Burt Tal, Rouse Douglas C, Lee Kihak, Wu Huali, Layton Anita T, Hawk Thomas C, Weitzel Douglas H, Chin Bennett B, Cohen-Wolkowiez Michael, Chow Shein-Chung, Noveck Robert J
Duke University, Durham, North Carolina; and
Duke University, Durham, North Carolina; and.
J Nucl Med. 2015 Nov;56(11):1793-9. doi: 10.2967/jnumed.115.160986. Epub 2015 Aug 27.
Intraarterial microdosing (IAM) is a novel drug development approach combining intraarterial drug delivery and microdosing. We aimed to demonstrate that IAM leads to target exposure similar to that of systemic full-dose administration but with minimal systemic exposure. IAM could enable the safe, inexpensive, and early study of novel drugs at the first-in-human stage and the study of established drugs in vulnerable populations.
Insulin was administered intraarterially (ipsilateral femoral artery) or systemically to 8 CD IGS rats just before blood sampling or 60-min (18)F-FDG uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius) and systemic muscles (spinotrapezius). The (18)F-FDG uptake slope analysis was used to compare the interventions. Plasma levels of insulin and glucose were compared using area under the curve calculated by the linear trapezoidal method. A physiologically based computational pharmacokinetics/pharmacodynamics model was constructed to simulate the relationship between the administered dose and response over time.
(18)F-FDG slope analysis found no difference between IAM and systemic full-dose slopes (0.0066 and 0.0061, respectively; 95% confidence interval [CI], -0.024 to 0.029; P = 0.7895), but IAM slope was statistically significantly greater than systemic microdose (0.0018; 95% CI, -0.045 to -0.007; P = 0.0147) and sham intervention (-0.0015; 95% CI, 0.023-0.058; P = 0.0052). The pharmacokinetics/pharmacodynamics data were used to identify model parameters that describe membrane insulin binding and glucose-insulin dynamics.
Target exposure after IAM was similar to systemic full dose administration but with minimal systemic effects. The computational pharmacokinetics/pharmacodynamics model can be generalized to predict whole-body response. Findings should be validated in larger, controlled studies in animals and humans using a range of targets and classes of drugs.
动脉内微量给药（IAM）是一种将动脉内药物递送与微量给药相结合的新型药物研发方法。我们旨在证明，IAM可实现与全身全剂量给药相似的靶点暴露，但全身暴露最小。IAM能够在人体首次给药阶段对新型药物进行安全、低成本的早期研究，并对弱势群体中的已上市药物进行研究。
在对同侧和对侧腿部肌肉（外侧腓肠肌）及全身肌肉（斜方肌）进行采血或60分钟（18）F-FDG摄取PET成像之前，对8只CD IGS大鼠经动脉（同侧股动脉）或全身给予胰岛素。采用（18）F-FDG摄取斜率分析比较不同干预措施。使用线性梯形法计算曲线下面积，比较胰岛素和葡萄糖的血浆水平。构建基于生理的计算药代动力学/药效学模型，以模拟给药剂量与随时间变化的反应之间的关系。
（18）F-FDG斜率分析发现，IAM与全身全剂量斜率之间无差异（分别为0.0066和0.0061；95%置信区间[CI]，-0.024至0.029；P = 0.7895），但IAM斜率在统计学上显著高于全身微量给药（0.0018；95%CI，-0.045至-0.007；P = 0.0147）和假干预（-0.0015；95%CI，0.023 - 0.058；P = 0.0052）。药代动力学/药效学数据用于确定描述膜胰岛素结合和葡萄糖 - 胰岛素动力学的模型参数。
IAM后的靶点暴露与全身全剂量给药相似，但全身效应最小。该计算药代动力学/药效学模型可推广用于预测全身反应。研究结果应在使用一系列靶点和药物类别的动物和人体大型对照研究中进行验证。
