E. Soto(1), B. Weatherley(1), M. Cella (2), P. Dua(2), S. Marshall (1)
(1) Pharmacometrics, Pfizer, UK; (2) Clinical Pharmacology, Neusentis, Pfizer, UK. Authors (except BW who is a Pfizer contractor) are employees and shareholders of Pfizer Inc
Objectives: The rising population prevalence of hyperuricemia (1) has renewed interest in the purine metabolic pathway (PMP). Dua et al (2) recently published a system pharmacology model which has determined sensitivity of the pathway to mono and dual inhibitory effects. This work highlighted the potential therapeutic value of simultaneous inhibition of XO (xanthine oxidase: enzyme responsible for oxidation of xanthine to uric acid (UA)) and URAT-1 (a transporter responsible for the reabsorption of UA). This therapeutic strategy is currently being explored via combination therapy (3) or as a target for a dual inhibitor (4). The aim of this work is to develop a mechanistic PKPD model to characterise the interaction between these points in the PMP in terms of impact on rate and extent of changes in serum and urinary concentrations of xanthine and UA.
Methods: A PKPD model was developed using NONMEM 7.2 starting from the systems model but simplified and calibrated based on healthy volunteer serum and urinary data from an internal compound (URAT-1 inhibition) and from literature data (5). The model consisted of 4 compartments, where xanthine will be either renally cleared or converted into UA prior to elimination to the UA urinary compartment. Drug effects were tested in the UA formation, UA clearance and on the xanthine clearance. Simulations were undertaken to explore the relationship between both mechanisms.
Results: Simulations showed that a potent URAT-1 inhibitor would be characterised by a significant increase in the amount of urinary uric acid eliminated on day 1 of treatment, which would then return to baseline levels as steady state is rapidly achieved. It was demonstrated that titration could minimise the day 1 effects. A similarly effective XO inhibitor on the other hand would result in a decrease in the UA over time but an increase in circulating and urinary xanthine.
Conclusions: Simulations provided greater insight into the interaction between two key mechanisms in the PMP and how balancing those may help optimize treatment with existing and emerging mono therapies while providing targets for future dual inhibitor development.
This case study also illustrates how systems pharmacology can help define specific research questions which can be explored by focused mechanistic PK/PD modelling which can ultimately be fed back into the wider systems pharmacology model.
References:
[1] Yanyan Zhu, ARTHRITIS & RHEUMATISM Vol. 63, No. 10, October 2011, pp 3136–3141.
[2] Dua et al, A systems pharmacology of purine metabolism to explore novel options for the treatment of gout, 7th Noordwijkerhout Symposium on Pharmacokinetics, Pharmacodynamics and Systems Pharmacology. April 23-25 2014, in Noordwijkerhout, The Netherlands.
[3] Xie et al, Relationship between the Dose of Urate Lowering Therapies and Serum Uric Acid in Healthy Volunteers and Gout Patients: A Model Based Meta-Analysis (MBMA), PAGE 2015.
[4] Warrell Raymond P et al, Profound Hypouricemia Induced in Human Subjects By Novel Bifunctional Inhibitors of Xanthine Oxidase and URAT1. American College of Rheumatology meeting abstracts, abstract number 830, 2014.
[5] Khosravan et al, Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a non-purine selective inhibitor of xanthine Oxidase, in a Dose Escaclation Study in Healthy Subjects.Clin Pharmacokinetics 2006, 45 (8): 821-841.
Reference: PAGE 24 (2015) Abstr 3529 [www.page-meeting.org/?abstract=3529]
Poster: Drug/Disease modeling - Other topics