title: The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients.
abstract: Everolimus (EVR) has inter-individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co-medications, and/or demographic variables accounted for inter-individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose-adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty-five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 ± 1.1 [n = 9] vs. CGC/XXX = 2.5 ± 1.7 [n = 36] vs. XXX/XXX = 2.7 ± 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 ± 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 ± 1.1 ng/mL per mg/d in LTxR not receiving DILT (p <0.001). Demographic variables, including cystic fibrosis, were not associated with EVR PK. DILT use increased EVR L/D, but selected polymorphisms in ABCB1, CYP3A5, CYP3A4, CYP2C8, and NR1I2 did not affect EVR L/D in LTxR. Genotyping LTxR for these polymorphisms is unlikely to aid clinicians in optimizing EVR therapy.
authors.affiliation: Department of Pharmacy, University of Colorado Hospital, Aurora, CO, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Schoeppler
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Tyree H
authors.initials: TH
authors.lastname: Kiser
authors.forename: Douglas N
authors.initials: DN
authors.lastname: Fish
authors.forename: Martin R
authors.initials: MR
authors.lastname: Zamora
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D003430:Cross-Sectional Studies; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003710:Demography; D004110:Diltiazem / Q000627:therapeutic use*; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D008171:Lung Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D000077297:Pregnane X Receptor; D011379:Prognosis; D011987:Receptors, Steroid / Q000235:genetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D066027:Transplant Recipients; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D015415:Biomarkers; D007166:Immunosuppressive Agents; C000625852:NR1I2 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014665:Vasodilator Agents; D000068338:Everolimus; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; D020123:Sirolimus
keywords: cystic fibrosis; diltiazem; everolimus; lung transplantation; pharmacogenetics