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Sequential Analysis of Tacrolimus Dosing in Adult Lung Transplant Patients With ABCB1 Haplotypes

From the School of Pharmacy, University of Southern California, Los Angeles (Dr Zheng, Dr Burckart); School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Zeevi, Dr McCurry, Dr Webber, Dr Iacono); and Department of Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee (Dr Schuetz, Dr Zhang, Dr Lamba).

The genetic polymorphisms in the ABCB1 gene, which encodes for the membrane pump, P-glycoprotein, have been previously demonstrated to have an association with tacrolimus dosing in organ transplant patients. This study associated the haplotype and genotype for ABCB1 G2677T and C3435T variants with a sequential analysis of tacrolimus blood level (ng/mL) per mg/day dosage ([L/D]) administered to 91 adult lung transplant patients at 1, 3, 6, 9, and 12 months after transplantation. Haplotype 22 carriers had a significantly higher tacrolimus [L/D] value in comparison with nonhaplotype 22 carriers (P = .04) only at 1 month after transplant. Sequential analysis demonstrated that ABCB1 genotypes 00 and 01 had low tacrolimus [L/D] values at 1 and 3 months, but these values increased substantially at 6, 9, and 12 months after transplantation. This was not true of the other genotypes with the exception of genotypes 10 and 21, which had small numbers of patients but had consistently low tacrolimus [L/D]. Haplotype analysis also suggested that the homozygous for ABCB1 2677 variant allele had more of an impact on tacrolimus [L/D] in haplotype analysis than that of ABCB1 3435. In conclusion, sequential analysis of tacrolimus [L/D] with haplotypes can explain previous clinical observations of changes in tacrolimus dosage over time but suggests that this effect is limited to individual patient haplotypes. Sequential analysis of drug dosing and haplotypes relationships can provide important information about the induction or inhibition of drug-drug and disease-drug interactions among specific haplotypes.

Key Words: P-glycoprotein • ABCB1 • polymorphism • haplotype • transplantation • tacrolimus dosing

Address for reprints: Gilbert J. Burckart, PharmD, FCP, University of Southern California, 1985 Zonal Avenue, PSC-100, Los Angeles, CA 90033-1086.

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