Pharmacokinetics and Metabolism of Ziritaxestat (GLPG1690) in Healthy Male Volunteers Following Intravenous and Oral Administration

Abstract

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600‐mg ziritaxestat labeled with a carbon‐14 tracer (14C‐ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100‐μg microdose, labeled with a microtracer amount of 14C radiation, was administered in a separate part of the study, following an unlabeled 600‐mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug‐related product. There were 7 treatment‐emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

Ziritaxestat Drug–Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition

“…Ziritaxestat PK parameters following the 600 mg q.d. dose were similar to those observed in previous studies in healthy male volunteers, 3,5 indicating that subjects were exposed as expected to ziritaxestat.…”

“…and oral contraceptive vs. oral contraceptive alone; however, ziritaxestat was generally well tolerated with a safety profile consistent with findings from previous studies in healthy male subjects. 3,5 Ziritaxestat PK parameters following the 600 mg q.d. dose were similar to…”

“…In vitro studies indicate that ziritaxestat is a weak inducer and inhibitor of CYP3A4. 3 Predictions based on the in vitro data indicated that ziritaxestat-mediated induction of CYP3A4 is expected to decrease exposure of a CYP3A4 probe substrate by ≤ 30%, with inhibition expected to result in a maximum increase in probe substrate metabolism of 1.5-fold. The inhibition of CYP3A4 was competitive and reversible (data on file).…”

“…Laboratory tests, vital signs measurement, 12-lead electrocardiograms (ECGs), and physical examinations were performed at screening, day 1, and at follow-up (full details shown in Table S1). Ziritaxestat PKs were also evaluated as a secondary end point in this study, but as these parameters have been described in detail previously, 3,5 they will not be reported further here. Other study end points included performing an in vivo analysis of SULT1E1 and UGT1A1 inhibition by ziritaxestat.…”

“…Ziritaxestat (GLPG1690) is an autotaxin inhibitor that was, until recently, in development for the oral treatment of fibrotic diseases, such as idiopathic pulmonary fibrosis (phase III clinical trial registration numbers: NCT03711162 and NCT03733444) and systemic sclerosis (phase IIa clinical trial registration number: NCT03798366). In vitro studies indicate that ziritaxestat is a weak inducer and inhibitor of CYP3A4 3 . Predictions based on the in vitro data indicated that ziritaxestat‐mediated induction of CYP3A4 is expected to decrease exposure of a CYP3A4 probe substrate by ≤ 30%, with inhibition expected to result in a maximum increase in probe substrate metabolism of 1.5‐fold.…”