title: Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype.
abstract: Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.
authors.affiliation: Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Paris Descartes University, Paris, France.|Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Pallet
authors.affiliation: Department of Nephrology-Clinical Immmunology, CHU Rouen, Rouen, France.
authors.forename: I
authors.initials: I
authors.lastname: Etienne
authors.affiliation: Department of Nephrology, CHU Tours, Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Buchler
authors.affiliation: Department of Nephrology, CHU Tours, Tours, France.
authors.forename: E
authors.initials: E
authors.lastname: Bailly
authors.affiliation: Department of Nephrology, CHU Caen, Caen, France.
authors.forename: B
authors.initials: B
authors.lastname: Hurault de Ligny
authors.affiliation: Department of Nephrology, CHU Amiens, Amiens, France.
authors.forename: G
authors.initials: G
authors.lastname: Choukroun
authors.affiliation: Department of Nephrology, CHU Reims, Reims, France.
authors.forename: C
authors.initials: C
authors.lastname: Colosio
authors.affiliation: Department of Nephrology, CHU Poitiers, Poitiers, France.
authors.forename: A
authors.initials: A
authors.lastname: Thierry
authors.affiliation: Department of Nephrology, CHU Rennes, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Vigneau
authors.affiliation: Department of Nephrology, CHU Strasbourg, Strasbourg, France.
authors.forename: B
authors.initials: B
authors.lastname: Moulin
authors.affiliation: Department of Nephrology, CHU Brest, Brest, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Le Meur
authors.affiliation: Department of Nephrology, CHU Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: A-E
authors.initials: AE
authors.lastname: Heng
authors.affiliation: Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Paris Descartes University, Paris, France.|Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Beaune
authors.affiliation: Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Paris Descartes University, Paris, France.|Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Loriot
authors.affiliation: Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.|Paris Descartes University, Paris, France.|Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Thervet
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: calcineurin inhibitor: tacrolimus; clinical research/practice; genetics; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology; patient survival; pharmacokinetics/pharmacodynamics; translational research/science