Steady‐state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients

Abstract

This open-label, nonrandomized study was conducted to evaluate the steady-state pharmacokinetics of sirolimus in 24 stable Chinese renal transplant patients receiving daily oral maintenance doses of sirolimus (1-4 mg). Repeated trough and serial whole blood sirolimus concentrations over a 24-hour dosing interval were collected and assayed using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Non-compartmental analysis (NCA) was employed to calculate sirolimus pharmacokinetic parameters. Cytochrome P450 (CYP) 3A5 genotyping was performed. Cyclosporine (CsA) levels were determined for patients who took concomitant CsA. Mean (±SD) sirolimus maximum concentration (Cmax ), area under the concentration-time curve within a dosing interval of τ (AUCτ ), oral clearance (CL/F), and trough concentration (Ctrough ) at steady state were: 14.1 ± 13.4 ng/mL, 199 ± 210 ng · h/mL, 10.1 ± 4.4 L/h, and 5.9 ± 6.3 ng/mL, respectively. Median tmax (range) was 2.49 hours (1-12 hours). A strong correlation was observed between Ctrough and AUCτ . Pharmacokinetics of sirolimus in patients with and without concomitant CsA were comparable. Allele frequency of CYP3A5*3 was 70.9% and a trend of higher oral clearance was observed in CYP3A5 expressers compared with non-expressers although the number of subjects in each genotype was small.

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring

“…We reviewed the literature regarding the association of the CYP3A5 genotype with the pharmacokinetic phenotype ( Supplementary Figure S1 ). Very few studies evaluated if the CYP3A5 genotype was associated with the effectiveness or toxicity (i.e., pharmacodynamics) of sirolimus–based immunosuppressive regimens ( Mourad et al, 2005 ; Renders et al, 2007 ; Lukas et al, 2010 ; Zochowska et al, 2012 ; Wang et al, 2014 ; Khaled et al, 2016 ; Rodriguez-Jimenez et al, 2017 ).…”

“…We reviewed the literature regarding the association of the CYP3A5 genotype with the pharmacokinetic phenotype (Supplementary Figure S1). Very few studies evaluated if the CYP3A5 genotype was associated with the effectiveness or toxicity (i.e., pharmacodynamics) of sirolimus-based immunosuppressive regimens (Mourad et al, 2005;Renders et al, 2007;Lukas et al, 2010;Zochowska et al, 2012;Wang et al, 2014;Khaled et al, 2016;Rodriguez-Jimenez et al, 2017). A variant in intron 3 of CYP3A5 (rs776746) creates a cryptic splice site which results in aberrant splicing and creates a premature stop codon that results in transcript degradation (Hustert et al, 2001;Kuehl et al, 2001).…”