Pharmacokinetic and Pharmacodynamic Characteristics of Subcutaneously Applied PTH-1-37

Abstract

Background/Aims: Parathyroid hormone (PTH) derivatives exert pronounced renal and osteoanabolic properties when given intermittently. The current study was performed to assess the pharmacokinetic and pharmacodynamic properties as well as safety of subcutaneously applied PTH-1-37 after repeated dosing in healthy subjects. Methods: This randomized, double-blind, dose-escalating, placebo and active comparator controlled study was conducted in 33 healthy postmenopausal women. Subjects were allocated to one of five treatment options: 10, 20, or 40 µg PTH-1-37, 20 µg PTH-1-34 or placebo, administered as once daily subcutaneous doses for three days. Plasma drug concentrations and serum levels of endogenous PTH-1-84, and calcium as markers of biological activity were monitored during the treatment. Results: PTH was absorbed rapidly from the subcutaneous tissue with a median t_max of 30 minutes for 20 and 40 µg of PTH-1-37. t_max was 45 minutes for 20 µg PTH-1-34. Elimination half-lives were estimated as 76 ± 34 min and 70 ± 13 min for 20 µg and 40 µg PTH-1-37 (mean ± SD), and 78 ± 34 for 20 µg PTH-1-34. Both PTH fragments (PTH-1-37 and PTH-1-34) increased serum calcium. For PTH-1-37 the effect on serum calcium was dose-dependent. Suppression of endogenous PTH-1-84 was seen after the application of both PTH-1-37 and PTH-1-34. During the study period, the subjects experienced no unexpected or serious adverse events. Conclusions: PTH-1-37 is rapidly absorbed after s.c. injection, has a short plasma elimination half-life, and does not accumulate during multiple dosing. Biological activity was demonstrated by rising serum calcium and decreasing endogenous PTH-1-84 in blood plasma. The study drugs were well tolerated and safe. Our investigation presents data that PTH-1-37 is an excellent drug candidate for intervening with syndromes of dysregulation of calcium metabolism.

Hope for CKD-MBD Patients: New Diagnostic Approaches for Better Treatment of CKD-MBD

“…Similar findings were seen in human observational studies [6][7][8][9] . Based on these data, guidelines for the treatment of too low and in particular too high PTH status in CKD patients were developed [10,11] and subsequently for the development of pharmaceutical tools to treat these abnormal statuses, such as PTH analogues [12] , for conditions of low PTH-related situations. The clinical management of CKD patients thus needs reliable analytical tools to measure PTH.…”

Ectopic osteogenesis by type I collagen loaded with a novel synthesized PTH‐related peptide‐1 in vivo

“…This peptide contains 34 amino acids at the N‐terminus of PTH and retains most of the function of PTH, particularly the osteogenic capacity. (Forssmann et al, ; Lindsay et al, ; Lindsay, Krege, Marin, Jin, & Stepan, ; Yewle et al, ; Zhang et al, ). However, teriparatide is expensive, can only be administered through systemic injection for a short period of time, and does not completely expose the active site, leading to hypercalcemia or even osteosarcoma (Culpepper, Phipps, Bonvallet, & Bellis, ; Tashjian Jr & Goltzman, ; Wang, Liu, Fan, & Li, ).…”

“…Osteogenic‐associated proteins consist of bone morphogenetic protein‐2 (BMP‐2; Sun et al, ; Zhan, Liu, & Yu, ), parathyroid hormone (PTH; Khundmiri, Murray, Lederer, & Vitamin, ), and enamel matrix protein derivative (Shahriari, Houshmand, Razavian, Khazaei, & Abbas, ). Some of the modified small molecule active peptides are osteopontin peptide, RADA16‐I peptide (Cormier, Ruiz‐Orta, Alamo, & Paravastu, ), PTH (1‐31), PTH (1‐34; Yewle, Puleo, & Bachas, ; Zhang et al, ), and PTH (1‐37; Forssmann et al, ).…”

Why Current PTH Assays Mislead Clinical Decision Making in Patients with Secondary Hyperparathyroidism

“…Low PTH concentrations, for example, after total parathyrctomy as well as high PTH concentrations in CKD patients are associated with excess morbidity and mortality [6][7][8][9] . These studies led to the development of guidelines for the treatment of too low and in particular too high PTH status in CKD patients [10,11] and subsequently to the development of pharmaceutical tools to treat these abnormal status such as PTH analogues [12] for conditions of low PTH-related situations as well a vitamin D analogues, calcimimetics, and phosphorus binders for conditions with high PTH [13][14][15][16] . The decision to use these drugs and the monitoring of the efficacy requires reliable analytical tools to measure PTH.…”