Safety, Tolerability, and Pharmacokinetics of IMU-935, a Novel Inverse Agonist of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γt: Results From a Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Retinoic acid receptor-related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin-17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU-935, an inverse agonist of RORγt, in a first-in-human phase 1 study. This was a double-blind, placebo-controlled trial that randomly assigned healthy subjects single ascending doses (25-400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU-935 or placebo. Dose escalation was determined by the safety, tolerability, and PK. Twenty-four and 70 subjects received placebo or IMU-935, respectively. Of the 70 subjects who received IMU-935, 59 received a single dose and 11 received multiple doses. Treatment-emergent adverse events (TEAEs) occurred in 21 subjects (88%) and 58 (83%) given any dose of placebo or IMU-935, respectively. Treatment-related TEAEs occurred in 6 (30%) and 25 (42%) subjects given a single dose of placebo and IMU-935, respectively. All treatment-related TEAEs were mild except for 2 moderate TEAEs and 1 moderate TEAE in the IMU-935 group and placebo group, respectively. No treatment-related discontinuations or serious adverse events occurred. The PK of IMU-935 were dose proportional with a half-life of ≈24 hours. In conclusion, IMU-935 was safe with no dose-limiting toxicities and had a PK profile that supports once-daily dosing.

Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects.

Tapentadol is a novel, centrally acting oral analgesic with a dual mode of action that has demonstrated efficacy in preclinical and clinical models of pain relief. The present study investigated and characterized the absorption, metabolism, and excretion of tapentadol in humans. Four healthy male subjects received a single 100-mg oral dose of 3-[14C]-labeled tapentadol HCl for evaluation of the pharmacokinetics of the drug and the excretion balance of radiocarbon. The concentration-time profiles of radiocarbon in whole blood and serum and radiocarbon excretion in the urine and feces, and the expired CO2 were determined. The serum pharmacokinetics and excretion kinetics of tapentadol and its conjugates were assessed, as was its tolerability. Absorption was rapid (with a mean maximum serum concentration [Cmax], 2.45 microg-eq/ml; a time to Cmax, 1.25-1.5 h), and the drug was present primarily in the form of conjugated metabolites (conjugated:unconjugated metabolites = 24:1). Excretion of radiocarbon was rapid and complete (>95% within 24 h; 99.9% within 5 days) and almost exclusively renal (99%: 69% conjugates; 27% other metabolites; 3% in unchanged form). No severe adverse events or clinically relevant changes in vital signs, laboratory measurements, electrocardiogram recording, or physical examination findings were reported. In our study group, it was found that a single oral dose of tapentadol was rapidly absorbed, then excreted into the urine, primarily in the form of conjugated metabolites, and was well tolerated.

The effects of tramadol on static and dynamic pupillometry in healthy subjects--the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status.

OBJECTIVES: The main objective of the present study was to provide information on whether static and dynamic pupillometry can be used for pharmacodynamic profiling, particularly when investigating opioid-like drugs, such as tramadol. METHODS: Healthy subjects (n = 26) participated in this randomised, double-blind, placebo-controlled, crossover Phase 1 study. Of these, 20 extensive metabolisers (EMs) with respect to polymorphic isoenzyme cytochrome P450 2D6 (CYP2D6) received up to 150 mg of tramadol-HCl and placebo. The 6 poor metabolisers (PMs) with respect to CYP2D6 received 100 mg tramadol-HCl and placebo. RESULTS: In EMs, serum concentrations of the enantiomers of tramadol and of O-demethylated metabolite (M1) increased with increasing doses. Comparing the 100-mg dose between EMs and PMs, the latter exhibited higher serum concentrations of both enantiomers of tramadol. Serum concentrations of (+)-M1 remained below the lower limit of quantification, and that of (-)-M1 were lower than those in EMs. In EMs, doses from 100 mg tramadol-HCl on induced a significant (P<0.05) miosis as compared with placebo. The maximum mean differences from placebo after dosing with 50, 100 and 150 mg tramadol-HCL were -0.5, -0.8 and -1.1 mm, respectively, indicating a dose-dependent character of the changes. Dynamic pupillometry revealed significant (P<0.05) effects for the amplitude, latency and duration of reaction. The amplitude and velocity of constriction were decreased only at the highest dose; whereas, the changes of the amplitude reached statistical significance (P<0.05). Both the latency and reaction duration behaved in a dose-dependent manner. For the latency, significant changes compared with placebo (P<0.05) were found at the 150-mg dose level, while the reaction duration was already significantly (P<0.05) decreased from the 100-mg dose on. The velocity of redilatation did not respond at all. In PMs, no effect on the initial pupil diameter was found. Although the statistical analysis failed to demonstrate any significant change from placebo for the dynamic pupillometry, the effect-time profiles of EMs and PMs were comparable. For both metaboliser groups, a decrease of amplitude, velocity of constriction and reaction duration as well as an increase of latency was observed. In principle, the direction and magnitude of changes were comparable between EMs and PMs. Most important was the finding that the time course of effects was completely different between both groups of metabolisers. In EMs, effects slowly reached a maximum between 4 h and 10 h after dosing and diminished until 24 h; whereas, in PMs, both maximum effects and the return to baseline occurred much earlier, at approximately 3 h and 8 h, respectively. CONCLUSIONS: The EMs and PMs of CYP2D6 treated with tramadol behaved differently in static and dynamic pupillometry. The reason for this could largely be explained with the aid of the metaboliser status and the pharmacokinetic properties of tramadol. In EMs, the pupillometric response was mainly driven by the (+)-M1, which comprises the mu action component of tramadol; whereas, in PMs, the non-mu component appears to play an important role. Thus, pupillometry was found to be useful in pharmacodynamic profiling and provides a good correlation with the pharmacokinetics.