Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia, USA.
Br J Clin Pharmacol. 2023 Oct;89(10):2964-2976. doi: 10.1111/bcp.15792. Epub 2023 Jun 4.
The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU).
Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed effects modelling was performed. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model.
A one-compartment model with first-order absorption and elimination best described the oxypurinol concentration-time data. Inhibition of SU by oxypurinol was described with a direct inhibitory E model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (-0.27 per A allele, 95% CI -0.38, -0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus requiring selection of alternative medications.
The proposed allopurinol dosing guide uses individuals' fat-free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.
本研究旨在量化可识别的变异性来源，包括黄嘌呤氧化酶药代动力学中的关键遗传变异及其对血清尿酸（SU）的药效学影响。
对 34 名苗族参与者（n=34）给予 100mg 别嘌醇每日两次，持续 7 天，然后给予 150mg 别嘌醇每日两次，持续 7 天。采用非线性混合效应模型进行序贯群体药代动力学药效学（PKPD）分析。根据最终的 PKPD 模型模拟达到目标 SU 的别嘌醇维持剂量。
一个具有一级吸收和消除的单室模型最能描述氧嘌呤醇浓度-时间数据。使用稳态氧嘌呤醇浓度描述 SU 对氧嘌呤醇的直接抑制 E 模型。无脂肪体质量、估计的肌酐清除率和 SLC22A12 rs505802 基因型（每 T 等位基因 0.32，95%CI 0.13，0.55）被发现可预测氧嘌呤醇清除率的差异。抑制黄嘌呤脱氢酶活性 50%所需的氧嘌呤醇浓度受 PDZK1 rs12129861 基因型的影响（每 A 等位基因减少 0.27，95%CI -0.38，-0.13）。大多数同时具有 PDZK1 rs12129861 AA 和 SLC22A12 rs505802 CC 基因型的个体，无论肾功能和体质量如何，只要别嘌醇低于最大剂量，就可以达到目标 SU（至少有 75%的成功率）。相比之下，同时具有 PDZK1 rs12129861 GG 和 SLC22A12 rs505802 TT 基因型的个体将需要超过最大剂量，因此需要选择替代药物。
提出的别嘌醇给药指南使用个体的无脂肪体质量、肾功能和 SLC22A12 rs505802 和 PDZK1 rs12129861 基因型来达到目标 SU。
