UNASSIGNED: Intra-Arterial Microdosing (IAM) is a novel drug development approach combining 'intra-arterial drug delivery' and 'microdosing'. We aimed to demonstrate that IAM leads to similar target exposure as systemic full-dose administration but with minimal systemic exposure. IAM could enable safe, inexpensive and early study of novel drugs at the first-in- @entity1 stage and the study of established drugs in vulnerable populations. METHODS: Insulin was administered intra-arterially ( @entity2096 ) or systemically to 8 CD @entity26972 @entity35 just prior to blood sampling or 60-minute @entity419 uptake PET imaging of ipsilateral and contralateral leg muscles (lateral gastrocnemius), and systemic muscles (spinotrapezius). @entity419 uptake slope analysis was used to compare the interventions. Plasma levels of insulin and @entity413 were compared using Area Under the Curve (AUC) calculated by the linear trapezoidal method. A physiologically-based computational pharmacokinetics (PK) / pharmacodynamics (PD) model was constructed to simulate the relationship between the administered dose and response over time. RESULTS: @entity419 slope analysis found no difference between IAM and systemic full-dose slopes (0.0066 and 0.0061, respectively; 95% 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 to 0.058; P = 0.0052). The PK/PD data was used to identify model parameters that describe membrane insulin binding and @entity413 -insulin dynamics. CONCLUSION: Target exposure post IAM was similar to systemic full dose administration but with minimal systemic effects. The computational PK/PD model can be generalized to predict whole-body response. Findings should be validated in larger, controlled studies in animals and @entity1 using a range of targets and classes of drugs.

Intra-Arterial Microdosing (IAM): A Novel Drug Development Approach, Proof-of-Concept PET Study in XXXX .

@entity1 :: ('9606', 'Species') :: ['humans', 'man'] @entity419 :: ('MESH:D019788', 'Chemical') :: ['(18)F-FDG'] @entity26972 :: ('OMIM:261100', 'Disease') :: ['IGS'] @entity35 :: ('10116', 'Species') :: ['rats'] @entity2096 :: ('MESH:D020428', 'Disease') :: ['ipsilateral femoral artery'] @entity413 :: ('MESH:D005947', 'Chemical') :: ['glucose']
@entity35 :: (10116,Species) :: ['Rats']
