Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa.
Antiviral Res. 2014 Feb;102:44-53. doi: 10.1016/j.antiviral.2013.11.011. Epub 2013 Dec 5.
Efavirenz (EFV) exhibits interindividual pharmacokinetic variability caused by differences in cytochrome P450 (CYP) expression. Most tuberculosis (TB) drugs interact with the CYP metabolizing enzymes, while the clinical validity of genotyping in predicting EFV plasma levels in Rwandan subjects is not known. We investigated in patients co-infected with human immunodeficiency virus (HIV) and TB recruited in Rwanda the effects of 10 SNPs in five drug-metabolizing enzymes on EFV plasma levels and treatment response when patients are treated with EFV-containing therapy alone (n=28) and when combined with rifampicin-based TB treatment (n=62), and the validity of genotyping for CYP2B6 single nucleotide polymorphisms in predicting supra-therapeutic EFV levels. There was a significant difference between CYP1A2 -739T/G and T/T genotypes when patients were treated with EFV-containing therapy combined with rifampicin-based TB treatment, but not when EFV-containing therapy was alone. CYP2B6 516T/T genotype was associated with high EFV levels compared to other CYP2B6 516G>T genotypes in the presence and in the absence of rifampicin-based TB treatment. Predictive factors of EFV plasma levels in the presence of rifampicin-based TB treatment were CYP2A6 1093G>A, CYP2B6 516G>T, and CYP2B6 983T>C accounting for 27%, 43%, and 29% of the total variance in EFV levels, respectively. There was a high positive predictive value (PPV) (100%) for CYP2B6 516T/T and 983T/T genotypes in predicting EFV plasma levels above the therapeutic range, but this PPV decreased in the presence of rifampicin-based TB treatment. Rifampicin-based TB treatment was also shown to affect EFV plasma levels significantly, but did not affect the significant reduction of HIV-RNA copies. These results indicate that genotyping for CYP2B6 SNPs could be used as a tool in predicting supra-therapeutic EFV plasma levels, which could minimize adverse drug events.
依非韦伦（EFV）表现出个体间药代动力学的可变性，这是由于细胞色素 P450（CYP）表达的差异造成的。大多数抗结核（TB）药物与 CYP 代谢酶相互作用，而在卢旺达受试者中，预测 EFV 血浆水平的基因分型的临床有效性尚不清楚。我们在卢旺达招募的合并人类免疫缺陷病毒（HIV）和结核病（TB）感染的患者中，研究了五个药物代谢酶中的 10 个 SNP 对 EFV 血浆水平的影响，以及在 EFV 单药治疗（n=28）和 EFV 联合利福平为基础的 TB 治疗（n=62）时的治疗反应，以及 CYP2B6 单核苷酸多态性基因分型预测超治疗 EFV 水平的有效性。当患者接受 EFV 联合利福平为基础的 TB 治疗时，CYP1A2-739T/G 和 T/T 基因型之间存在显著差异，但当仅接受 EFV 单药治疗时则没有。与利福平为基础的 TB 治疗存在和不存在时的其他 CYP2B6 516G>T 基因型相比，CYP2B6 516T/T 基因型与 EFV 水平较高相关。在存在利福平为基础的 TB 治疗的情况下，EFV 血浆水平的预测因素是 CYP2A6 1093G>A、CYP2B6 516G>T 和 CYP2B6 983T>C，分别占 EFV 水平总方差的 27%、43%和 29%。CYP2B6 516T/T 和 983T/T 基因型对预测 EFV 血浆水平超过治疗范围具有很高的阳性预测值（PPV）（100%），但在存在利福平为基础的 TB 治疗时，这种 PPV 降低。利福平为基础的 TB 治疗也显著影响 EFV 血浆水平，但对 HIV-RNA 拷贝数的显著降低没有影响。这些结果表明，CYP2B6 SNP 的基因分型可用于预测超治疗 EFV 血浆水平，从而最大限度地减少药物不良反应事件。
