title: Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations.
abstract: CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.
authors.affiliation: Clinical Chemistry, 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.forename: A-S
authors.initials: AS
authors.lastname: Jannot
authors.forename: M
authors.initials: M
authors.lastname: El Bahri
authors.forename: I
authors.initials: I
authors.lastname: Etienne
authors.forename: M
authors.initials: M
authors.lastname: Buchler
authors.forename: B H
authors.initials: BH
authors.lastname: de Ligny
authors.forename: G
authors.initials: G
authors.lastname: Choukroun
authors.forename: C
authors.initials: C
authors.lastname: Colosio
authors.forename: A
authors.initials: A
authors.lastname: Thierry
authors.forename: C
authors.initials: C
authors.lastname: Vigneau
authors.forename: B
authors.initials: B
authors.lastname: Moulin
authors.forename: Y
authors.initials: Y
authors.lastname: Le Meur
authors.forename: A-E
authors.initials: AE
authors.lastname: Heng
authors.forename: J-F
authors.initials: JF
authors.lastname: Subra
authors.forename: C
authors.initials: C
authors.lastname: Legendre
authors.forename: P
authors.initials: P
authors.lastname: Beaune
authors.forename: C
authors.initials: C
authors.lastname: Alberti
authors.forename: M A
authors.initials: MA
authors.lastname: Loriot
authors.forename: E
authors.initials: E
authors.lastname: Thervet
mesh_terms: D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: Clinical research; immune modulation; immunosuppressant, calcineurin inhibitor: tacrolimus, pharmacokinetics; nephrology, immunosuppression; pharmacodynamics, genetics; pharmacology, kidney transplantation; practice