Intraarterial Microdosing: A Novel Drug Development Approach, Proof-of-Concept PET Study in Rats.
Tal Burt, Douglas C Rouse, Kihak Lee, Huali Wu, Anita T. Layton, Thomas C Hawk, Douglas H Weitzel, Bennett B. Chin, Michael Cohen-Wolkowiez, Shein-Chung Chow, Robert J. Noveck
Journal of Nuclear Medicine November 2015 DOI: 10.2967/jnumed.115.160986 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal experiment Peer reviewed |
|---|---|
| Sample size | 8 |
| Population | CD IGS rats |
| Intervention | Insulin |
| Duration | 60-min 18F-FDG uptake PET imaging |
| Measures | 18F-FDG uptake slope analysis, area under the curve, physiologically based computational pharmacokinetics/pharmacodynamics model |
| Topics | Microdosing |
| Keywords | PET Imaging Drug development Intra-arterial |
| Key findings | Intraarterial microdosing of insulin produced target muscle 18F-FDG uptake similar to systemic full-dose insulin but with minimal systemic exposure, and significantly greater than systemic microdose or sham. The authors argue IAM could allow safe, inexpensive first-in-human drug study and testing in vulnerable populations, though validation in larger controlled studies is needed. |
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. 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. (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. 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.
Comparable studies
Other preclinical and animal studies on microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats | 2018 | Experimental study | n = 40 |
| Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats. Rats | 2023 | Experimental study | |
| Repeated microdoses of LSD do not alter anxiety or boldness in zebrafish. Zebrafish (Danio rerio) | 2024 | Experimental study | |
| Application of microarray patches for the transdermal administration of psychedelic drugs in micro-doses. Excised neonatal porcine skin and rats | 2025 | Experimental study | |
| Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing Paired sensitive and resistant cancer cell lines, AML cell lines, and 10 viably... | 2018 | Preclinical cell line study with a pilot retrospective analysis of primary patient samples | n = 10 |
Citations in the library
Cited by 6
- Phase 0/microdosing approaches: time for mainstream application in drug development? Nature Reviews Drug Discovery September 8, 2020
- Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development Clinical and Translational Science February 26, 2016
- Phase 0 trials/ Intra-Target-Microdosing (ITM) and the lung: a review BMC Pulmonary Medicine September 1, 2024
- Intra‐Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans Clinical and Translational Science July 8, 2017
- Intra‐Target Microdosing (ITM): A Novel Drug Development Approach Aimed at Enabling Safer and Earlier Translation of Biological Insights Into Human Testing Clinical and Translational Science April 18, 2017
and 1 more in the library
Cites 5
- Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development European Journal of Clinical Pharmacology September 1, 2003
- Big physics, small doses: the use of AMS and PET in human microdosing of development drugs Nature Reviews Drug Discovery February 28, 2003
- Microdosing and drug development: past, present and future Expert Opinion on Drug Metabolism & Toxicology April 4, 2013
- Impact of microdosing clinical study — Why necessary and how useful? Advanced Drug Delivery Reviews October 14, 2010
- Predicting Drug Candidate Victims of Drug-Drug Interactions, using Microdosing Clinical Pharmacokinetics February 16, 2012