Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats

Journal of Nuclear Medicine

Thomas C. Hawk¹  Robert J. Noveck¹  Anita T. Layton¹  Douglas C. Rouse¹  Huali Wu¹  Kihak Lee¹  Bennett B. Chin¹  Shein-Chung Chow¹  Tal Burt¹  Michael Cohen-Wolkowiez¹  Douglas H. Weitzel¹ 

关键词: microdosing;    intra-arterial;    PET imaging;    drug development;    exploratory investigational new drug (eIND);   

DOI  :  10.2967/jnumed.115.160986

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 18F-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: 18F-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.

【 授权许可】

Unknown