Thomas Peyret (1), Benjamin Rich (1), JF Marier (1), Nicole Sherry (2), Richard Finkelman (2) and Ivy Song (2)
(1) Certara Strategic Consulting, Princeton, NJ, (2) Shire Human Genetic Therapies, Inc., Lexington, MA, USA, a member of the Takeda group of companies
Objectives: rhPTH(1-84), a full-length Recombinant Human Parathyroid Hormone, is approved in the US and Europe as an adjunct to calcium and active vitamin D to control hypocalcemia in patients with chronic hypoparathyroidism (hypoPT). rhPTH(1-84) is indicated for once daily (QD) dosing, and the dose is to be individualized to achieve a serum calcium level in the lower half of the normal range (target range). A quantitative systems pharmacology (QSP) model of integrated calcium homeostasis and bone remodeling[1] was originally adapted for patients with hypoPT by including 1) the concentration-time profiles of PTH, 2) oral intake of calcium and active vitamin D, and 3) by performing various adjustments on the parathyroid gland pool and the ability of the gland to grow in size and in capacity for secretion. The objective of this project was 1) to enhance the QSP model by integrating additional drug- and disease-specific components to further improve the predictive performance of the model, and 2) to perform simulations to ultimately determine the effects of QD and twice daily (BID) administrations of rhPTH(1-84) on serum calcium and urinary calcium excretion in patients with hypoPT.
Methods: Additional drug- and disease-specific components were integrated into the QSP model, and qualification was performed based on pharmacokinetic (PK) and pharmacodynamic (PD) data available in 135 adult subjects with hypoPT in five clinical studies including QD (25, 50, 100 µg) and BID (25 or 50 µg) regimens. Simulations were performed with the enhanced QSP model to predict concentration-time profiles of PTH, serum calcium, and urinary calcium excretion, as well as the probability of hypercalciuria (defined as 24-h urinary calcium above the normal range) following various QD and BID does of rhPTH(1-84) of total daily doses of 25 µg, 50 µg, and 100 µg as well as standard of care (SOC, calcium supplement+ active vitamin D).
Results: The following components were included in the QSP model to improve predictive performance: 1) an input function of PTH with subject- and occasion-specific rate of absorption and bioavailability originally derived with a population model to optimally characterize double absorption peak profiles of PTH, and 2) a refinement of the disease model (i.e., primary hypoPT) which included a lower renal reabsorption of calcium, believed to be due to hormone resistance in renal tubules where it promotes calcium reabsorption by PTH. The enhanced QSP model presented an adequate predictive performance of plasma PTH, serum calcium and urinary calcium excretion. Based on simulations in patients with partial PTH production (endogenous PTH levels ranging from 5.63 to 27.2 ng/mL), following various rhPTH(1-84) QD and BID doses, serum calcium concentrations are maintained within the target range similar to those from the SOC while urinary calcium excretion is reduced. The predicted percentage of hypercalciuria (>7.5mmol over 24 hours in males and >6.25mmol over 24 hours in females) for various rhPTH(1-84) QD and BID regimens are presented below.
- 100 µg QD, 30.6% and 40.8% for males and females, respectively.
- 50 µg QD, 45.0% and 57.0% for males and females, respectively.
- 25 µg QD, 62.2% and 74.4% for males and females, respectively.
- 50 µg BID, 12.4% and 19.4% for males and females, respectively.
- 25 µg BID, 28.6% and 39.6% for males and females, respectively.
- 12.5 µg BID, 50.8% and 63.6% for males and females, respectively
The frequency of hypercalciuria following rhPTH(1-84) QD and BID doses is predicted to be largely reduced compared to that following the SOC (predicted at 100% based on the current model).
Conclusions: An enhanced QSP model was developed and qualified using PK and PD data from a large number of patients with hypoPT. Based on the current model, both QD and BID dosing regimens of rhPTH(1-84) at daily doses from 25 µg to 100 µg markedly reduced urinary calcium excretion and the possibility of hypercalciuria while maintaining serum calcium level in target range as compared to the SOC. Patients with hypoPT treated with rhPTH(1-84) BID dosing regimens are predicted to have a lower likelihood of hypercalciuria than the QD dosing regimens. A clinical study is planned to confirm these findings.
References:
[1] Peterson MC, Riggs MM (2010). A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling. Bone 46: 49–63
Reference: PAGE 28 (2019) Abstr 9002 [www.page-meeting.org/?abstract=9002]
Poster: Drug/Disease Modelling - Endocrine