Absorption, metabolism, and excretion of [14 C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers.

Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [14 C]dersimelagon in healthy adult volunteers (N = 6) who participated in phase 1, single-center, open-label, mass balance study (NCT03503266), and in preclinical animal models are presented. Rapid absorption and elimination were observed following oral administration of [14 C]dersimelagon in clinical and nonclinical studies, with a mean Tmax of 30 min in rats and 1.5 h in monkeys, and a median Tmax of 2 h in humans. In rats, there was a widespread distribution of [14 C]dersimelagon-related material, but little or no radioactivity was detected in the brain or fetal tissues. In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose. Based on these findings, dersimelagon is not retained in the human body. Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut. The results to date for this orally administered agent elucidate the ADME of dersimelagon in human and animal species and support its continued development for the treatment of photosensitive porphyrias and dcSSc.

Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist.

PURPOSE: To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). METHODS: In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated. RESULTS: Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon. CONCLUSION: Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP. TRIAL REGISTRATION: A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442 , registration began July 2016.

The Oral Bioavailability and Effect of Various Gastric Conditions on the Pharmacokinetics of Dersimelagon in Healthy Adult Volunteers.

Dersimelagon is a novel orally administered selective agonist for melanocortin receptor 1 being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. In this open-label, multicenter, randomized, two-cohort, sequential crossover study, the relative oral bioavailability of two tablet formulations of dersimelagon was evaluated, and the effect of various gastric conditions (from a high-fat meal, a proton-pump inhibitor, and an acidic carbonated beverage) on the pharmacokinetics of dersimelagon were assessed in healthy participants (N = 50). Both tablet formulations demonstrated rapid absorption, and the 100-mg tablets showed a 97% relative oral bioavailability versus 50-mg tablets. No effect was observed on overall exposure (area under the plasma concentration versus time curve [AUC]) following consumption of a high-fat meal, and Cmax was higher (22%, 90% confidence interval [CI] 1.05-1.42) in a fed state compared with fasted conditions. Similarly, overall exposure AUC of dersimelagon was comparable following administration alone or in combination with esomeprazole; however, coadministration of esomeprazole led to a slight decrease in Cmax (fasted: 9%, 90%CI 0.77-1.07; fed: 24%, 90%CI 0.66-0.88) compared with administration of dersimelagon alone. In general, the consumption of an acidic beverage increased time to Cmax regardless of fed or fasted status and decreased overall exposure AUC and Cmax of dersimelagon.

Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays.

Chemical reactivity of acyl glucuronides (AGs) is believed to be involved in the toxicity of carboxylic acid-containing drugs. Both direct and immune-mediated toxicity have been suggested as possible mechanisms of toxicity; however, it remains unclear. In the present study, we performed assays of half-lives, peptide adducts, and immunostimulation to evaluate the potential risk of AGs of 21 drugs and analyzed the relationship to the toxic category. AGs of all withdrawn drugs tested in this study showed short half-lives and peptide adducts formation, but so did those of several safe drugs. In contrast, only AGs of withdrawn and warning drugs induced interleukin-8 (IL-8) in human peripheral blood mononuclear cells (hPBMCs). Using a DNA microarray assay, we found that zomepirac AG induced the mRNAs of 5 genes, including IL-8 in hPBMCs. In addition, withdrawn and warning drugs were distinguished from safe drugs by an integrated score of relative mRNA expression levels of 5 genes. The immunostimulation assay showed higher sensitivity, specificity, and accuracy compared with other methods. In preclinical drug development, the evaluation of the reactivity of AGs using half-lives and peptide adducts assays followed by the evaluation of immunostimulation by highly reactive AGs using hPBMCs can contribute to improved drug safety.

Interactions of organic anion transporters and organic cation transporters with mycotoxins.

Mycotoxins are secondary metabolites of moulds that which exert adverse effects in humans and animals. It is known that direct cellular toxicity is often associated with increased cellular accumulation of toxic compounds, and membrane transport may be the first fundamental stage in the development of the cytotoxicity. To elucidate the entry pathway for mycotoxins into cells, we have investigated the interactions of human and rat organic anion transporters (hOATs/rOats) and human organic cation transporters (hOCTs) with mycotoxins using cells stably expressing hOATs/rOats/hOCTs. The mycotoxins tested were aflatoxin B1, alpha-zearalenol, citrinin, citrioveridine, cyclopiazonic acid, fumonisin B1, gliotoxin, patulin, penicillic acid, rubratoxin B, and zearalenone. These mycotoxins inhibited organic anion uptake mediated by hOAT1-4, and organic cation uptake mediated by hOCT1-2. By comparing the IC(50) values of mycotoxins for hOATs, it was found that hOAT1 and hOAT3 exhibited higher affinity interactions with mycotoxins than hOAT2 and hOAT4. There was no interspecies difference between humans and rats for the interactions of OATs with mycotoxins except that of OAT3 with rubratoxin B. Finally, we observed that hOAT1-4 and hOCT1-2 mediated the uptake of aflatoxin B1. In conclusion, hOATs and hOCTs interacted with various mycotoxins. Considering the localization of hOATs/rOats and hOCTs, it was suggested that these transporters were the possible entrance pathway for mycotoxins in kidney and liver, leading to the induction of adverse effects in humans and rats.

Substrate deacylation mechanisms of serine-beta-lactamases.

The substrate deacylation mechanisms of serine-beta-lactamases (classes A, C and D) were investigated by theoretical calculations. The deacylation of class A proceeds via four elementary reactions. The rate-determining process is the tetrahedral intermediate (TI) formation and the activation energy is 24.6 kcal/mol at the DFT level. The deacylation does not proceed only by Glu166, which acts as a general base, but Lys73 also participates in the reaction. The C3-carboxyl group of the substrate reduces the barrier height at the TI formation (substrate-assisted catalysis). In the case of class C, the deacylation consists of two elementary processes. The activation energy of the TI formation has been estimated to be 30.5 kcal/mol. Tyr150Oeta is stabilized in the deprotonated state in the acyl-enzyme complex and works as a general base. This situation can exist due to the interaction with two positively charged side chains of lysine (Lys67 and Lys315). The deacylation of class D also consists of two elementary reaction processes. The activation energy of the TI formation is ca. 30 kcal/mol. It is thought that the side chain of Lys70 is deprotonated and acts as a general base. When Lys70 is carbamylated, the activation energy is reduced to less than 20 kcal/mol. This suggests that the high hydrolysis activity of class D with carbamylated Lys70 is due to the reduction of activation energy for deacylation. From these results, it is concluded that the contribution of the lysine residue adjacent to the serine residue is indispensable for the enzymatic reactions by serine-beta-lactamases.

[A study of the long-term continuation rate of respiratory rehabilitation in a day care service].

The purpose of this study is to report on the continuation rate of an outpatient pulmonary rehabilitation service for people with pulmonary disease. In Japan, Kaigo Hoken, the long-term care insurance system for the elderly, went into effect on April 1, 2000. Under this system, a special day care service was established in our hospital in order to continue outpatient rehabilitation for the elderly with pulmonary diseases. In the present study we analyzed the continuation rate of pulmonary rehabilitation in day care for a period of 2 years. Sixty-five stable patients with chronic respiratory failure were enrolled in the program. The continuation rates for 1 year and 2 years were 67.7% and 50.8%. We found that the continuation rate was high even for patients over 75 years old. Twenty patients died during the course of the program. When these 20 cases are excluded, the continuation rates for one year and 2 years become 88.9% and 73.3%. Our day care is the first service of its kind in Japan designed specifically for chronic pulmonary disease patients. It also includes a pick-up service and social activity support. In the future, the use of social resources like our day care service for the elderly with pulmonary diseases may play an important and beneficial role in continuing outpatient rehabilitation.

[A case of allergic bronchopulmonary aspergillosis followed by diagnostic imaging for 27 years].

This patient was a 28-year-old man who had been treated with steroids for recurrent asthmatic attacks since around the age of 20. At one time the steroid therapy was discontinued and other treatments, including bronchodilator therapy and desensitization therapy, were substituted. At age 28, he first consulted our hospital due to the recurrence of attacks. We found peripheral eosinophlia and a cytologic examination revealed Curschmann spirals in his sputum. Migratory infiltrate recurred, and steroids and antibiotics were prescribed each time. A confirmed diagnosis of allergic bronchopulmonary aspergillosis was made at age 35. The patient was treated with continuous oral steroids for recurrent infiltrates. After the start of inhale steroid therapy at age 44, the frequency of attacks decreased and tapering of the oral steroids became possible. It is notable that lung tissue destruction progressed by recurrent pneumonia and emphysema extended into all portions of the lung. Furthermore, this case history is of value since it yields a series of images taken over a period of 27 years.