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06.04.2019 | Original Research Article | Ausgabe 9/2019 Open Access

Clinical Pharmacokinetics 9/2019

Population Pharmacokinetic and Pharmacodynamic Analysis of GLPG1690, an Autotaxin Inhibitor, in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis

Clinical Pharmacokinetics > Ausgabe 9/2019
Amit Taneja, Julie Desrivot, Paul Matthias Diderichsen, Roland Blanqué, Lisa Allamasey, Liesbeth Fagard, Ann Fieuw, Ellen Van der Aar, Florence Namour
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s40262-019-00755-3) contains supplementary material, which is available to authorized users.


Background and Objectives

GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure–response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis.


Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300–1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure–response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily.


The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50–1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily.


Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis.

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