My Profile

Search abstracts

Lewis Sheiner


2014
Alicante, Spain



2013
Glasgow, Scotland

2012
Venice, Italy

2011
Athens, Greece

2010
Berlin, Germany

2009
St. Petersburg, Russia

2008
Marseille, France

2007
KÝbenhavn, Denmark

2006
Brugge/Bruges, Belgium

2005
Pamplona, Spain

2004
Uppsala, Sweden

2003
Verona, Italy

2002
Paris, France

2001
Basel, Switzerland

2000
Salamanca, Spain

1999
Saintes, France

1998
Wuppertal, Germany

1997
Glasgow, Scotland

1996
Sandwich, UK

1995
Frankfurt, Germany

1994
Greenford, UK

1993
Paris, France

1992
Basel, Switzerland



Printable version

PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
ISSN 1871-6032

Reference:
PAGE 18 (2009) Abstr 1507 [www.page-meeting.org/?abstract=1507]


PDF poster/presentation:
Click to openClick to open

Oral Presentation: Clinical Applications


William Denney Modeling and Simulation for Determination of the Therapeutic Window of MK-2295: a TRPV1 Antagonist

WS Denney (1), Y Hang (2), MF Dockendorf (1), C-C Li (1), SR Eid (3), R Valesky (1), T Laethem (5), P Van Hoydonck (5), I DeLepeleire (5), JNJM de Hoon (6), M Crutchlow (4), R Blanchard (4)

(1) Drug Metabolism and Pharmacokinetics, (2) BARDS, (3) Pain Research, (4) Clinical Pharmacology Merck Research Laboratories, PA, USA, (5) Clinical Pharmacology, MSD (Europe), (6) Center for Clinical Pharmacology, University Hospital Gasthuisberg (K.U. Leuven), Leuven, Belgium

Objectives: MK-2295 is a potent TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonist currently in clinical development for chronic pain. The therapeutic window and the dose to maintain plasma concentrations within that therapeutic window were determined with the goal of determining a dosing regimen that would allow safe, efficacious administration.

Methods: Population pharmacokinetic (PK) and PK/pharmacodynamic (PK/PD) analyses were performed using NONMEM VI based on data from five clinical trials with approximately 182 subjects treated with drug and/or placebo. A 2-compartment PK model with covariates for age and gender was developed to describe the MK-2295 PK. A series of PK/PD models was developed which related MK-2295 concentration to markers of on-target and undesired activity: core body temperature (CBT, standard Emax with diurnal variation), capsaicin-induced dermal vasodilation (CIDV, competitive Emax), warmth sensation threshold (WS, standard Emax), and hot water bath hand withdrawal time (HWT, Weibull time to event with a standard Emax as the scale parameter).

Results:The EC50s for CBT and CIDV, both markers for MK-2295 on-target activity, were 69.9 and 57.9 nM, respectively. The EC50s for WS and HWT were 267 and 292 nM. While effects on HWT strongly suggest on-target activity, effects of MK-2295 on WS may reflect undesired activity. PK/PD simulation indicated that thermal sensitivity was highly correlated with other target engagement measures (CBT and CIDV) and thus it was impossible to identify a dosing regimen of MK-2295 that was predicted to be efficacious yet also devoid of risk for burn injury.

Conclusions:Modeling and simulation suggested that it is not possible to decouple the loss of temperature sensitivity from the on-target effects of MK-2295. Such modeling efforts can greatly inform decision making.

References:
[1] Van der Schueren J, et al. (2007a) MK-0974, an oral CGRP antagonist, inhibits capsaicin-induced vasodilation in the human skin. Basic Clin Pharmacol Toxicol 101 (Suppl 1): 33.
[2] Szallasi A, et al. (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nature Drug Discovery: 6.