First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

BACKGROUND: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. OBJECTIVES: The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. METHODS: This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary outcomes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. RESULTS: No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the exception of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. CONCLUSIONS: Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetration and permitted characterization of platelet dynamics and selection of phase IIa doses. TRIAL REGISTRATION: EUDRACT No. 2015-003721-33, filed 30 October 2015.

Impact of Chiral Bioanalytical Methods on the Bioequivalence of Ibuprofen Products Containing Ibuprofen Lysinate and Ibuprofen Base.

The purpose was to assess the impact of the use of a chiral bioanalytical method on the conclusions of a bioequivalence study that compared two ibuprofen suspensions with different rates of absorption. A comparison of the conclusion of bioequivalence between a chiral method and an achiral approach was made. Plasma concentrations of R-ibuprofen and S-ibuprofen were determined using a chiral bioanalytical method; bioequivalence was tested for R-ibuprofen and for S-ibuprofen separately and for the sum of both enantiomers as an approach for an achiral bioanalytical method. The 90% confidence interval (90% CI) that would have been obtained with an achiral bioanalytical method (90% CI: Cmax: 117.69-134.46; AUC0 (t) : 104.75-114.45) would have precluded the conclusion of bioequivalence. This conclusion cannot be generalized to the active enantiomer (90% CI: Cmax : 103.36-118.38; AUC0 (t) : 96.52-103.12), for which bioequivalence can be concluded, and/or the distomer (90% CI: Cmax : 132.97-151.33; AUC0 (t) : 115.91-135.77) for which a larger difference was observed. Chiral bioanalytical methods should be required when 1) the enantiomers exhibit different pharmacodynamics and 2) the exposure (AUC or Cmax ) ratio of enantiomers is modified by a difference in the rate of absorption. Furthermore, the bioequivalence conclusion should be based on all enantiomers, since the distomer(s) might not be completely inert, in contrast to what is required in the current regulatory guidelines. In those cases where it is unknown if the ratio between enantiomers is modified by changing the rate of absorption, chiral bioanalytical methods should be employed unless enantiomers exhibit the same pharmacodynamics. Chirality 28:429-433, 2016. © 2016 Wiley Periodicals, Inc.

Ibuprofen lysinate, quicker and less variable: relative bioavailability compared to ibuprofen base in a pediatric suspension dosage form.

OBJECTIVES: To assess and compare the bioavailability of ibuprofen enantiomers (R and S) of two different pediatric suspensions: the first one with ibuprofen lysinate (Algidrin® Pediátrico, FARDI S.A., Barcelona, Spain) and the second one with ibuprofen base (Dalsy®, Abbott Laboratories S.A., Madrid, Spain). METHODS: A randomized, open-label, single-dose, balanced, crossover study under fasting conditions was performed at the CIM-Sant Pau. 24 healthy volunteers received a single dose of ibuprofen lysinate (Algidrin® Pediátrico, FARDI S.A.) and ibuprofen base (Dalsy®, Abbott Laboratories S.A.) equivalent to 400 mg of ibuprofen. 18 blood samples were drawn and ibuprofen enantiomer plasma concentrations were determined using an enantioselective analytical method. An analysis of variance (ANOVA) model was used, and the 90% confidence intervals (CI) were calculated; further analyses were made regarding rate of absorption and variability. RESULTS: The pharmacokinetic parameters (Algidrin® Pediátrico vs. Dalsy® (Mean±SD)) were: S-enantiomer: Cmax=22.39±5.33 vs. 19.97±3.19 µg/mL; AUC0t=74.83±16.69 vs. 74.64±14.80 µg×h/mL, and AUC0∞=77.46±19.33 vs. 76.98±17.13 µg×h/mL; and for R-enantiomer: Cmax=21.74±3.76 vs. 15.20±2.03 µg/mL; AUC0t=57.55±10.17 vs. 46.13±9.61 µg×h/mL, and AUC0∞ value was 58.49±10.57 vs. 47.03±10.02 µg×h/mL. The tmax (Median) for S-enantiomer (active) were: 0.5 vs. 1.33 hours (p=0.001) and for R-enantiomer: 0.5 vs. 1.0 hours (p=0.004). Ibuprofen pharmacokinetic values may vary under fed state and in pediatric population. CONCLUSIONS: While S-ibuprofen shows a similar bioavailability for AUC0t, AUC0∞, and Cmax, R-ibuprofen shows suprabioavailability for the lysinate formulation. The rate of absorption of the ibuprofen lysinate suspension is quicker and less variable than that of the ibuprofen base reference suspension and it exhibits a shorter tmax, which is of particular interest for achieving a rapid and homogeneous analgesic and antipyretic effect.