Early-Phase Development: Phase-0 / Microdosing

Localized administration of an NMBD into the radial artery would have effects on hand muscles within seconds to minutes (1,2). Reduction in muscle strength, measured as percent ‘twitch response’, serves as the biomarker associated with drug efficacy. The electrical stimulus is applied to the proximal ulnar nerve to induce a depolarization with the subsequent release of acetylcholine (Ach) at the neuromuscular junction. The resulting contraction of the adductor pollicis muscle is the ‘twitch response’. This response is calibrated as a full twitch (100%). When the NMBD is administered, the reduction of the twitch can be graded (0 - 100%) where 0% represents full neuromuscular blockade. The PD action of the drug (onset, duration of the blockade and offset) can then be recorded in terms of % twitch.

This approach represents a considerable advantage over the current NMBD development process whereby a dose is administered systemically with resultant complete muscle paralysis requiring full ventilatory support. In addition, systemic NMBD studies are conducted under general anesthesia to avoid the extreme anxiety-provoking experience of complete paralysis. The utility of ITM would be the ability to administer NMBD peripherally to a circumscribed target for the purpose of studying its effects while sparing the rest of the body unnecessary exposure and expensive procedures. Furthermore, the reversal of the NMBD residual muscular block is of clinical importance and could also be studied in a safe and controlled manner using ITM in the early clinical development of NMBDs (3,4). This could prove of particular value in vulnerable populations such as children and the elderly (5,6).

An SGLT-2 (Sodium/Glucose Transporter Type 2) inhibitor is administered into the renal artery. Glucose reabsorption into the proximal tubule is thus inhibited and glucose is excreted in the urine (7). The biomarkers would be urine glucose, obtained by catheter in real-time, and 18F-FDG excretion and reabsorption (a proxy of glucose excretion and reabsorption), or 11C-labeled drug as measured by dynamic PET-imaging.

Natriuretic peptide (analog of the naturally occurring Atrial Natriuretic Peptide [ANP] and Brain Natriuretic Peptide [BNP]), a proposed vascular modulator with cardio-protective properties, is administered into the radial artery (8). Vasodilatation and cGMP concentrations serve as physical and chemical biomarkers, respectively, of drug action, and have been shown to take place within minutes of infusion 9. Vasodilatation, conveniently studied in peripherally accessed vessels, is measured using venous occlusion plethysmography. Plasma cGMP concentrations are measured using enzyme immunoassay (9).

A chemotherapeutic agent for hepatocellular carcinoma is administered into the hepatic artery (10). The drug or a biomarker (e.g., FDG) is radiolabelled. Demonstration of binding to tumor tissue through PET-imaging will be proof-of-concept that the chemotherapeutic agent reaches, penetrates, and binds to cellular targets (11). Displacement studies could confirm binding to a target of interest by administering competitive agonists or antagonists (12). Chemical biomarkers could be obtained in the downstream vein. If done during surgery, blood samples could be more easily obtained, and tissue samples of the tumor could be obtained for histological markers of therapeutic or toxic effects. Since the concentration returning to the systemic circulation becomes a microdose the traditional microdose study where systemic PK and binding to extra-hepatic tissues can be studied as well. Dynamic PET-imaging obtained to show concentrations over time could help study intra-tumour PK, systemic microdose PK, and together with the chemical data could be used to scale results to the whole-body full-pharmacological exposure (13).