H. Markus Weiss

LYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.

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 q.d.) and three fed cohorts (20-80 mg b.i.d.) 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 b.i.d. Steady state was achieved after ~3 days with mean accumulation of 2.1-fold for 5 mg q.d. and {less than or equal to}1.4-fold for all higher doses. Despite limited accumulation, a long terminal T_1/2 was observed. The long T_1/2 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 substrate of OAT3, OAT4, BCRP, and MRP4. 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, 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.

Fevipiprant, an oral, non-steroidal, highly selective, reversible, and competitive antagonist of the prostaglandin D₂ receptor 2, is eliminated by glucuronidation, and by direct renal excretion. This study aimed to assess the effect of simultaneous UDP-glucuronosyltransferase (UGT) and organic anion transporter (OAT) 3 inhibition by probenecid on the pharmacokinetics of fevipiprant and its acyl glucuronide (AG) metabolite. This was a single-center, open-label, single sequence, two-period, crossover study in healthy subjects. Liquid chromatography with tandem mass spectrometry was used to measure concentrations of fevipiprant and its AG metabolite in plasma and urine. In the presence of probenecid, the mean maximum concentration of fevipiprant increased approximately 1.7-fold, and the area under the curve (AUC)_last and AUC_inf increased approximately 2.5-fold, while the mean apparent volume of distribution as well as the AG metabolite-fevipiprant ratio decreased. The apparent systemic clearance decreased by approximately 60% and the renal clearance decreased by approximately 88% in the presence of probenecid. Using the data from this study and previous studies, the relative contribution of OAT and UGT inhibition to the overall effect of probenecid was determined. This allowed development of a general disposition scheme for fevipiprant and estimation of quantitative contributions for the involved pathways: OATP1B1-mediated hepatic uptake, OAT3-mediated renal excretion and glucuronidation via UGT1A3, UGT2B7 and UGT2B17. Significance Statement In this drug-drug interaction (DDI) study probenecid was used as a tool to inhibit both glucuronidation and renal excretion of fevipiprant. The combination of plasma and urine pharmacokinetic data from this study with available data allowed the development of a quantitative scheme to describe the fate of fevipiprant in the body, illustrating why the DDI effect on fevipiprant is low-to-moderate, even if a perpetrator drug inhibits several elimination pathways.

This drug-drug interaction (DDI) study determined the effect of cyclosporine, an inhibitor of OATP1B3 and P-gp, on the pharmacokinetics (PK) of fevipiprant, an oral, highly selective, competitive antagonist of the prostaglandin D2 receptor 2 and a substrate of the two transporters. The concomitant administration of an intravenous (IV) microdose of stable isotope-labeled fevipiprant provided the absolute bioavailability of fevipiprant, as well as mechanistic insights in its PK and sensitivity to drug interactions. Liquid chromatography-mass spectrometry/mass spectrometry was used to measure plasma and urine concentrations. Geometric mean ratios (90% CI) for oral fevipiprant with or without cyclosporine were: for Cmax, 3.02 (2.38, 3.82); for AUClast, 2.50 (2.17, 2.88); and for AUCinf, 2.35 (1.99, 2.77). The geometric mean ratios (90% CI) for fevipiprant IV microdose with or without cyclosporine were: for Cmax, 1.04 (0.86, 1.25); for AUClast, 2.04 (1.83, 2.28) and for AUCinf, 1.95 (1.76, 2.16). The absolute bioavailability for fevipiprant was approximately 0.3-0.4 in the absence and 0.5 in the presence of cyclosporine. The IV microdose allowed differentiation between systemic and pre-systemic effects of cyclosporine on fevipiprant, demonstrating a small (approximately 1.2-fold) pre-systemic effect of cyclosporine and a larger (approximately 2-fold) effect on systemic elimination of fevipiprant. Uptake by OATP1B3 appears to be the rate-limiting step in the hepatic elimination of fevipiprant while P-gp does not have a relevant effect on oral absorption. SIGNIFICANCE STATEMENT The drug interaction investigated here with cyclosporine, an inhibitor of several drug transporters, provides a refined quantitative understanding of the role of active transport processes in liver and intestine for the absorption and elimination of fevipiprant, as well as the basis to assess the need for dose adjustment in the presence of transporter inhibitors. The applied IV microdose approach presents a strategy to maximize learnings from a trial, limit the number and duration of clinical trials, and enhance mechanistic DDI understanding.

The bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. To investigate drug biodistribution and elimination, ¹⁴C-zoledronic acid was administered intravenously to rats and dogs in single or multiple doses and assessed for its in vitro blood distribution and plasma protein binding in rat, dog, and human. Drug exposure in plasma, bones, and noncalcified tissues was investigated up to 240 days in rats and 96 h in dogs using radiometry after dissection. Drug biodistribution in the rat and within selected bones from dog was assessed by autoradiography. Concentrations of radioactivity showed a rapid decline in plasma and noncalcified tissue but only a slow decline in bone, to ∼50% of peak at 240 days post dose, whereas the terminal half-lives (50–200 days) were similar in bone and noncalcified tissues, suggesting redistribution of drug from the former rather than prolonged retention in the latter. Uptake was highest in cancellous bone and axial skeleton. At 96 h after dose, the fraction of dose excreted was 36% in rat and 60% in dog; 94 to 96% of the excreted radioactivity was found in urine. Blood/plasma concentration ratios were 0.52 to 0.59, and plasma protein binding of zoledronic acid was moderate to low in all species. The results suggest that a fraction of zoledronic acid is reversibly taken up by the skeleton, the elimination of drug is mainly by renal excretion, and the disposition in blood and noncalcified tissue is governed by extensive uptake into and slow release from bone.