A novel quinoline with airway relaxant effects and anti-inflammatory properties.

BACKGROUND: In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). METHODS: The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. RESULTS: RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. CONCLUSIONS: RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

First-In-Human, Phase 1, Randomized, Dose-Escalation Trial with Recombinant Anti-IL-20 Monoclonal Antibody in Patients with Psoriasis.

BACKGROUND: The current trial was a first-in-human clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the recombinant monoclonal anti-interleukin-20 (IL-20) antibody, NNC0109-0012, which targets the inflammatory cytokine IL-20. METHODS: In total, 48 patients aged 18 to 75 years with moderate to severe stable chronic plaque psoriasis with affected body surface area ≥15% and physician global assessment score ≥3 were enrolled in this randomized, double-blind, multicenter, placebo-controlled, phase 1 dose-escalation trial. Patients were randomized within each single dose cohort (0.01, 0.05, 0.2, 0.6, 1.5, or 3.0 mg/kg) or multiple dose cohort (0.05, 0.2, 0.5, 1.0, or 2.0 mg/kg; 1 dose every other week for 7 weeks) of NNC0109-0012 or placebo in a 3:1 ratio. In the expansion phase, 7 patients were randomized to weekly doses of 2.0 mg/kg NNC0109-0012 or placebo for 7 weeks. The primary objective, safety and tolerability, was assessed by evaluating adverse events (AEs). Additional endpoints included pharmacokinetics, pharmacodynamics, and clinical response (assessed using the Psoriasis Area and Severity Index [PASI] score). RESULTS: AEs were reported in 85% of patients (n = 40) in the initial study phases (NNC0109-0012, 83%; placebo, 92%) and in 4 of 7 patients in the multiple-dose expansion phase. One serious AE was reported but was judged not to be causally related to NNC0109-0012. No dose-limiting toxicities were reported. NNC0109-0012 pharmacokinetics was similar to other monoclonal antibodies, with an average half-life of approximately 3 weeks. There was a dose-proportional increase in area under the curve and maximum concentration after single dosing. No substantial changes in pharmacodynamic parameters were observed. The expansion phase was terminated early due to apparent lack of PASI improvement. CONCLUSION: Single and multiple doses of NNC0109-0012, ranging from 0.05 to 3.0 mg/kg, were well tolerated in patients with psoriasis and exhibited pharmacokinetics similar to that of other monoclonal antibodies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01261767.

Differences in CYP2C9 Genotype and Enzyme Activity Between Swedes and Koreans of Relevance for Personalized Medicine: Role of Ethnicity, Genotype, Smoking, Age, and Sex.

Global personalized medicine demands the characterization of person-to-person and between-population differences in drug pharmacokinetics and pharmacodynamics. CYP2C9 pharmacokinetic pathway is subject to modulation by both genetic and environmental factors. CYP2C9 genotype-based dose recommendations (e.g., for warfarin) is advocated. However, the overall contribution of genotype for variation in enzyme activity may differ between populations. We evaluated the importance of ethnicity, genotype, smoking, body weight, age, and sex for CYP2C9 enzyme activity. CYP2C9 genotype and phenotype was determined in 148 Swedes and 146 Koreans using losartan as a probe. CYP2C9 enzyme activity was assessed using urinary losartan/metabolite E-3174 ratio. The frequency of CYP2C9 defective variant alleles (*2 and *3) was significantly higher in Swedes (10.8% and 12.5%) than in Koreans (0% and 5.8%). In matched genotypes, CYP2C9 enzyme activity was significantly lower in Swedes compared to Koreans (p<0.0001). In a univariate analysis, age, weight, ethnicity, genotype, and smoking were significant predictors of CYP2C9 phenotype. A stepwise multivariate analysis indicated ethnicity, genotype, and smoking remained as significant predictors of CYP2C9 enzyme activity, accounting for 50% of the total variance. In both study populations, CYP2C9 genotype was a significant predictor of CYP2C9 enzyme activity, but its contribution in explaining the total variance was lower in Koreans (26.6%) than Swedes (40%). In conclusion, we report significantly lower CYP2C9 enzyme activity in Swedes compared to Koreans, partly but not exclusively due to CYP2C9 pharmacogenetic variations. Ethnicity and environment factors need to be considered together with genotype for population-specific dose optimization and global personalized medicine.

Clinical pharmacokinetics of the anti-interleukin-20 monoclonal antibody NNC0109-0012 in healthy volunteers and patients with psoriasis or rheumatoid arthritis.

INTRODUCTION: NNC0109-0012, a novel human monoclonal antibody that binds to and neutralizes the activity of interleukin-20, was investigated as a potential treatment for inflammatory diseases. Pharmacokinetic (PK) modeling was performed using data from four completed clinical phase 1/2 trials to better understand the clinical PK of NNC0109-0012. METHODS: The populations included were patients with rheumatoid arthritis (RA), chronic plaque psoriasis, and healthy volunteers. NNC0109-0012 was administered subcutaneously at various dose levels (0.01-3 mg/kg) as single dose, once weekly, or multiple doses every second week for up to 12 doses. Noncompartmental methods were used to describe the PK parameters. Population PK was analyzed using nonlinear mixed-effects modeling, with body weight as the main covariate and gender, age, and population as additional covariates. RESULTS: Across studies (N = 116), mean age and body weight ranged from 38 to 58 years and 72 to 96 kg, respectively. NNC0109-0012 displays linear PK. Time to maximum plasma concentration occurred at approximately 1 week, and the terminal half-life was approximately 3 weeks. Clearance and volume of distribution increased proportionally to body weight. No difference in clearance or volume of distribution was observed between gender or different age groups; however, clearance was slightly lower in healthy volunteers than in patients with RA. CONCLUSION: The PK profile of NNC0109-0012 is similar to other monoclonal antibodies directed against soluble targets.

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population.

OBJECTIVE: The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese. METHODS AND RESULTS: The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7--18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; chi(2) test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n=45) (95% CI: 10.8--19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6--5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3-5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7--11.4%) and 5.3% (95% CI: 3.7--7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0--9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses. CONCLUSION: The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

Biosynthesis of epoxyeicosatrienoic acids varies between polymorphic CYP2C enzymes.

Arachidonic acid is oxidized by cytochromes P450 2C (CYP2C) to epoxyeicosatrienoic acids (EETs), possessing vasoactive properties, with 11,12-EET as the endothelium derived hyperpolarization factor. Genetic variants of CYP2C enzymes have altered drug metabolizing capacity. Our primary aim was to determine whether EET biosynthesis differed in human liver microsomes with known CYP2C genotypes. Human liver microsomes (n = 25) of different CYP2C genotypes or yeast-expressed CYP2C enzymes were used. Analysis of metabolites was performed by liquid chromatography/mass spectrometry. Samples genotyped as CYP2C8*3/*3/CYP2C9*2/*2 exhibited a 34% (p < 0.05) decreased EET biosynthesis, compared to other CYP2C8/CYP2C9 haplotypes. Inhibition experiments suggested CYP2C8 and CYP2C9 to be the predominant catalysts of EETs. We found no differences between the three recombinantly expressed CYP2C9 variants, but CYP2C8.1 had lower K(m) than these isoforms. In conclusion, there are genetic differences in the CYP2C-dependent oxidation of arachidonic acid to vasoactive metabolites, of which the relevance to cardiovascular pathophysiology is still unclear.