A mechanistic PKPD model relating early asthmatic response to anti-leukotriene drug PK and biomarker levels in allergen challenge studies
Victor Sokolov (1), Tatiana Yakovleva (1), Kirill Zhudenkov (1), Anne-Kristina Mercier (3), Gabriel Helmlinger (2), Kirill Peskov(1), Ulf Eriksson (3)
(1) M&S Decisions, Moscow, Russia (2) Quantitative Clinical Pharmacology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Waltham, USA and (3) Gothenburg, Sweden
Objectives: Inhibition of leukotriene (LT) production in asthmatic patients attenuates the drop in Forced Expiratory Volume in 1 second (FEV1) after allergen provocation . Measurement of LTE4 (uLTE4) levels in urine is an efficacy biomarker used in early phase clinical development, while FEV1 is an endpoint of choice in later phases. FEV1 is highly variable and dependent upon multiple factors, thus the prediction of FEV1 response based on early clinical biomarker data is a challenge. Our aim was to describe the relationship between LT-inhibitor pharmacokinetics (PK), pre-challenge suppression of blood LTB4 and uLTE4 levels, and the degree of early FEV1 reduction in the context of an allergen challenge study in asthma.
Methods: Published data from clinical Phase I and II studies of a 5-Lipoxigenase-activating-protein inhibitor (GSK2190915) and a 5-Lipoxigenase inhibitor (MK-0591) were used to build the model [2-4]. Only early asthmatic response (within 2 hours after allergen challenge) was incorporated into the model.
Modeling was performed in the IQM Tools (replacing the SBTOOLBOX2 by IntiQuan - http://www.intiquan.com/). The model was based on a 2-compartment module for PK, an “Imax” transit compartment to describe the biomarker, and an indirect response function to describe the allergen challenge and the FEV1 endpoint estimation.
Results: The model reproduced uLTE4 suppression by 10-450 mg of GSK2190915  and 50-500 mg of MK-0591  and evidenced a quantitative link between pre-challenge uLTE4 levels and FEV1 within the first 2 hours following allergen challenge. The basic shape of the early FEV1 response was dependent upon the type of challenge and followed the same exponential form across the studies analyzed [2-4], while trough FEV1 levels were linearly dependent upon LT suppression. Predictions of FEV1 levels were in full agreement with the data reported for the 250 mg MK-0591 study (13% maximal drop in FEV1 comparing to baseline)  and for the 10-100 mg GSK2190915 studies (0.8-0.5 L maximal drop in FEV1 comparing to baseline) [3, 4].
Conclusions: We developed a PKPD model describing the relationship between LT-inhibitor PK, pre-allergen-challenge uLTE4 levels and early post-allergen-challenge FEV1. Such a model may be applied towards the prediction of FEV1 response in Phase II allergen challenge studies, based on Phase I compound PK and uLTE4 suppression data.
 Pol Merkur Lekarski. 1998 Dec;5(30):317-20
 J Allergy Clin Immunol. 1995 Jan;95(1 Pt 1):42-51
 Clin Exp Allergy. 2013 Feb;43(2):177-86
 Int J Gen Med. 2013 Dec 9;6:897-903
 Br J Clin Pharmacol. 2013 Mar;75(3):779-90
 Br J Clin Pharmacol. 1995 Jul;40(1):59-66