Laboratoire de Pharmacologie, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Henri Mondor, Université Paris Est-Créteil, Créteil, France.
Centre de référence pour les syndromes drépanocytaires majeurs, AP-HP, Hôpitaux Universitaires Henri Mondor, Université Paris Est-Créteil, Créteil, France.
Br J Clin Pharmacol. 2021 May;87(5):2274-2285. doi: 10.1111/bcp.14653. Epub 2020 Dec 14.
This prospective study aimed to develop a population pharmacokinetics (PK) model of hydroxyurea (HU) in patients with sickle cell disease. This model can be used to determine the impact of glomerular filtration rate (GFR) on HU kinetics.
We included 30 patients. They underwent HU pharmacokinetics analyses of plasma and urine. Six underwent PK analyses in 2 periods with and without angiotensin-converting enzyme inhibitor. HU was assayed with a validated high-performance liquid chromatography-UV method. Noncompartmental PK analysis was conducted and a population PK model built with Monolix. This model was validated externally on another 56 patients. HU PK was simulated as a function of GFR.
The HU PK model was constructed as a 2-compartment model with first-order absorption and elimination. The quality criteria were good, including for external validation. We found that estimated GFR (eGFR) and body weight affected HU PK, with lower eGFR or body weight associated with a higher HU area under the curve. We recommend the monitoring of HU through eGFR and body weight, which together account for 47% of its variability. Urinary HU fractions and renal clearance were higher in the glomerular hyperfiltration group and lower in the moderate chronic kidney disease group, respectively. No differences in nonrenal HU clearance were observed.
Estimated GFR has an impact on the kinetics of hydroxyurea, and HU dose should be adapted accordingly. Angiotensin-converting enzyme inhibitor seems to have minor effect on HU PK in adults with sickle cell disease.
本前瞻性研究旨在建立镰状细胞病患者羟基脲（HU）的群体药代动力学（PK）模型。该模型可用于确定肾小球滤过率（GFR）对 HU 动力学的影响。
我们纳入了 30 名患者。他们进行了 HU 血浆和尿液的 PK 分析。其中 6 名患者在使用和不使用血管紧张素转换酶抑制剂的 2 个时期进行了 PK 分析。HU 采用经过验证的高效液相色谱-紫外法测定。进行非房室 PK 分析，并使用 Monolix 构建群体 PK 模型。该模型在另外 56 名患者中进行了外部验证。HU PK 模拟为 GFR 的函数。
HU PK 模型构建为具有一级吸收和消除的 2 室模型。质量标准良好，包括外部验证。我们发现估计的肾小球滤过率（eGFR）和体重影响 HU PK，较低的 eGFR 或体重与较高的 HU 曲线下面积相关。我们建议通过 eGFR 和体重监测 HU，它们共同解释了其 47%的变异性。肾小球滤过率增高组的尿 HU 分数和肾清除率较高，而中度慢性肾脏病组的肾清除率较低。非肾 HU 清除率无差异。
估计的肾小球滤过率对羟基脲的动力学有影响，应相应调整 HU 剂量。血管紧张素转换酶抑制剂似乎对镰状细胞病成人的 HU PK 影响较小。
