The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease

Abstract

The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD₃ ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n = 14) and controls (n = 5) with suboptimal 25-VitD levels (<30 ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD₃ (5000 IU) and MDZ (2 mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD₃ and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7) L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.

Keywords: CYP3A4; cholecalciferol; chronic kidney disease; metabolism; midazolam; pharmacokinetics; vitamin D.

Figure 1.

Major metabolism pathways of midazolam. 1′-OHMDZ, 1′-hydroxymidazolam; CYP3A, cytochrome P450 3A; MDZ, midazolam; UGT, uridine glucuronosyltransferase.

Figure 2.

Schematic of the structural pharmacokinetic model of orally administered midazolam. A 2-compartmental model was used to describe midazolam pharmacokinetics. CL/F, apparent oral clearance from the central compartment; CL2/F, apparent clearance from the peripheral compartment; Ka, oral absorption rate constant; V/F, apparent volume of distribution of the central compartment; V2/F, apparent volume of distribution of the peripheral compartment.

Figure 3.

Median plasma concentration versus time curve of (a) MDZ, (b) 1′-OHMDZ, and (c) 1′-OHMDZ-G observed in chronic kidney disease, phase 1 (closed circle and dashed line), chronic kidney disease, phase 2 (open circle and solid line), healthy control, phase 1 (closed square and dashed line), and healthy control, phase 2 (open square and solid line). Error bars indicate 95%CIs. 1′-OHMDZ, 1′-hydroxymidazolam; 1′-OHMDZ-G, 1′-OHMDZ glucuronide; MDZ, midazolam.

Figure 4.

The change in pharmacokinetic parameters from phase 1 (circles) to phase 2 (squares) of (a) MDZ, (b) 1′-OHMDZ, and (c) 1′-OHMDZ-G in healthy control and chronic kidney disease where each gray line represents an individual subject and the black line represents the median of each subject group. 1′-OHMDZ, 1′-hydroxymidazolam; 1′-OHMDZ-G, 1′-hydroxymidazolam glucuronide; C_max, maximum plasma concentration; CKD, chronic kidney disease; CL/F, apparent oral clearance from central compartment; CL_R, renal clearance; MDZ, midazolam; t_1/2, half-life; V2/F, apparent volume of distribution of the peripheral compartment.