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Influence of CYP2B6 516G > T and Long Term HAART on Population Pharmacokinetics of Efavirenz in Rwandan Adults on HIV and Tuberculosis Cotreatment

机译:CYP2B6 516G> T和长期HAART对卢旺达成年人依法韦伦的人口药代动力学对艾滋病毒和结核病共同治疗的影响

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Aim: To describe the pharmacokinetic parameters of efavirenz and estimate its clearance (CL/F) accounting simultaneously for drug-drug interactions and CYP2B6 genetic polymorphism. Methods: Genotyping of 516G > T single nucleotide polymorphism of CYP2B6 was performed using a PCR-based technology and plasma efavirenz concentrations were measured by high performance liquid chromatography on blood samples from 76 HIV adults co-infected with tuberculosis who had received an efavirenz-based regimen. Data were analyzed using population modeling with NONMEM. Results: The absorption rate constant and the apparent volume of distribution in the final model were 1.9 h-1 and 580 L/70kg, respectively. The CL/F at baseline was 11.8 L/h/70kg, 8.8 L/h/70kg and 3.9 L/h/70kg for patients carrying the G/G, G/T and T/T genotypes of CYP2B6 516G > T, respectively, in patients who were administered tuberculosis (TB) treatment prior to HIV treatment (Group A); and 16.7 L/h/70kg, 10.6 L/h/70kg and 1.8 L/h/70kg for G/G, G/T and T/T genotype patients respectively, in patients with previous exposure to HIV treatment (Group B). The CL/F at baseline and steady state was always higher in Group B compared to Group A patients. Expectedly, carriers of CYP2B6 516G/G and T/T genotypes exhibited higher and lower CL/F, respectively. Conclusion: Our results indicated that the CL/F of efavirenz in the population studied was predictably different due to whether the patients were mono-treated for TB with HAART deferred or for HIV before initiation of TB therapy, and to CYP2B6 516G > T variant, implying that both CYP2B6 genetic polymorphisms and previous efavirenz-based HAART should be taken into account when adjusting efavirenz dose.
机译:目的:描述依非韦伦的药代动力学参数,并同时评估其与药物相互作用和CYP2B6基因多态性的清除率(CL / F)。方法:采用基于PCR的技术对CYP2B6的516G> T单核苷酸多态性进行基因分型,并通过高效液相色谱法对76例经依非韦伦治疗的艾滋病合并感染艾滋病毒成年人的血样进行血浆依非韦伦浓度的测定。养生。使用NONMEM进行总体建模分析数据。结果:最终模型中的吸收速率常数和表观分布体积分别为1.9 h-1和580 L / 70kg。对于携带CYP2B6 516G> T G / G,G / T和T / T基因型的患者,基线时的CL / F分别为11.8 L / h / 70kg,8.8 L / h / 70kg和3.9 L / h / 70kg ,在接受HIV治疗之前接受结核病(TB)治疗的患者(A组);在以前接受过HIV治疗的基因型患者中,G / G,G / T和T / T基因型患者分别为16.7 L / h / 70kg,10.6 L / h / 70kg和1.8 L / h / 70kg(B组)。与A组患者相比,B组在基线和稳态时的CL / F始终较高。预期,CYP2B6 516G / G和T / T基因型的携带者分别表现出较高和较低的CL / F。结论:我们的结果表明,依法韦仑的CL / F差异可预测,这是由于患者在开始TB治疗之前是否接受了HAART延迟治疗的TB或HIV的单药治疗,以及CYP2B6 516G> T变体,提示在调整依非韦伦剂量时应同时考虑CYP2B6基因多态性和以前基于依非韦伦的HAART。

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