title: Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats.
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.
  
  
  CONCLUSIONS
  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.
authors: Duke University, Durham, North Carolina; and tal.burt@duke.edu.
authors: Tal
authors: T
authors: Burt
authors: Duke University, Durham, North Carolina; and.
authors: Douglas C
authors: DC
authors: Rouse
authors: Siemens Medical Solutions USA, Knoxville, Tennessee.
authors: Kihak
authors: K
authors: Lee
authors: Duke University, Durham, North Carolina; and.
authors: Huali
authors: H
authors: Wu
authors: Duke University, Durham, North Carolina; and.
authors: Anita T
authors: AT
authors: Layton
authors: Duke University, Durham, North Carolina; and.
authors: Thomas C
authors: TC
authors: Hawk
authors: Duke University, Durham, North Carolina; and.
authors: Douglas H
authors: DH
authors: Weitzel
authors: Duke University, Durham, North Carolina; and.
authors: Bennett B
authors: BB
authors: Chin
authors: Duke University, Durham, North Carolina; and.
authors: Michael
authors: M
authors: Cohen-Wolkowiez
authors: Duke University, Durham, North Carolina; and.
authors: Shein-Chung
authors: SC
authors: Chow
authors: Duke University, Durham, North Carolina; and.
authors: Robert J
authors: RJ
authors: Noveck
mesh_terms: D000465:Algorithms; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003198:Computer Simulation; D016503:Drug Delivery Systems; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007090:Image Interpretation, Computer-Assisted; D007269:Injections, Intra-Arterial; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008297:Male; D015233:Models, Statistical; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18
keywords: PET imaging; drug development; exploratory investigational new drug (eIND); intra-arterial; microdosing