Safety and Pharmacokinetics of DS-1040 Drug-Drug Interactions With Aspirin, Clopidogrel, and Enoxaparin.

DS-1040, a novel low-molecular-weight inhibitor of activated thrombin-activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS-1040 along with the effect on DS-1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single-dose DS-1040 with multiple-dose aspirin, multiple-dose clopidogrel, or single-dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding-related TEAEs, and no significant changes in coagulation parameters. DS-1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS-1040 PK was evaluated following the concomitant administration with multiple-dose aspirin, where the plasma DS-1040 exposure (peak plasma concentration [Cmax ] and area under the concentration-time curve [AUCinf ]) was to be similar to the data previously published in the first-in-human study of DS-1040 in healthy subjects. The PK parameters of DS-1040 coadministered with clopidogrel were similar to those of DS-1040 alone, with small increases in geometric means for Cmax (7%) and AUClast (9%). When coadministered with enoxaparin, the PK parameters of DS-1040 were not affected (1.1% and 1.5% decreases in geometric means for Cmax and AUClast , respectively). Therefore, concomitant administration of DS-1040 and clopidogrel or enoxaparin did not demonstrate PK drug-drug interactions.

Effects of the glycine reuptake inhibitors bitopertin and RG7118 on glycine in cerebrospinal fluid: results of two proofs of mechanism studies in healthy volunteers.

RATIONALE: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1). OBJECTIVES: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers. METHODS: The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively. RESULTS: Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg. CONCLUSIONS: The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.

Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers.

Deficient N-methyl-D-aspartate (NMDA) receptor transmission is thought to underlie schizophrenia. An approach for normalizing glutamate neurotransmission by enhancing NMDA receptor transmission is to increase glycine availability by inhibiting the glycine transporter type 1 (GlyT1). This study investigated the relationship between the plasma concentration of the glycine reuptake inhibitor bitopertin (RG1678) and brain GlyT1 occupancy. Healthy male volunteers received up to 175 mg bitopertin once daily, for 10-12 days. Three positron emission tomography scans, preceded by a single intravenous infusion of ∼30 mCi [(11)C]RO5013853, were performed: at baseline, on the last day of bitopertin treatment, and 2 days after drug discontinuation. Eighteen subjects were enrolled. At baseline, regional volume of distribution (V(T)) values were highest in the pons, thalamus, and cerebellum (1.7-2.7 ml/cm(3)) and lowest in cortical areas (∼0.8 ml/cm(3)). V(T) values were reduced to a homogeneous level following administration of 175 mg bitopertin. Occupancy values derived by a two-tissue five-parameter (2T5P) model, a simplified reference tissue model (SRTM), and a pseudoreference tissue model (PRTM) were overall comparable. At steady state, the relationship between bitopertin plasma concentration and GlyT1 occupancy derived by the 2T5P model, SRTM, and PRTM exhibited an EC(50) of ∼190, ∼200, and ∼130 ng/ml, respectively. E(max) was ∼92% independently of the model used. Bitopertin plasma concentration was a reliable predictor of occupancy because the concentration-occupancy relationship was superimposable at steady state and 2 days after drug discontinuation. These data allow understanding of the concentration-occupancy-efficacy relationship of bitopertin and support dose selection of future molecules.