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Determinants of darunavir cerebrospinal fluid concentrations: Impact of once-daily dosing and pharmacogenetics

机译：达拉那韦脑脊液浓度的决定因素：每日一次给药和药物遗传学的影响

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摘要

Objectives: To compare cerebrospinal fluid (CSF) darunavir and ritonavir concentrations in patients receiving darunavir/ritonavir 800/100mg once daily or 600/100mg twice daily. To determine the influence of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters (ABCB1 3435 C>T, ABCB1 1236 C>T, ABCB1 2677 G>T, SLCO1A2 38 A>G, SLCO1A2 516 A>C, ABCC2-24 G>A) on darunavir and ritonavir penetration into CSF. Design: Comparative pharmacokinetics study in patients. Methods: Plasma and CSF darunavir and ritonavir concentrations (2-26h after drug intake) were determined by a validated HPLC coupled with mass spectrometry method in adults on darunavir-based combination antiretroviral therapy undergoing a lumbar puncture. Results: HIV-infected patients on once-daily darunavir/ritonavir had significantly lower CSF darunavir trough concentrations and CSF-to-plasma ratios than patients on darunavir/ritonavir twice-daily (10.7 versus 38.2ng/ml and 0.32 versus 0.90%; P<0.05). No significant effect of single-nucleotide polymorphisms in the genes encoding for blood-brain barrier transporters was noted apart from slightly higher CSF darunavir penetration in patients carrying OATP1A2 uncommon variants. CONCLUSIONS:: This is the first study to compare darunavir CSF concentrations in patients taking the once-daily or the twice-daily dosage: our data show that darunavir and ritonavir dosing significantly affects not only CSF concentrations but also the extent of drug penetration into the CSF. Furthermore a minority of patients in the once-daily arm presented very low CSF concentration of potential concern for HIV control in the central nervous system. The relative importance of pharmacogenetics in influencing CSF darunavir pharmacokinetics deserves further clinical investigation.
机译：目的：比较接受每日一次darunavir / ritonavir 800 / 100mg或每日两次600 / 100mg darunavir / ritonavir的患者的脑脊液（CSF）darunavir和利托那韦的浓度。若要确定单核苷酸多态性对编码血脑屏障转运蛋白的基因的影响（ABCB1 3435 C> T，ABCB1 1236 C> T，ABCB1 2677 G> T，SLCO1A2 38 A> G，SLCO1A2 516 A> C， ABCC2-24 G> A）对darunavir和利托那韦渗透入CSF。设计：患者的比较药代动力学研究。方法：采用经验证的高效液相色谱-质谱联用技术，对以达那那韦为基础的联合抗逆转录病毒疗法进行腰穿的成年人，通过验证的HPLC和质谱法测定血浆和脑脊液中达那那韦和利托那韦的浓度（药物摄入后2-26h）。结果：每天使用一次darunavir / ritonavir的HIV感染患者的脑脊液darunavir谷浓度和CSF /血浆比率显着低于每天两次使用darunavir / ritonavir的患者（10.7对38.2ng / ml和0.32对0.90％; P <0.05）。除了携带OATP1A2罕见变体的患者中CSF​​ darunavir渗透率略高外，在编码血脑屏障转运蛋白的基因中单核苷酸多态性没有显着影响。结论：这是第一项比较每日一次或每日两次的患者中达那那韦CSF浓度的研究：我们的数据表明，达那那韦和利托那韦的剂量不仅显着影响了CSF浓度，而且还影响药物渗透到脑中的程度。脑脊液。此外，每天使用一次的患者中，少数患者的脑脊液浓度非常低，可能引起中枢神经系统中的HIV控制。药物遗传学在影响CSF darunavir药代动力学中的相对重要性值得进一步的临床研究。

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