Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.
Clin Pharmacokinet. 2021 Oct;60(10):1325-1334. doi: 10.1007/s40262-021-01023-z. Epub 2021 May 6.
Theoretically, the separate estimation of clearance (CL) and bioavailability (F) requires both intravenous and extravascular injection data. This study investigated whether CL and subcutaneous F of therapeutic monoclonal antibodies (mAbs) in humans can be separately estimated from subcutaneous injection data only.
First, the geometric mean of linear pharmacokinetic parameters (CL, intercompartmental CL [Q], volume of distribution in the central compartment [V], and volume of distribution in the peripheral compartment [V]) after intravenous injection for mAbs in humans that have been reported in public data sources was estimated from 103 mAbs with linear pharmacokinetics and 44 mAbs with nonlinear pharmacokinetics. Next, we estimated the CL and F of 25 mAbs with linear pharmacokinetics from plasma/serum mAb concentration-time profiles after subcutaneous injection in humans by fixing the geometric mean of Q, V, and V based on the public data. Moreover, the plasma/serum concentration-time profile of 25 mAbs after intravenous injection was simulated using the estimated CL and the geometric mean of Q, V, and V.
There were no significant differences in parameters among subclasses (immunoglobulin [Ig] G1, 2, and 4) or in linearity (derivation from linear and nonlinear pharmacokinetics). Using only subcutaneous injection data, we successfully estimated the CL of 23/25 mAbs (92%) and F of all 25 mAbs (100%) within 1.5-fold of the observed value. Moreover, overall, the simulated concentration-time profiles were largely consistent with observed data (90.8% within 1.5-fold of the observed values).
This approach does not require intravenous injection data to separately estimate CL and F after subcutaneous injection in humans and can therefore accelerate the clinical development of mAbs.
理论上，清除率（CL）和生物利用度（F）的分别估算需要静脉内和血管外注射数据。本研究旨在探讨能否仅从皮下注射数据分别估算治疗性单克隆抗体（mAb）在人体内的 CL 和皮下 F。
首先，根据公共数据来源中报告的 103 种具有线性药代动力学的 mAb 和 44 种具有非线性药代动力学的 mAb，估算了静脉内注射后人体 mAb 的线性药代动力学参数（CL、隔室间 CL [Q]、中央隔室分布容积 [V] 和外周隔室分布容积 [V]）的几何平均值。接下来，我们通过固定 Q、V 和 V 的几何平均值，根据公共数据估算了 25 种具有线性药代动力学的 mAb 皮下注射后在人体中的 CL 和 F。此外，使用估算的 CL 和 Q、V 和 V 的几何平均值模拟了 25 种 mAb 静脉内注射后的血浆/血清 mAb 浓度-时间曲线。
在亚类（免疫球蛋白[Ig]G1、2 和 4）或线性度（来自线性和非线性药代动力学）方面，参数之间没有显著差异。仅使用皮下注射数据，我们成功估算了 23/25 mAb（92%）的 CL 和所有 25 mAb（100%）的 F，均在观察值的 1.5 倍以内。此外，总体而言，模拟的浓度-时间曲线与观察数据基本一致（90.8%在观察值的 1.5 倍以内）。
该方法不需要静脉内注射数据即可分别估算人体皮下注射后的 CL 和 F，因此可以加速 mAb 的临床开发。
