CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone
Abstract
BACKGROUND: Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2 *1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. METHODS: Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2 *1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. RESULTS: The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL -1 and the area under the receiver operating characteristic curve was 0.701 ( P = 0.024). The pirfenidone concentration-to-dose ratio ( C/D ) in CYP1A2 *1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL -1 ; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039).…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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