PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 27 (2018) Abstr 8470 [www.page-meeting.org/?abstract=8470]
Poster: Drug/Disease modelling - Other topics
M. Machacek (1), L. Renaud (1), C. Kohl (2), M. Vercauteren (2), L. Remen (2), R. Welford (2)
(1) LYO-X GmbH, Ringstrasse 9, 4123 Allschwil, Switzerland. (2) Idorsia Pharmaceuticals Limited, Hegenheimermattweg 91, 4123 Allschwil, Switzerland
Objectives: High levels of systemic serotonin (5-HT) are implicated in several diseases including carcinoid syndrome, pulmonary arterial hypertension and obesity. Systemic 5-HT is produced from dietary tryptophan (Trp) where the rate limiting step its catalysis by tryptophan hydroxylase 1 (TPH1). A TPH1 enzyme inhibitor was recently approved for treatment of carcinoid syndrome and others are in development. To enable observation of changes in 5-HT synthesis in vivo on an hour time scale and to test new TPH1 inhibitors we previously described an approach utilizing a stable isotope Trp tracer (h-Trp) . The aim of the current study was to develop a Systems Pharmacology model to explain the kinetics, distribution and compartmentalization involved in h-5-HT and 5-HT production and to utilize the model to predict from single dose experiments long term effects on 5-HT with chronic dosing of TPH1 inhibitors.
Methods: Data from a h-Trp study in Beagle dog was used to develop a pharmacokinetic (PK)/ pharmacodynamic (PD) model. Dogs received a single oral dose of 12 mg/kg h-Trp one hour after receiving orally vehicle, 0.2, 1 or 5 mg/kg of a TPH1 inhibitor. TPH1 inhibitor PK, h-Trp, Trp, h-5-HT and 5-HT observations were available for 1 day, and 5-HT pathway observations in the vehicle group for 11 days. As expected for a single dose treatment, no effect on whole blood 5-HT was observed due to its slow turnover. A compartmental population PK/PD approach was used to describe the concentration-time curves of the enzyme inhibitor in plasma, and h-Trp, Trp, h-5-HT and 5-HT in whole blood. It was assumed that the distribution parameters were identical for the isotope labeled and non-labeled species. Further, the enzymatic reaction rates were assumed to be identical and the competition between Trp and h-Trp for the enzyme TPH1 was modelled as described in . The simples t compartment structure was sought that would explain the observed data and the model parameters were estimated with Monolix 4.3.3.
Results: Trp had a three-compartmental kinetics with the first two distribution half-lives of 6.5 minutes and 7.6 hours, and a terminal half-life of 5.8 days. The conversion of Trp to 5-HT occurred in two different peripheral effect compartments with two very different exchange rate constants for 5-HT with the plasma compartment. These two reaction compartments were different from the two peripheral compartments for the distribution of Trp and simpler models were unable to describe the observed h-Trp and h-5-HT. In the first compartment, h-5-HT had a half-life equivalent of 6.7 seconds and in the second compartment of 16.9 hours. Thus, after oral intake of h-Trp there was immediate appearance of h-5-HT in the circulation because of the fast compartment; while the slow compartment was responsible for the storage and release of h-5-HT into the circulation after h-Trp has been eliminated. The half-life of whole blood 5-HT in dog was estimated as 4.2 days. Plate lets, that are the main site of 5-HT storage in blood have a half-life of 3.3 days . From the model, it was found that 90% of the 5-HT is in blood, 10 % in the slow storage compartment and 0.001% in the fast storage compartment. For model validation, the effect of daily dosing of 30 mg/kg of the TPH1 test inhibitor administration for 2 weeks on whole blood 5-HT in dogs was successfully predicted. Further, the model correctly predicted the blood Trp levels in dog after 24 hours fasting followed by daily feeding for 11 days.
Conclusions: The model built from the stable isotope tracing data indicated the need for slow and fast 5-HT production compartments. The fast release compartment is likely the gut, the major site of peripheral 5-HT synthesis. The second compartment may represent synthesis in other organs such as lung  or a slower release process from gut at a different time scale. 90% of the 5-HT is stored in platelets and only 10% at the site where it is synthesized. Different sites of peripheral 5-HT synthesis and different exchange rates will be critically relevant to the design and development of novel effective TPH1 inhibitors. Further, the System Pharmacology model can be further developed as a translational tool to predict doses of TPH1 inhibitors to reach different 5-HT lowering thresholds in patients.