title: 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.
authors.affiliation: Medical and Development, Emerging Market and Established Products Business Unit, Pfizer Inc, Groton, CT, USA.
authors.forename: Huifen Faye
authors.initials: HF
authors.lastname: Wang
authors.affiliation: Center of Transplantation, Renji Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qiu
authors.affiliation: Department of Nephrology, Third Military Medical University Southwest Hospital, Chongqing, China.
authors.forename: Xiongfe
authors.initials: X
authors.lastname: Wu
authors.affiliation: Research and Development, Pfizer Inc, Groton, CT, USA.
authors.forename: Juanzhi
authors.initials: J
authors.lastname: Fang
authors.affiliation: Clinical Pharmacology/Clinical Assay Group, Pfizer Inc, New York, NY, USA.
authors.forename: Penelope
authors.initials: P
authors.lastname: Crownover
authors.affiliation: Medicines Development Group, Pfizer Inc, Collegeville, PA, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Korth-Bradley
authors.affiliation: Medicines Development Group, Pfizer Inc, Collegeville, PA, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Schulman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D002681:China; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus
keywords: Chinese; pharmacogenomics; pharmacokinetics; renal transplant; sirolimus