Duong Janna K, Kroonen M Y A M, Kumar S S, Heerspink H L, Kirkpatrick C M, Graham G G, Williams K M, Day R O
School of Medical Sciences, Medicine, University of New South Wales, Sydney, Australia.
Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, Australia.
Eur J Clin Pharmacol. 2017 Aug;73(8):981-990. doi: 10.1007/s00228-017-2251-1. Epub 2017 Apr 28.
The aims of this study were to investigate the relationship between metformin exposure, renal clearance (CL), and apparent non-renal clearance of metformin (CL/F) in patients with varying degrees of kidney function and to develop dosing recommendations.
Plasma and urine samples were collected from three studies consisting of patients with varying degrees of kidney function (creatinine clearance, CL; range, 14-112 mL/min). A population pharmacokinetic model was built (NONMEM) in which the oral availability (F) was fixed to 0.55 with an estimated inter-individual variability (IIV). Simulations were performed to estimate AUC, CL, and CL/F.
The data (66 patients, 327 observations) were best described by a two-compartment model, and CL was a covariate for CL. Mean CL was 17 L/h (CV 22%) and mean CL/F was 1.6 L/h (69%).The median recovery of metformin in urine was 49% (range 19-75%) over a dosage interval. When CL increased due to improved renal function, AUC decreased proportionally, while CL/F did not change with kidney function. Target doses (mg/day) of metformin can be reached using CL/3 × 100 to obtain median AUC of 18-26 mg/L/h for metformin IR and AUC of 38-51 mg/L/h for metformin XR, with C < 5 mg/L.
The proposed dosing algorithm can be used to dose metformin in patients with various degrees of kidney function to maintain consistent drug exposure. However, there is still marked IIV and therapeutic drug monitoring of metformin plasma concentrations is recommended.
本研究旨在调查不同肾功能程度患者中二甲双胍暴露量、肾清除率（CL）和二甲双胍表观非肾清除率（CL/F）之间的关系，并制定给药建议。
从三项研究中收集血浆和尿液样本，这些研究包含不同肾功能程度（肌酐清除率，CL；范围为14 - 112 mL/min）的患者。建立了一个群体药代动力学模型（NONMEM），其中口服生物利用度（F）固定为0.55，并估计个体间变异性（IIV）。进行模拟以估计AUC、CL和CL/F。
数据（66例患者，327次观察）用二室模型能得到最佳描述，且CL是CL的协变量。平均CL为17 L/h（CV 22%），平均CL/F为1.6 L/h（69%）。在一个给药间隔内，二甲双胍在尿液中的中位回收率为49%（范围19 - 75%）。当肾功能改善导致CL增加时，AUC成比例下降，而CL/F不随肾功能改变。使用CL/3×100可达到二甲双胍的目标剂量（mg/天），使二甲双胍速释片的中位AUC为18 - 26 mg/L/h，二甲双胍缓释片的AUC为38 - 51 mg/L/h，C<5 mg/L。
所提出的给药算法可用于不同肾功能程度患者的二甲双胍给药，以维持一致的药物暴露。然而，个体间变异性仍然显著，建议对二甲双胍血浆浓度进行治疗药物监测。
