Inhibition of salivary glands to reduce uptake and toxicity of PSMA-ligands

Many pharmaceuticals can damage salivary glands, and this can lead to a dry
mouth (xerostomia) with detrimental effect on quality of life. Systemically
administered pharmaceuticals reach the salivary glands via blood supply and
diffusion, and their accumulation can be further augmented by active or passive
transporters. This mechanism also applies to radiopharmaceuticals used in
radionuclide therapy (RNT). Radiolabelled ligands to the prostate-specific
membrane antigen (PSMA) are increasingly used to treat metastatic prostate
cancer. The currently applied Lutetium-177-PSMA-617 ligand (Lu-PSMA) shows very
high uptake in salivary glands, which is explained by the high perfusion of
salivary glands and the abundant expression of the PSMA receptor on their
acinar and ductal seromucous cells. As a result, salivary glands are
inadvertently exposed to high radiation doses in Lu-PSMA treatment, with
xerostomia as a known dose-limiting factor. Other pharmaceutical treatments
with potentially significant salivary gland toxicity include RNT with
Iodine-131 and various chemotherapies (often in combination with external beam
radiotherapy).
Salivation can be inhibited with anticholinergic / antimuscarinergic
pharmaceuticals that target the sympatic and parasympatic nerve systems.
Glycopyrronium bromide (GPB) inhibits salivary glands and induces
vasoconstriction in afferent vasculature via antagonizing the muscarine
receptor subtype 3 (M3) and to a lesser extent subtype 2 (M2). Intravenous
administration of 0.2mg GPB results in a temporary reduction in salivation to
about 25%, that lasts for a few hours and recovers in the course of 6-8 hours.
Central effects hardly occur since it does not cross the blood-brain barrier.
Temporary peripheral side effects have been described (e.g. vomiting,
constipation, urine retention, tachycardia and flushes), however with a single
dose of 0.2mg the incidence and extent of peripheral side effects is limited.
The hypothesis is that inhibition with GPB during the biodistribution phase of
toxic pharmaceuticals leads to reduced delivery to and accumulation in salivary
glands, consequentially resulting in less toxicity. The uptake of PSMA-ligands
can be assessed with quantitative PET/CT imaging using the diagnostic
radiopharmaceutical Gallium-68-PSMA (Ga-PSMA). A reduction in Ga-PSMA uptake in
salivary glands achieved by GPB will predict a similar protective effect for
treatment with Lu-PSMA, and potentially for treatments with other systemically
administered pharmaceuticals.
A secondary hypothesis is that suppressed local perfusion in salivary glands is
the main effector mechanism in the anticipated reduction of pharmaceutical
uptake by GPB. Reductions in local perfusion can be assessed using quantitative
arterial spin labelling magnetic resonance (ASL MR) imaging. This technique
allows continuous sampling of perfusion parameters in vivo, without a need for
administration of intravenous contrast and thus without toxicity.

To determine if inhibition with GPB can provide a significant reduction in the
accumulation of systemically administered Ga-PSMA in salivary glands on PET/CT,
with the aim to determine if GPB can prevent toxicity from Lu-PSMA or other
pharmaceuticals. Perfusion will be measured to determine if ASL MRI provides a
measurable signal for application in subsequent studies.

Prospective interventional phase II study.

Intravenous administration of the investigational product GPB.

Participating patients will visit the hospital for 1 extra day, for a single
administration of GPB by IV canula, a single PSMA PET/CT including tracer
administration by the same IV canula, and (optional) 2 x ASL MR of the neck
without contrast fluid. In addition, patients will experience temporary signs
of the effect of GPB, including the feeling of a dry mouth or skin, which will
disappear after an average of 8 hours.