Background: Teriparatide PTH (1-34) is an osteoanabolic agent for treatment of osteoporosis. PTH (1-34) can also be used as replacement therapy in hypoparathyroidism and to accelerate fracture healing. Abaloparatide, PTHrP (1-36) analogue is a novel anabolic drug for treatment of osteoporosis. PTH (1-34) has also been used to assess response to PTH in conditions such as pseudohypoparathyroidism (PHP) (Ellsworth-Howard test (EHT))
Aims: To review the use of PTH (1-34) measurements in drug development studies, and in the diagnosis of patients with PHP. To highlight the potential use of measurement of PTHrP (1-36) using our LC-MS/MS method for measurement of intact PTHrP (1-36), intact PTH (1-34) and their respective oxidised forms simultaneously.
Methods: Pharmacokinetic (PK) profiles from human subjects given either single subcutaneous (sc) injection of 20 ug Teriparatide (n=6) or 0.69 mg (n=4), 2.07 mg (n=6) oral PTH (1-34) (EnteraBio) were analysed using a validated LC-MS/MS method for intact/oxidised PTH (1-34). In EHT, urinary phosphate (spectrophotometric assay; Roche, Germany) and urine/plasma cyclic adenosine 3’,5’–monophosphate (cAMP) (LC-MS/MS) were performed on samples before and after 20ug sc adminstration of Teriparatide.
Results/Discussion: PK profiles (Figure 1A) of oral PTH (1-34) showed a rapid absorption then rapid elimination. In contrast, teriparatide injection showed a slower rate of plasma clearance, possibly due to continuous absorption from the site of administration. Cmax was proportional to oral dosage given and the 2.07 mg of oral PTH (1-34) produced comparable Cmax to that produced by 20ug teriparatide injection (Figure 1B). We found the oxidised form of PTH (1-34) represent 20-30% of intact PTH (1-34) in the studied subjects. The EHT profile from a patient suspected of PHP showed a lack of cAMP response despite significant increase in plasma PTH (1-34) concentration. On the contrary, a post dose plasma cAMP concentration of >100 pmol/L and an increase from baseline level of urine cAMP exclude the diagnosis of PHP. Our LC-MS/MS PTHrP (1-36) assay produced a linear calibration curve from 10-2000 pg/mL (r2 >0.990), inter-/ intra-assay CV of <10% and a recovery of >98.6% (CV 3.6%).
Conclusion: Our method for measurements of intact/oxidised form PTH (1-34) and PTHrP (1-36) can offer new insights into the therapeutic use of osteoanabolic agents, and the development of combination therapy with other anti-resorptive/anti-remodelling agents.
|Publication status||Published - 10 Sep 2017|
|Event||ASBMR 2017 Annual Meeting - Colorado Convention Center, ASBMR Discovery Hall, United States|
Duration: 8 Sep 2017 → 11 Sep 2017
|Conference||ASBMR 2017 Annual Meeting|
|Period||8/09/17 → 11/09/17|