RT Journal Article SR Electronic T1 Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1793 OP 1799 DO 10.2967/jnumed.115.160986 VO 56 IS 11 A1 Tal Burt A1 Douglas C. Rouse A1 Kihak Lee A1 Huali Wu A1 Anita T. Layton A1 Thomas C. Hawk A1 Douglas H. Weitzel A1 Bennett B. Chin A1 Michael Cohen-Wolkowiez A1 Shein-Chung Chow A1 Robert J. Noveck YR 2015 UL http://jnm.snmjournals.org/content/56/11/1793.abstract AB 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.