Continuous administration of PTH is favoured over intermittent dosing because it permanently increases phosphate clearance, as demonstrated through a PKPD model developed from a single patient treated with multiple PTH dosing regimens including continuous infusion.
Key Findings
Methods
A one-compartment PKPD model for PTH was developed using Edsim++ that described the effect of PTH through relative clearance of calcium and phosphate.
The model was constructed from data of a single 42-year-old male patient with chronic primary hypoparathyroidism following total thyroidectomy
PTH was measured in plasma; calcium and phosphate were measured in both plasma and urine
The patient received intermittent PTH followed by off-label continuous infusion of PTH
Various dosing regimens were studied, including continuous infusion
Results
The PKPD model showed a marked effect of PTH on phosphate clearance but less effect on calcium clearance.
The PKPD model 'showed visually a marked effect on phosphate clearance, but less on calcium clearance'
Phosphate was chosen as the primary effect parameter because the patient received concomitant medications that influenced calcium homeostasis but to a lesser extent phosphate homeostasis
This made phosphate a more reliable pharmacodynamic endpoint than calcium for model development
Results
The EC50 for PTH effect on phosphate clearance was determined to be 6.3 pmol/L PTH.
EC50 of 6.3 pmol/L PTH was derived using phosphate as the effect parameter
This value was obtained from the completed PKPD model using data from the single patient
The EC50 represents the PTH plasma concentration at which half-maximal effect on phosphate clearance is achieved
Background
Once-daily administration of PTH per dosing guidelines adequately controls calcium plasma levels but has only a transient effect on urinary calcium excretion, which does not lower the risk of nephrolithiasis.
The patient developed recurrent nephrolithiasis on conventional therapy, prompting consideration of rhPTH(1-84) treatment
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 limitation of once-daily dosing motivated the investigation of multiple-daily or continuous administration
Conclusions
Continuous administration of PTH is favoured over intermittent dosing because it permanently increases phosphate clearance.
Continuous administration 'permanently increases the phosphate clearance' compared to intermittent dosing regimens
The PKPD model was completed with data from a single patient who received PTH according to various dosing regimens including continuous infusion
Continuous PTH administration was given as an off-label infusion
The authors concluded that continuous administration of PTH 'needs to be further investigated'
Visscher M, Schuls-Fouchier M, Berends A, Muller Kobold A, Punt N, Touw D. (2025). Personalized parathyroid hormone therapy for hypoparathyroidism: Insights from pharmacokinetic-pharmacodynamic modelling.. British journal of clinical pharmacology. https://doi.org/10.1111/bcp.16342