RT Journal Article
SR Electronic
T1 Human Pharmacokinetics of LYS006, an Oral Leukotriene A4 Hydrolase Inhibitor Displaying Target-Mediated Drug Disposition
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1472
OP 1482
DO 10.1124/dmd.121.000803
VO 50
IS 12
A1 Birk Poller
A1 David Pearson
A1 Luc Alexis Leuthold
A1 Martin Fink
A1 Astrid Jullion
A1 Patrick Schweigler
A1 Ester  Tor Carreras
A1 Cyrille Marvalin
A1 Christian Loesche
A1 H. Markus Weiss
YR 2022
UL http://dmd.aspetjournals.org/content/50/12/1472.abstract
AB LYS006 is a potent leukotriene A4 hydrolase inhibitor currently in clinical development for long-term treatment of various neutrophil-driven inflammatory conditions. Here, we present pharmacokinetics from the first-in-human study with complementary metabolism and transporter profiling data. The randomized first-in-human study included nine cohorts receiving 5–2*100 mg of LYS006 or placebo, a crossover food-effect part, and a multiple-dose part consisting of two fasted (5 mg and 15 mg once daily) and three fed cohorts (20–80 mg twice a day) of LYS006 or placebo. LYS006 and metabolites were assessed in plasma and urine, and transporters involved in LYS006 disposition were analyzed in vitro. Systemic plasma exposure increased with dose; steady-state exposure was dose proportional up to 40 mg twice a day. Steady state was achieved after ∼3 days, with mean accumulation of 2.1-fold for 5 mg once daily and ≤1.4-fold for all higher doses. Despite limited accumulation, a long terminal half-life (T1/2) was observed. The long T1/2 and saturable binding to blood cells, which causes a highly nonlinear blood-to-plasma distribution, reflect a strong impact of target binding on drug distribution at lower concentrations. Skin biopsy and blister fluid concentration data indicated saturable binding in the former but not the latter, suggesting saturable binding in tissues beyond blood. Major excretion of LYS006 (∼90% of dose) through urine at steady state triggered renal transporter investigations that identified LYS006 as a substrate of organic anion transporter (OAT)3, OAT4, breast cancer resistance protein, and multidrug resistance-associated protein 4. Seven metabolites were identified in human plasma and urine, comprising only 4% of the dose recovered in urine at steady state.SIGNIFICANCE STATEMENT Pharmacokinetic data from a first-in-human study combined with in vitro work support dose and regimen selection for patient studies with LYS006 and provide guidance on drug interaction investigations and other clinical pharmacology work needed for further development. Mass balance information at steady state without the use of a radiolabel, skin concentrations, and identification of the major clearance pathway, as well as the transporters driving elimination, make this a particularly conclusive early study despite nonlinear pharmacokinetics impacted by target binding.