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

Abstract

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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

• Authors: Amit Taneja, Julie Desrivot, Paul Matthias Diderichsen, Roland Blanqué, Lisa Allamasey, Liesbeth Fagard, Ann Fieuw, Ellen Van der Aar, Florence Namour
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 58 Issue 9 Pg. 1175-1191 (09 2019) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 30953319 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Antibiotics, Antitubercular
• Biomarkers, Pharmacological
• GLPG1690
• Imidazoles
• Lysophospholipids
• Pyrimidines
• Phosphoric Diester Hydrolases
• alkylglycerophosphoethanolamine phosphodiesterase
• lysophosphatidic acid
• Rifampin

Topics

• Adult
• Aged
• Antibiotics, Antitubercular (administration & dosage)
• Biomarkers, Pharmacological (blood)
• Case-Control Studies
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• Healthy Volunteers
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, physiopathology)
• Imidazoles (administration & dosage, pharmacokinetics, pharmacology)
• Lysophospholipids (blood, pharmacokinetics, pharmacology)
• Male
• Middle Aged
• Phosphoric Diester Hydrolases (drug effects)
• Pyrimidines (administration & dosage, pharmacokinetics, pharmacology)
• Rifampin (administration & dosage)