Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats
Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats
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DOI：
10.2967/jnumed.115.160986
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发表时间：
2015-11-01
影响因子：
9.3
通讯作者：
Noveck, Robert J.
中科院分区：
文献类型：
--
作者：
Burt, Tal;Rouse, Douglas C.;Noveck, Robert J.
动脉内微量给药（IAM）是一种结合动脉给药和微量给药的新型药物开发方法。我们的目的是证明IAM导致的目标暴露量与全身全剂量给药相似，但全身暴露量最小。IAM可以使安全，廉价和早期的新药研究在第一次在人类阶段，并在脆弱人群中的既定药物的研究。研究方法：8只CD IGS大鼠在采血或同侧和对侧腿部肌肉（腓肠肌外侧）和全身肌肉（脊肌）60分钟（18 F）-FDG摄取PET成像前，动脉内（同侧股动脉）或全身给予胰岛素。使用F-18-FDG摄取斜率分析来比较干预措施。使用通过线性梯形法计算的曲线下面积比较胰岛素和葡萄糖的血浆水平。构建了基于生理学的计算药代动力学/药效学模型，以模拟给药剂量与反应随时间的关系。结果如下：F-18-FDG斜率分析发现IAM和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大于全身微剂量（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。结论：IAM后的目标暴露量与全身全剂量给药相似，但全身效应最小。计算药代动力学/药效学模型可以推广到预测全身反应。研究结果应该在动物和人类中使用一系列靶点和药物类别的大型对照研究中得到验证。
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. Methods: Insulin was administered intraarterially (ipsilateral femoral artery) or systemically to 8 CD IGS rats just before blood sampling or 60-min (18F)-FDG uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius) and systemic muscles (spinotrapezius). The F-18-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. Results: F-18-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. Conclusion: 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.