Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

Frontiers in Pharmacology

卷:8

Laure Elens¹  Arnaud Capron²  Ron H. van Schaik³  Teun van Gelder⁵  Dennis A. Hesselink⁵  Jean-Baptiste Woillard⁶  Pierre Marquet⁶  Michel Mourad⁷  Michael Neely⁸  Vincent Haufroid⁹  Nuria Lloberas¹⁰ 

[1] 0Department of Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université catholique de LouvainBrussels, Belgium;

[2] Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Université catholique de LouvainBrussels, Belgium;

[3] Department of Clinical Chemistry, Erasmus MC-University Medical Centre RotterdamRotterdam, Netherlands;

[4] Department of Hospital Pharmacy, Erasmus MC-University Medical Centre RotterdamRotterdam, Netherlands;

[5] Department of Internal Medicine, Erasmus MC-University Medical Centre RotterdamRotterdam, Netherlands;

[6] Department of Pharmacology and Toxicology, Centre Hospitalier Universitaire à LimogesLimoges, France;

[7] Kidney and Pancreas Transplantation Unit, Cliniques Universitaires Saint-Luc, Université catholique de LouvainBrussels, Belgium;

[8] Laboratory of Applied Pharmacokinetics, Children’s Hospital Los Angeles, Los AngelesCA, United States;

[9] Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de LouvainBrussels, Belgium;

[10] Nephrology Service and Laboratory of Experimental Nephrology, University of BarcelonaBarcelona, Spain;

关键词: tacrolimus;    kidney transplantation;    CYP3A;    single nucleotide polymorphisms;    population pharmacokinetics;    dosage recommendations;   

DOI  :  10.3389/fphar.2017.00358

来源: DOAJ

【 摘 要 】

Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics®. Patients were genotyped for the CYP3A4∗22 and CYP3A5∗3 alleles and were classified into 3 different categories [poor-metabolizers (PM), Intermediate-metabolizers (IM) or extensive-metabolizers (EM)]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Δ-2LL = -73). Our model estimated that tacrolimus concentrations were 33% IC95%[20–26%], 41% IC95%[36–45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile.

【 授权许可】

Unknown