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

J Nucl Med. 2015 Nov;56(11):1793-9. doi: 10.2967/jnumed.115.160986. Epub 2015 Aug 27.

Abstract

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 (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.

Results: (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.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Blood Glucose / metabolism
  • Computer Simulation
  • Drug Delivery Systems
  • Fluorodeoxyglucose F18 / administration & dosage*
  • Fluorodeoxyglucose F18 / adverse effects
  • Fluorodeoxyglucose F18 / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Image Interpretation, Computer-Assisted
  • Injections, Intra-Arterial
  • Insulin / blood
  • Insulin / pharmacology
  • Male
  • Models, Statistical
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / administration & dosage*
  • Radiopharmaceuticals / adverse effects
  • Radiopharmaceuticals / pharmacokinetics
  • Rats

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Radiopharmaceuticals
  • Fluorodeoxyglucose F18