Model-Guided Transdermal Formulation of 1α,25-Dihydroxyvitamin D3 for Improved Safety and Efficacy

1α,25-Dihydroxyvitamin D3 [1,25(OH)2D3], the active ligand of vitamin D receptor (VDR), is useful for the prevention and treatment of various diseases, including chronic kidney disease (CKD), cardiovascular disease, hypercholesterolemia and neurodegenerative diseases. However, the therapeutic utility of 1,25(OH)2D3 is limited due to its propensity to cause hypercalcemia. Our aim is to develop a transdermal formulation of 1,25(OH)2D3 that allows for controlled drug delivery with minimal stimulation of the intestinal calcium ion channel (TRPV6), thereby avoiding the toxic outcome of hypercalcemia. By incorporation an ethylene vinyl acetate (EVA) rate-controlling membrane to slow down and regulate the rate of drug release, we were able to control the slow release from the patch not skin as the rate-limiting step for permeation. A physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model was further established to interpret the complex PK and PD interplay of 1,25(OH)2D3 and guide dosing selection. Based on the modeling and studies in vivo, we were able to determine that patches containing loadings of 70-560 pmol‧cm-2 1,25(OH)2D3 (or ~0.0004-0.0048% w/w) to be noncalcemic. The apparent half-life of 1,25(OH)2D3 in mice following the patch formulation was prolonged when compared to the repeated intravenous (IV) and intraperitoneal (IP) doses, due to the more gradual release of 1,25(OH)2D3 from the patch, rendering lesser stimulation of the degradation enzyme, Cyp24a1, for 1,25(OH)2D3 elimination and Trpv6 for calcium absorption. Additionally, the 1,25(OH)2D3 transdermal patch (~0.0004-0.0048% w/w) provided sustained, desirable pharmacodynamic effects in the suppression of the parathyroid hormone (PTH) in CKD mice in vivo for the correction of secondary hyperthyroidism (SHPT) without notable toxicity. In conclusion, our transdermal 1,25(OH)2D3 delivery system provides a safe and effective way for the delivery of 1,25(OH)2D3.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2019

Author dc:creator

• Yang, Qi Joy

Advisors dc:contributor.advisor

• Pang, K. Sandy
• Lee, Ping I

• chronic kidney disease
• Controlled drug delivery
• Model-guided drug formulation
• Pharmacokinetics/Pharmacodynamics
• Physiologically-based Pharmacokinetic Modeling
• vitamin D

Handle dc:identifier.uri

http://hdl.handle.net/1807/106774

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/106774