PKPD modelling to predict altered disposition of 1α,25‐dihydroxyvitamin D₃ in mice due to dose‐dependent regulation of CYP27B1 on synthesis and CYP24A1 on degradation

Abstract

BACKGROUND AND PURPOSE Concentrations of 1α,25(OH)2D3], the active ligand of the vitamin D receptor, are tightly regulated by CYP27B1 for synthesis and CYP24A1 for degradation. However, the dose-dependent pharmacokinetic (PK)-pharmacodynamic (PD) relationship between these enzymes and 1,25(OH)2D3 concentrations has not been characterized. EXPERIMENTAL APPROACHThe pharmacokinetics of 1,25(OH)2D3 were evaluated after administration of single (2, 60 and 120 pmol) and repeated (2 and 120 pmol q2d ×3) i.v. doses to male C57BL/6 mice. mRNA expression of CYP27B1 and CYP24A1 was examined by quantitative PCR and 1,25(OH)2D3 concentrations were determined by enzyme immunoassay. KEY RESULTSCYP27B1 and CYP24A1 changes were absent for the 2 pmol dose and biexponential decay profiles showed progressively shorter terminal half-lives with increasing doses. Fitting with a two-compartment model revealed decreasing net synthesis rates and increasing total clearances with dose, consistent with a dose-dependent down-regulation of renal CYP27B1 and the induction of renal/intestinal CYP24A1 mRNA expression. Upon incorporation of PD parameters for inhibition of CYP27B1 and induction of CYP24A1 to the simple two-compartment model, fitting was significantly improved. Moreover, fitted estimates for the 2 pmol dose, together with the PD parameters as modifiers, were able to predict profiles reasonably well for the higher (60 and 120 pmol) doses. Lastly, an indirect response model, which considered the synthesis and degradation of enzymes, adequately described the PK and PD profiles. CONCLUSIONS AND IMPLICATIONSThe unique PK of exogenously administered 1,25(OH)2D3 led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)2D3. BJP

Physiologically-Based Pharmacokinetic-Pharmacodynamic Modeling of 1 ,25-Dihydroxyvitamin D3 in Mice

“…Cyp27b1 as a subcompartment of the kidney was not considered, because the synthesis rate was low (50 fmol  h 21 ) (Hsu et al, 1987) and Cyp27b1 synthesis was immediately and completely inhibited upon administration of 1,25(OH) 2 D 3 (Quach et al, 2015). The mPBPK-PD model (Fig.…”

“…The assumption that 1,25(OH) 2 D 3 is confined to the plasma space is consistent with compartmental estimates of 61.5 mL Â kg 21 or 1.23 mL for a 20 g mouse for V 1 , the central volume of distribution of 1,25(OH) 2 D 3 for mice given the 120 pmol i.v. dose (Quach et al, 2015). By assuming a hematocrit (Hct) of 0.45, then the estimated blood volume for the central compartment is 1.23/(1-0.45) or 2.24 mL.…”

“…with I max as the maximum inhibitory effect, IC 50 as the renal 1,25(OH) 2 D 3 concentration producing 50% of I max , and g 2 as the Hill coefficient of Cyp27b1 in kidney (Mager et al, 2003;Quach et al, 2015). Regression of data from each dose and for the entire data set was performed according to eqs.…”

“…administration (120 pmol) (Chow et al, 2013) as well as assayed data for repeated i.v. administration with different (2, 60, and 120 pmol) 1,25(OH) 2 D 3 doses (Quach et al, 2015). Final parameter estimates and assigned constants were used for simulations.…”

“…A recent compartmental model showed that changes in the pharmacodynamics of Cyp27b1 and Cyp24a1, when incorporated into the pharmacokinetic model, greatly improved description of the kinetic profiles of 1,25(OH) 2 D 3 in mice after increasing i.v. doses of 1,25(OH) 2 D 3 (Quach et al, 2015) , suggesting the need to simultaneously incorporate pharmacodynamics into modeling. In this study, we revisited the rich data obtained from repeated i.p.…”