Calcitriol or 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] is the active ligand of the vitamin D receptor (VDR) that plays a vital role in health and disease. Vitamin D is converted to the relatively inactive metabolite, 25-hydroxyvitamin D 3 [25(OH)D 3 ], by CYP27A1 and CYP2R1 in the liver, then to 1,25(OH) 2 D 3 by a specific, mitochondrial enzyme, CYP27B1 (1α-hydroxylase) that is present primarily in the kidney. The degradation of both metabolites is mostly carried out by the more ubiquitous mitochondrial enzyme, CYP24A1. Despite the fact that calcitriol inhibits its formation and degradation, allometric scaling revealed strong interspecies correlation of the net calcitriol clearance (CL estimated from dose/AUC ∞ ), production rate (PR), and basal, plasma calcitriol concentration with body weight (BW). PBPK-PD (physiologically based pharmacokinetic-pharmacodynamic) modeling confirmed the dynamic interactions between calcitriol and Cyp27b1/Cyp24a1 on the decrease in the PR and increase in CL in mice. Close scrutiny of the literature revealed that basal levels of calcitriol had not been taken into consideration for estimating the correct AUC ∞ and CL after exogenous calcitriol dosing in both animals and humans, leading to an overestimation of AUC ∞ and underestimation of the plasma CL. In humans, CL was decreased in chronic kidney disease but increased in cancer. Collectively, careful pharmacokinetic data analysis and improved definition are achieved with PBPK-PD modeling, which embellishes the complexity of dose, enzyme regulation, and disease conditions. Allometric scaling and PBPK-PD modeling were applied successfully to extend the PBPK model to predict calcitriol kinetics in cancer patients. K E Y W O R D Sallometric scaling, calcitriol or 1,25(OH) 2 D 3 , CYP24A1, CYP27B1, pharmacokinetics

Calcitriol or 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3] is the active ligand of the vitamin D receptor (VDR) that plays a vital role in health and disease. Vitamin D is converted to the relatively inactive metabolite, 25‐hydroxyvitamin D3 [25(OH)D3] by CYP27A1 and CYP2R1 in the liver, then to 1,25(OH)2D3 by a specific, mitochondrial enzyme, CYP27B1 (1α‐hydroxylase) that is present primarily in the kidney. Degradation of both metabolites is mostly carried out by the more ubiquitous mitochondrial enzyme, CYP24A1. Despite that calcitriol inhibits its formation and degradation, allometric scaling revealed strong interspecies (mouse, rat, dog and human) correlations of the net calcitriol clearance (CL from dose/AUC∞), production rate (PR), and basal, plasma calcitriol concentration (CBL) with body weight (BW). A closer scrutiny of the collated literature data revealed that the basal plasma concentration of calcitriol was not taken into consideration in the estimation of AUC∞ (with subtraction of CBL) and CL after exogenous calcitriol dosing in both animals and humans. This led to an overestimation of AUC∞ and underestimation of CL. After correction, the allometric equations [plots of log(CL) or log(PR) versus log(body weight) or log(BW)] were: CL=0.654xBW0.807 and PR=36.6xBW0.718. The CL of calcitriol was further influenced by diseased states, and was found to be reduced in chronic kidney disease but increased in cancer when compared to healthy humans. These changes, however, were not discerned with allometric scaling since all clinical data appeared as a cluster of closely similar values on the allometric plot. PBPK‐PD (physiologically‐based pharmacokinetic‐pharmacodynamic) modeling (Ramakrishnan et al 2016), however, confirmed the dynamic interactions between calcitriol and Cyp27b1/Cyp24a1, showing the increase in CL as well as decrease in PR in a dose‐dependent fashion for the intravenous, murine data of Quach et al (2015). The PBPK model was successful in predicting data from the escalating oral and intravenous doses of calcitriol given to cancer patients upon scale‐up.