Original Clinical ScienceVariants in mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and leukopenia in heart transplant recipients
Section snippets
XXX
Leukopenia is a major cause of morbidity following heart transplantation, occurring in approximately 30% of patients.1,2 In the heart transplant setting, leukopenia is often caused by administration of mycophenolate and cytomegalovirus (CMV) antiviral drugs (i.e., ganciclovir and valganciclovir). The occurrence of leukopenia often results in a dose reduction or temporary discontinuation of one or both of these medications.3 When the mycophenolate dose is reduced or held, it places patients at
Study population
Patients recruited from a previous pharmacogenetic study (ClinicalTrials.gov, NCT01686191), hereafter referred to as the parent study, were considered for inclusion in this retrospective analysis. The parent study enrolled 253 adult heart transplant recipients followed at the University of Colorado Advanced Heart Failure and Transplant Program who were transplanted between March 1985 and August 2016. Participants were included in the parent study if they received a heart-only transplant, were
Patient characteristics
Demographic and clinical characteristics of the 148 participants that met the inclusion criteria for this analysis are listed in Table 1. The cohort consisted primarily of men (76.4%) and individuals of European ancestry (77.7%), with the mean ± SD age at transplant of 49 ± 13 years. Patients were transplanted between October 1996 and August 2016. All patients received mycophenolate mofetil, although four patients (2.7%) were transitioned to mycophenolate sodium due to gastrointestinal adverse
Discussion
This is the first pharmacogenetic study to comprehensively assess the relationship between SNPs in a broad range of mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and drug-induced leukopenia in adult heart transplant recipients. In addition to lower pre-transplant weight and reason for transplant other than ischemic cardiomyopathy, the HNF1A rs1169288 variant C allele was associated with a higher odds of mycophenolate and/or CMV antiviral drug-induced leukopenia
Disclosure statement
J.L. reports consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, and VWave and grants from AstraZeneca, Volumetrix, and Sensible Medical. All other authors have no conflicts of interest to report.
Acknowledgments
The parent study was funded by a grant from the American Heart Association (12GRNT12040211). This project/publication is supported by the National Institutes of Health/ National Center for Advancing Translational Sciences (NIH/NCATS) Colorado Clinical and Translational Science Award (CTSA) Grant Number UL1 TR002535 and by NIH/NCATS Colorado CTSA Grant Number TL1 TR002533. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views. The authors are thankful
References (47)
- et al.
Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients
J Heart Lung Transplant
(2005) - et al.
Mycophenolate mofetil dose reduction for gastrointestinal intolerance is associated with increased rates of rejection in heart transplant patients
J Heart Lung Transplant
(2008) - et al.
Mycophenolate mofetil and its mechanisms of action
Immunopharmacology
(2000) - et al.
Ganciclovir inhibits lymphocyte proliferation by impairing DNA synthesis
Biol Blood Marrow Transplant
(2007) - et al.
Pharmacogenomics
Lancet
(2019) - et al.
Genetic polymorphisms influence mycophenolate mofetil-related adverse events in pediatric heart transplant patients
J Heart Lung Transplant
(2010) - et al.
Multidrug resistance-associated protein 4 (MRP4) controls ganciclovir intracellular accumulation and contributes to ganciclovir-induced neutropenia in renal transplant patients
Pharmacol Res
(2016) - et al.
Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection
J Heart Lung Transplant
(2005) - et al.
Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1alpha
Biochem Pharmacol
(2006) - et al.
A myosin-like dimerization helix and an extra-large homeodomain are essential elements of the tripartite DNA binding structure of LFB1
Cell
(1990)