Personalized parathyroid hormone therapy for hypoparathyroidism: Insights from pharmacokinetic-pharmacodynamic modelling.

Abstract

Aims: A 42-year-old male developed chronic primary hypoparathyroidism after total thyroidectomy. Conventional therapy led to recurrent nephrolithiasis and therefore rhPTH(1-84) (parathyroid hormone [PTH]) treatment was considered. According to the dosing guideline for PTH, calcium plasma levels are adequately controlled with once-daily administration. However, the effect on urinary calcium excretion is only transient and hence does not lower the risk of nephrolithiasis. This raises the question of whether multiple-daily or continuous administration of PTH is more effective in lowering urinary calcium excretion. We aimed to construct a pharmacokinetic-pharmacodynamic (PKPD) model to answer this question.

Methods: A single patient was treated with intermittent PTH followed by off-label continuous infusion of PTH. PTH was measured in plasma, calcium and phosphate in plasma and urine. A one-compartment PKPD model for PTH was developed with Edsim++. The effect of PTH was described by the relative clearance of calcium and phosphate.

Results: The PKPD model for PTH showed visually a marked effect on phosphate clearance, but less on calcium clearance. During the study, the patient also received medication that influenced calcium homeostasis but to a lesser extent phosphate homeostasis. Therefore, phosphate was chosen as the effect parameter, resulting in an EC50 of 6.3 pmol/L PTH.

Conclusions: The PKPD model for PTH was completed with the unique data of a single patient who received PTH according to various dosing regimens, including continuous infusion. Continuous administration of PTH is favoured because it permanently increases the phosphate clearance and therefore needs to be further investigated.