Pharmacokinetic Estimation Models-based Approach to Predict Clinical Implications for CYP Induction by Calcitriol in Human Cryopreserved Hepatocytes and HepaRG Cells

Abstract

Calcitriol, a vitamin D3 metabolite, is approved for various indications because it is the bioactive form of vitamin D in the body. The purpose of this study was to predict the clinical significance of cytochrome P450 (CYP) induction by calcitriol using in vitro human cryopreserved hepatocytes, HepaRG experimental systems, and various pharmacokinetic estimation models. CYP2B6, 3A4, 2C8, and 2C9 mRNA levels increased in a concentration-dependent manner in the presence of calcitriol in human cryopreserved hepatocytes and HepaRG cells. Using the half maximal effective concentration (EC50) and maximum induction effect (Emax) obtained from the in vitro study, a basic kinetic model was applied, suggesting clinical relevance. In addition, a static mechanistic model showed the improbability of a clinically significant effect; however, the calculated area under the plasma concentration–time curve ratio (AUCR) was marginal for CYP3A4 in HepaRG cells. To clarify the effect of CYP3A4 in vivo, physiologically based pharmacokinetic (PBPK) modeling was applied as a dynamic mechanistic model, revealing a low clinically significant effect of CYP3A4 induction by calcitriol. Therefore, we conclude that CYP induction by calcitriol treatment would not be clinically significant under typical clinical conditions.

Comparative pharmacokinetic study of bicalutamide administration alone and in combination with vitamin D in rats

“…After oral dosed, BCL is extensively metabolized via phase I (oxidation by CYP 3A4) and phase II (glucuronidation) transformations in the liver [43]. On the other hand, VDR is found binding to the promoter of CYP 3A genes, and ligands like 1,25-(OH)D 3 , up-regulates the transcription of CYP 3A in different species [45][46][47][48][49]. VDR also participates in the regulation of phase II metabolic enzymes, such as UDP-glucuronosyl transferases: UGT2B15/2B17, UGT2A1/2 and sulfotransferase 2A1 (SULT2A1) [45,50].…”

TNBC: Potential Targeting of Multiple Receptors for a Therapeutic Breakthrough, Nanomedicine, and Immunotherapy

“…The antagonist bicalutamide was the first AR-based drug that was clinically evaluated in 2013; however, limited efficacy and adverse effects, such as limb edema, fatigue, and hot flashes, were observed. Enzalutamide has been clinically evaluated in patients with AR-positive TNBC, and the most common adverse effects observed were fatigue and nausea [ 52 ]. The PFS and safety of abiraterone, a selective inhibitor of CYP17 was clinically evaluated, and hypokalemia and hypertension were the most common adverse events.…”