ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO2362

The Influence of Vitamin D Status and CKD on the CYP3A Metabolism Substrate Midazolam

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Tuey, Stacey M., University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
  • Prebehalla, Linda, University of Pittsburgh, Department of Pharmacy & Therapeutics, Pittsburgh, Pennsylvania, United States
  • Wempe, Michael F., University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
  • Chonchol, Michel, University of Colorado, Division of Renal Diseases and Hypertension, Aurora, Colorado, United States
  • Shah, Nirav A., University of Pittsburgh, Department of Medicine Renal Electrolyte Division, Pittsburgh, Pennsylvania, United States
  • Nolin, Thomas D., University of Pittsburgh, Department of Pharmacy & Therapeutics, Pittsburgh, Pennsylvania, United States
  • Joy, Melanie S., University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, United States
Background

Patients with chronic kidney disease (CKD) have a high prevalence of vitamin D (VitD) deficiency. Given its widespread use and knowledge of CYP gene induction, there is a paucity of data on how the pharmacokinetics (PK) of CYP3A substrates may be impacted by VitD in CKD. This study sought to investigate the role of VitD status (deficient vs. replete state) on CYP3A drug metabolism in CKD and healthy control (HC) subjects using midazolam (MDZ) as a prototypical probe substrate.

Methods

CKD (n=19) and HC (n=6) subjects with VitD deficiency (25(OH)D < 30ng/mL) were enrolled in a 2-phase study. In Phase 1, subjects were given one dose of oral cholecalciferol (D3, 5000 IU) and oral MDZ (2 mg). In Phase 2, subjects received D3 5000 IU daily for up to 14 weeks to repletion (25(OH)D >30 ng/mL) and were again given one dose of oral D3 5000 IU and MDZ 2 mg. Blood was serially collected for up to 48 h at each phase. MDZ plasma concentrations were measured by LC-MS/MS. Population PK analysis was performed using Phoenix NLME (v.8.2, Certara®).

Results

A 2-compartment model with delayed absoprtion and a mixed ratio residual error model was fit to the observed MDZ plasma concentration data. Glomerular filtration rate (GFR) and study phase were included as covariates in the model. MDZ population parameter estimates (%RSE) were: central volume of distribution (Vc/F) 95.6 L (26.8%), clearance (CL/F) 31.1 L/h (25.0%), peripheral volume of distribution (Vp/F) 213 L (39.5%), inter-compartmental clearance (Q/F) 36.5 L/h (24.3%), and absorption rate constant (ka) 16.4 h-1 (42%). Individual subject PK parameter estimates were determined from the population PK model (Table).

Conclusion

VitD status did not significantly influence the PK of MDZ in either HC or CKD subjects. There was a trend in CL/F being slower in CKD compared to HC regardless of phase, which may be due to decreased renal elimination or reduced ability for induction of CYP3A secondary to renal impairment. Future analyses will explore additional covariates to further reduce the error on MDZ PK parameters in order to discern differences between subjects in this small study.

Funding

  • Other NIH Support