboneformation],andC-telopeptidetype1collagen[CTX-markerof bone resorption], and anti-BA058 antibody) and urine (calcium, phosphorus,cyclicAMP[c-AMP],andcreatinine)werecalculatedusingSAS®.
RESuLtSPharmacokinetics:
• ThemeanplasmaBA058concentrations-timeprofilefollowingBA058dosesarepresentedinFigure1.
• PlasmaBA058PKparametersfollowingBA058dosesforDays1and7aresummarizedinTables2and3.
• BA058wascharacterizedbyarapidabsorptionfollowingscadministrationwithameanCmaxoccurringwithinapproximately1hourpostdose.
• BA058exhibitedashorthalf-lifewithmeant1/2valuesof1.05to2.59hours.
• Apparentclearancewas28.56L/hrfollowingthelowestdose(5μg)andrangedfrom82.74L/hrto103.9L/hrfollowingthe20,40,and80μgdoses.
• TheresultsindicatedthatexposuretoBA058wasrelativelycomparablebetweenDays1and7foreachBA058dose.
• MeanAI values ranged from0.844 to 1.12 followingmultiple dosing ofBA058.Moreover,meanPKparameters values of Tmax, t1/2, andCL/Fwere comparablebetweenDays1and7.
• DoseproportionalitywasconcludedforCmaxandAUCfollowingtheBA058dosesinvestigated(Table4andFigures2and3.Note:AUC0-∞andAUC0-tarepresentedasAUC0-infandAUC0-tau,respectivelyinthefigures).
Pharmacodynamics:
• Themeanbaseline-adjustedtotalandionizedcalcium,phosphorus:PTH(184),vitaminD,P1NP,andCTXfollowingBA058dosesandplaceboarepresentedinFigures4and5.
• Themeanurinaryexcretion rateofcalcium,phosphorus,c-AMP,andcreatininefollowingBA058dosesandplaceboarepresentedFigure6.
• Comparedtoplaceboandpredose levels, repeatedscadministrationofBA058dosesresultedinasmalltransientincreaseinserumcalciumthatremainedwithinthenormallaboratoryranges(normalrangefortotalcalcium:8.4to10.4mg/dL,normalrangeforionizedcalcium:1.11to1.37mmol/L).
• SerumphosphoruslevelstemporarilydecreasedfollowingthescadministrationofBA058dosescomparedtoplaceboandpredoselevels(normalrange:2.6to4.7mg/dL).
• Consistent with physiological expectations, serum PTH (1-84) concentrationsmarginallyandbrieflydecreasedandvitaminDconcentrationsslightlyincreasedfollowingBA058dosescomparedtoplaceboandpredoselevels.
• SerumP1NPconcentrationsroseabovebaselineforalldosegroupsbyDay8inanapparentbutnon-significantdose-dependentmanner.
• Serum CTX fluctuated around baseline values without any apparent dose-proportionality.
• Whilemeanurinaryexcretionratesofc-AMPincreasedimmediatelyfollowingBA058administration;thoseofcalcium,phosphorus,andcreatininegenerallystayedatthepredoselevels.
• ThemajorityofobservedchangesinthelevelsofPDmarkersinserumandurineweresmallinmagnitudeandremainedwithin1SDofthemean.
• NoantibodiestoBA058weredetectedpriortoorfollowingtheadministrationofBA058orplacebodoses.
Figure5:MeanBaseline-AdjustedPTH(1-84),P1NP,andCTXFollowing BA058 Doses and Placebo
Figure6:MeanUrinaryExcretionRateofCalcium,Phosphorus, c-AMP,andCreatinineFollowingBA058andPlacebo
Figure4:MeanBaseline-AdjustedTotalandIonizedCalcium,PhosphorusandVitaminDFollowingBA058DosesandPlacebo
Table4: DoseProportionalityAnalysisofPlasmaBA058Following5μgThough80μgBA058Doses
Figure3:DoseProportionalityAssessmentsofBA058Doses–Day7Table3: SummaryofPlasmaBA058PharmacokineticParametersFollowing
5μgThrough80μgBA058Doses-Day7
Figure2:DoseProportionalityAssessmentsofBA058Doses–Day1
Table2: SummaryofPlasmaBA058PharmacokineticParametersFollowing 5μgThrough80μgBA058Doses-Day1
Figure1:MeanPlasmaBA058ConcentrationsFollowingBA058DosesTable1: DemographicSummaryofSubjectsEnrolledintheCurrentInvestigation
REFERENCES1. Rizzoli R, Bonjour JP, and Ferrari SL. Osteoporosis, genetics and hormones. J Mol Endocrinol 2001;
26:79-94.
2. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, and Mitlak BH. 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.
3. Reeve J. Recombinant human parathyroid hormone. BMJ 2002; 324:435-436.
4. Strewler GJ, Nissenson RA. Parathyroid Hormone-Related Protein. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Chapter 14, Fourth Edition. Philadelphia: Lippincott, Williams and Wilkins, 1999.
5. Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, Su H, Tong X, Amizuka N, Gupta A, Genant HK, Kronenberg HM, Goltzman D, and Karaplis AC. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 2005; 115:2402-2411.
6. Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, and Stewart AF. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2003; 88:569-575.
7. Culler MD, Dong J, Shen Y, Taylor JE, Carlile L, Sullivan T, Batista I, Bonin P, Carlson M, Lauer J, Savola A, Kasprzyk P, Morgan BA, Fisch C, Becret A, Legrand J, and Woon CW. BIM44058, a novel analog of PTHrP with enhanced bone building activity, but decreased calcium mobilization potential. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S540.
8. Legrand J, Guillaumat P, Forster R, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, does not increase total plasma calcium in cynomolgus monkeys at an effective pharmacological dose. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S539.
9. Legrand J, Becret A, Fisch C, Attia M, de Jouffrey S, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, increases bone formation but not bone resorption histomorphometric parameters in old ovariectomized osteopenic cynomolgus monkeys. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16 (suppl.1):S539.
10. Legrand J, Fisch C, Guillaumat P, de Jouffrey S, Dong JZ, Woon CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, restores in vivo spinal bone mineral density in old ovariectomized osteopenic cynomolgus monkeys. Twenty third Annual Meeting of the American Society of Bone and Mineral Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16
Treat 5 µg 20 µg 40 µg 80 µg PooledActive
PooledPlacebo
Total
Gender Female 8 8 8 8 32 7 39
Race Black 1 3 0 0 4 0 4Caucasian 4 3 8 8 23 7 30Hispanic 3 2 0 0 5 0 5
Frame Size Small 2 1 1 0 4 0 4Medium 5 7 4 8 24 5 29Large 1 0 3 0 4 2 6
Treatment A Treatment B Treatment C Treatment DPharmacokinetic
ParametersMean± SD
(N)Mean± SD
(N)Mean± SD
(N)Mean± SD
(N)Cmax (pg/mL) 43.1 ± 10.7 115 ± 53.9 223 ± 99.0 310 ± 54.3
(7) (8) (8) (8)Tmax (hr) # 0.566 (0.531, 1.00) 0.296 (0.250, 0.624) 0.494 (0.262, 0.579) 0.752 (0.251, 1.01)
(7) (8) (8) (8)
Tlast (hr)# 2.01 (1.50, 4.00) 2.01 (1.00, 4.00) 4.00 (1.51, 6.01) 7.00 (4.00, 12.0)(7) (8) (8) (8)
AUC0-t (pg*hr/mL) 78.439 ± 45.472 160.52 ± 110.83 419.89 ± 275.15 949.89 ± 493.58(7) (8) (8) (8)
AUC0-∞ (pg*hr/mL) 187.36 ± 54.536 257.17 ± 119.05 592.94 ± 281.40 1055.6 ± 513.61(4) (5) (6) (8)
AUC0-τ (pg*hr/mL) 186.92 ± 54.397 257.16 ± 119.02 592.90 ± 281.37 1053.2 ± 511.27(4) (5) (6) (8)
t1/2 (hr) 2.59 ± 0.690 1.05 ± 0.314 1.65 ± 0.254 2.30 ± 0.715(4) (5) (6) (8)
kel (1/hr) 0.282 ± 0.0722 0.713 ± 0.229 0.428 ± 0.0603 0.335 ± 0.127(4) (5) (6) (8)
AUCR 0.521 ± 0.111 0.828 ±0.0449 0.838 ± 0.0703 0.892 ± 0.0369(4) (5) (6) (8)
CL/F (L/hr) 28.56 ± 8.727 94.20 ± 46.04 84.15 ± 46.04 94.61 ± 51.09# = Tmax and Tlast are presented as Median(Minimum,Maximum)
Treatment A Treatment B Treatment C Treatment DPharmacokinetic
ParametersMean± SD
(N)Mean± SD
(N)Mean± SD
(N)Mean± SD
(N)Cmax (pg/mL) 40.8 ± 7.63 109 ± 19.2 207 ± 77.7 436 ± 68.8
(6) (8) (8) (8)Tmax (hr) # 1.05 (0.514, 1.53) 0.512 (0.250, 3.05) 0.492 (0.349, 1.00) 0.507 (0.500, 1.00)
(6) (8) (8) (8)Tlast (hr)# 2.53 (1.50, 4.08) 3.00 (1.11, 4.00) 3.49 (2.00, 8.02) 6.00 (4.00, 8.02)
(6) (8) (8) (8)AUC0-t (pg*hr/mL) 80.704 ± 30.441 171.58 ± 82.031 407.98 ± 219.70 1003.0 ± 383.45
(6) (8) (8) (8)AUC0-τ (pg*hr/mL) NC 228.20 ± 95.154 481.88 ± 226.19 1080.3 ± 408.57
(0) (6) (8) (8)t1/2 (hr) NC 1.05 ± 0.244 1.43 ± 0.397 1.69 ± 0.425
(0) (6) (8) (8)kel (1/hr) NC 0.694 ± 0.165 0.527 ± 0.192 0.437 ± 0.124
(0) (6) (8) (8)CL/F (L/hr) NC 103.9 ± 53.01 102.0 ± 53.34 82.74 ± 26.95
(0) (6) (8) (8)AI NC 1.10 ± 0.369 0.844 ± 0.0673 1.12± 0.353
(0) (5) (6) (8)# = Tmax and Tlast are presented as Median (Minimum,Maximum)NC= Not calculable
DayPharmacokinetic
Parameters SlopeStandardError 95%CI
1 Cmax 0.77861 0.1375 (0.4935, 1.0637)
AUC0-t 0.90714 0.1237 (0.6542, 1.1600)
AUC0-∞ 0.99565 0.2024 (0.5685, 1.4228)
7 Cmax 0.99804 0.0985 (0.7938, 1.2023)
AUC0-τ 1.14127 0.1649 (0.7974, 1.4852)
A: 5 ug BA058B: 20 ug BA058C: 40 ug BA058D: 80 ug BA058
Day 1 Day 7
Pla
sma
BA
058
Con
cent
ratio
n (p
g/m
L)
0
50
100
150
200
250
300
350
400
450
500
550
Time (hr)0 4 8 12 16 20 24 48 72 96 120 144 148 152 156 160 164 168 172
Plasma BA058 Pharmaco k ine t ic Pa ramet er ln(Cmax) Versus ln(Do se) - Day 1
ln(Cmax) = ( 0 .732 * ln(Do se) ) + 2 .537
ln(C
max
)
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
ln(Do se)
1.5 2.0 2.5 3.0 3.5 4.0 4.5
P lasma BA058 Pharmaco kine t ic Pa ramet er ln[AUC(0- t ) ] Versus ln(Do se) - Day 1
ln[ AU C ( 0 - t ) ] = ( 0 .907 * ln( Do se ) ) + 2 .529
ln[A
UC
(0-t)
]
3
4
5
6
7
8
ln(Do se)
1.5 2.0 2.5 3.0 3.5 4.0 4.5
P lasma BA058 Pharmaco kine t ic Pa ramet er ln[AUC(0- inf) ] Versus ln(Do se) - Day 1
ln[AU C ( 0 - inf) ] = ( 0 .64 * ln( Do se ) ) + 3 .925
ln[A
UC
(0-in
f)]
4
5
6
7
8
ln(Do se)
1.5 2.0 2.5 3.0 3.5 4.0 4.5
Plasma BA058 Pharmacokinet ic Parameter ln(Cmax) Versus ln(Dose) - Day 7
ln(Cmax) = ( 0 .847 * ln(Do se) ) + 2 .238
ln(C
max
)
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
ln(Do se)
1.5 2.0 2.5 3.0 3.5 4.0 4.5
Plasma BA058 Pharmacokinet ic Parameter ln[AUC(0-tau)] Versus ln(Dose) - Day 7
ln[AUC(0- t au) ] = ( 1 .141 * ln(Do se) ) + 1 .90 6
ln[A
UC
(0-ta
u)]
4
5
6
7
8
ln(Do se)
1.5 2.0 2.5 3.0 3.5 4.0 4.5
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a Single SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a Single SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
To tal Serum Calcium
Bas
elin
e-A
djus
ted
Tota
l Ser
um C
alci
umC
once
ntra
tion
(mg/
dL)
Day 1 Day 7
Hours Hours
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Serum Ionized Calcium
Bas
elin
e-A
djus
ted
Seru
m Io
nize
d C
alci
umC
once
ntra
tion
(mm
ol/L
)
Day 1 Day 7
Hours Hours
-0.05
-0.03
-0.01
0.01
0.03
0.05
0.07
0.09
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Serum Pho spho rus
Bas
elin
e-A
djus
ted
Seru
m P
hosp
horu
sC
once
ntra
tion
(mg/
dL)
Day 1 Day 7
Hours Hours
-0.8
-0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Serum 1,25 dihydroxyvitamin D
Bas
elin
e-A
djus
ted
Seru
m 1
,25
dihy
drox
yvita
min
DC
once
ntra
tion
(pg/
mL)
Day 1 Day 7
Hours Hours
-20
-10
0
10
20
30
40
50
0 4 8 12 16 20 24 0 4 8 12 16 20 24
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a Single SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ ra t ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ rat ion o f a Single SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
Serum PTH1-84
Bas
elin
e-A
djus
ted
Seru
m P
TH1-
84C
once
ntra
tion
(pg/
mL)
Day 1 Day 7
Hours Hours
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Se rum Pro co llagen t ype 1 N-pr o pep t ide (P1NP)
Bas
elin
e-A
djus
ted
Seru
m P
roco
llage
n ty
pe 1
N-p
rope
ptid
e(P
1NP)
Con
cent
ratio
n (n
g/m
L)
Days
-10
-5
0
5
10
15
20
25
30
-2 3 8 14
Se rum C- t e lo pep t ide t ype 1 co llagen (CT X)
Bas
elin
e-A
djus
ted
Seru
m C
-telo
pept
ide
type
1 c
olla
gen
(CTX
) Con
cent
ratio
n (n
g/m
L)
Days
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
-2 3 8 14
-21 -15 -6 3 9 18 3 9 18
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ ra t ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
-21 -15 -6 3 9 18 3 9 18
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ ra t ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
-21 -15 -6 3 9 18 3 9 18
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ ra t ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
-21 -15 -6 3 9 18 3 9 18
A: Administ ra t io n o f a S ingle SC Do se o f 5 ug BA058 fo r Seven DaysB: Administ rat ion o f a Single SC Dose o f 20 ug BA058 fo r Seven DaysC: Administ ra t ion o f a S ingle SC Dose o f 40 ug BA058 fo r Seven DaysD: Administ rat ion o f a Single SC Dose o f 80 ug BA058 fo r Seven DaysP: Placebo
Calcium
Urin
ary
Excr
etio
n of
Cal
cium
(mg/
hr)
Day 1 Day 7
Time (hr )#
# Time present ed as midpo int o f co llect ion int erval using nominal elapsed t ime from most recent dose.
2
4
6
8
10
12
14
Pho spho rus
Urin
ary
Excr
etio
n of
Pho
spho
rus (
mg/
hr)
Day 1 Day 7
Time (hr )#
# Time present ed as midpo int o f co llect ion int erval using nominal elapsed t ime from most recent dose.
10
20
30
40
50
60
70
Cyc lic AMP
Urin
ary
Excr
etio
n of
Cyc
lic A
MP
(µm
ol/h
r)
Day 1 Day 7
Time (hr )#
# Time present ed as midpo int o f co llect ion int erval using nominal elapsed t ime from most recent dose.
0.05
0.10
0.15
0.20
0.25
Creat inine
Urin
ary
Excr
etio
n of
Cre
atin
ine
(mg/
hr)
Day 1 Day 7
Time (hr )#
# Time present ed as midpo int o f co llect ion int erval using nominal elapsed t ime from most recent dose.
30
40
50
60
