Abstract

1. Intra-tumoral (I-TUMOUR) delivery is being widely explored for novel anti-cancer agents. This route is anticipated to result in high tumour concentrations leading to better efficacy and safety. Prediction of human systemic pharmacokinetics (PK) from non-clinical species facilitates understanding of pharmacokinetic-pharmacodynamic relationships, efficient dose selection, and risk assessment of novel drugs. However, there is limited knowledge on the predictability of human pharmacokinetics following I-TUMOUR delivery.

2. In this publication, we present a case study wherein human systemic PK of a novel agent administered intra-tumourally was prospectively predicted and compared with observed human PK.

3. Simple allometry was used to project the human clearance (10.5 mL/min/kg) and steady-state volume of distribution (1.4 L/kg) after intravenous (IV) dosing. Using these IV PK parameters and assuming rapid absorption and complete I-TUMOUR bioavailability, human plasma PK profile was simulated. The projected 30 min concentrations and AUC_(0–6h) were within 1.9 to 2.5-fold and 1 to 1.4-fold of the observed PK indicating a reasonable concordance between predicted and observed PK.

4. To our knowledge, this is the first article that prospectively projected human pharmacokinetics after I-TUMOUR dosing. The results from this study indicate that similar approaches can be used to project the human PK of other I-TUMOUR agents.

摘要

1. 肿瘤内 (I-TUMOUR) 递送正在被广泛探索用于新型抗癌药物。预计该途径将导致高肿瘤浓度，从而导致更好的疗效和安全性。从非临床物种预测人体全身药代动力学 (PK) 有助于理解药代动力学-药效学关系、有效的剂量选择和新药的风险评估。然而，关于 I-TUMOUR 递送后人体药代动力学的可预测性知识有限。

2. 在本出版物中，我们提出了一项案例研究，其中前瞻性地预测了肿瘤内给药的新型药物的人体全身 PK，并与观察到的人体 PK 进行了比较。

3. 使用简单的异速生长法来预测静脉 (IV) 给药后的人体清除率 (10.5 mL/min/kg) 和稳态分布容积 (1.4 L/kg)。使用这些 IV PK 参数并假设快速吸收和完整的 I-TUMOUR 生物利用度，模拟了人血浆 PK 曲线。预计的 30 分钟浓度和 AUC _{（0-6 小时）}在观察到的 PK 的 1.9 至 2.5 倍和 1 至 1.4 倍内，表明预测和观察到的 PK 之间存在合理的一致性。

4. 据我们所知，这是第一篇前瞻性预测 I-TUMOUR 给药后人体药代动力学的文章。这项研究的结果表明，类似的方法可用于预测其他 I-TUMOUR 试剂的人类 PK。