Model-based meta-analysis for comparing Vitamin D2 and D3 parent-metabolite pharmacokinetics

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Nutritional Science
• Endocrinology

Background:

• The dose-equivalency of Vitamin D3 (D3) and D2, and their metabolite 25OHD, is not well-defined.
• Understanding these differences is crucial for managing Vitamin D status and associated diseases.

Purpose of the Study:

• To develop a population pharmacokinetic (PK) model for D2 and its metabolite 25OHD2.
• To compare the 25OHD-raising efficacy of D2 and D3 using established PK models.

Main Methods:

• A population PK model was developed for D2 and 25OHD2 using data from 17 studies (278 individuals).
• Nonlinear mixed-effects modeling (NONMEM v7.2) was employed, utilizing 1- and 2-compartment models.
• Simulations compared 25OHD exposures from oral D2 and D3 administration across various dosing and baseline scenarios.

Main Results:

• Both D2 and 25OHD2 were described by 2-compartment models; parent D2 clearance was first-order, unlike the saturable D3 clearance.
• 25OHD2 elimination was approximately twice as fast as 25OHD3.
• At lower doses and baseline 25OHD levels, D3 was more effective at increasing 25OHD concentrations.

Conclusions:

• D3 demonstrates superior efficacy in raising 25OHD at lower doses due to its non-saturable clearance.
• At higher doses, D2's efficacy increases, potentially surpassing D3 due to D3 clearance saturation.
• Clinical differences between D2 and D3 are unlikely when 25OHD levels exceed 75 nmol/L.