Grasping the Underlying Mechanisms of drug Disposition and Receptor Occupancy by Positron-emission tomography Studies (GUMDROPS)

Intervention in the renin-angiotensin-aldosterone-system is a cornerstone treatment to slow renal function decline in diabetes. Accordingly, the guideline suggests that all patients should be treated with an Angiotensin-Converting-Enzym-inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB). Yet, a significant proportion of patients does not respond to ACEi or ARB therapy both in terms of its surrogates like albuminuria and hard renal outcomes. Consequently, a considerable proportion of patients remain at high risk of progressive renal function loss. We hypothesize that the variability in drug response between individuals is the result of between individual variability in drug disposition to target tissues. To test this hypothesis we have synthesized an 11C PET radiotracer of the ARB telmisartan, retaining the original molecular structure. As a first step, we will evaluate 11C-telmisartan receptor specific binding, receptor occupancy, and optimal PET scanning time. As such, in this clinical feasibility study, we will generate essential PET data to optimize the design of a future clinical study in patients with type 2 diabetes and microvascular complications.

We hypothesize that the underlying mechanisms of the varying response in multiple parameters within an individual can be attributed to variability in the causal path between drug administration, drug tissue distribution, and tissue receptor interaction.

In this clinical feasibility study we will assess radiolabeled telmisartan pharmacokinetic characteristics and determine specific receptor binding, receptor occupancy and optimal scanning time in patients with diabetes and microvascular complications. The main objectives are;

To assess telmisartan target (i.e. receptor) specific binding in vivo

To assess receptor occupancy of telmisartan in vivo

During the study day, for all patients, after radiotracer drug administration, arterial plasma samples will be taken obtained by an automated sampler for radioactivity in full blood and plasma. After administration of oral telmisartan 10 venous blood samples will be obtained for telmisartan PK assessment. 24-hour urine will be collected for the measurement of 24-h protein, albumin, sodium, potassium, creatinine, and urea excretion.

On the study day, a non-diagnostic dose CT scan will be performed to optimally position the individual patient for the dynamic PET scan (e.g. with kidney, aorta and part of the liver inside the field of view) and attenuation correction, respectively. At time=0, patients will receive an intravenous diagnostic dose of 400Mbq 11Ctelmisartan radiotracer followed by a 90-minute dynamic PET scan. Then, three dose groups will receive an oral dose of 20, 80 or 120 mg telmisartan, respectively at t=3h. At the approximate time of maximal plasma telmisartan concentration (tmax, t=4h) a second intravenous radiotracer dose will be administered immediately followed by a second 90-minute dynamic PET scan. In this second scan, receptor binding sites are occupied by telmisartan, hence the reduction of radiotracer uptake compared to the baseline scan can be used to determine the receptor occupancy based on the binding potentials obtained from both scans. In all patients arterial plasma samples will be taken after radiotracer administration, to quantify radiation measure and venous blood samples will be taken after oral telmisartan administration to obtain plasma concentrations of telmisartan.