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.

Prediction of Human Distribution Volumes of Compounds in Various Elimination Phases Using Physiologically Based Pharmacokinetic Modeling and Experimental Pharmacokinetics in Animals.

Predicting the pharmacokinetics of compounds in humans is an important part of the drug development process. In this study, the plasma concentration profiles of 10 marketed compounds exhibiting two-phase elimination after intravenous administration in humans were evaluated in terms of distribution volumes just after intravenous administration (V 1), at steady state (V ss), and in the elimination phase (Vß ) using physiologically based pharmacokinetic (PBPK) modeling implemented in a commercially available simulator (Simcyp). When developing human PBPK models, the insight gained from prior animal PBPK models based on nonclinical data informed the optimization of the lipophilicity input of the compounds and the selection of the appropriate mechanistic tissue partition methods. The accuracy of V 1, V ss, and Vß values predicted that using human PBPK models developed in accordance with prior animal PBPK models was superior to using those predicted using conventional approaches, such as allometric scaling, especially for V 1 and Vß By conventional approaches, the V 1 and Vß values of 4-5 of 10 compounds were predicted within a 3-fold error of observed values, whereas V ss values for their majority were predicted as such. PBPK models predicted V 1, V ss, and Vß values for almost all compounds within 3-fold errors, resulting in better predictions of plasma concentration profiles than allometric scaling. The distribution volumes predicted using human PBPK models based on prior animal PBPK modeling were more accurate than those predicted without reference to animal models. This study demonstrated that human PBPK models developed with consideration of animal PBPK models could accurately predict distribution volumes in various elimination phases.

Effect of Hepatic and Renal Impairment on the Pharmacokinetics of Dersimelagon (MT-7117), an Oral Melanocortin-1 Receptor Agonist.

Dersimelagon is an orally administered selective melanocortin-1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n = 7) or moderate (n = 8) hepatic impairment or normal hepatic function (n = 8) received a single oral 100-mg dersimelagon dose. Participants with mild (n = 8), moderate (n = 8), or severe (n = 8) renal impairment or normal renal function (n = 8) received a single 300-mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.

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.

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.

In vivo evaluation of drug-drug interaction via mechanism-based inhibition by macrolide antibiotics in cynomolgus monkeys.

Irreversible inhibition, characterized as mechanism-based inhibition (MBI), of cytochrome P450 in drugs has to be avoided for their safe use. A comprehensive assessment of drug-drug interaction (DDI) potential is important during the drug discovery process. In the present study, we evaluated the effects of macrolide antibiotics, erythromycin (ERM), clarithromycin (CAM), and azithromycin (AZM), which are mechanism-based inhibitors of CYP3A, on biotransformation of midazolam (MDZ) in monkeys. These macrolides inhibited the formation of 1'-hydroxymidazolam in monkey microsomes as functions of incubation time and macrolide concentration. Furthermore, the inactivation potentials of macrolides (k(inact)/K(I): CAM congruent with ERM > AZM) were as effective as that observed in human samples. In in vivo studies, MDZ was administered orally (1 mg/kg) without or with multiple oral dosing of macrolides (15 mg/kg, twice a day on days 1-3). On day 3, the area under the plasma concentration-time curve (AUC) of MDZ increased 7.0-, 9.9-, and 2.0-fold with ERM, CAM, and AZM, respectively, compared with MDZ alone. Furthermore, the effects of ERM and CAM on the pharmacokinetics of MDZ were also observed on the day (day 4) after completion of macrolide treatments (AUC changes: 7.3- and 7.3-fold, respectively). Because the plasma concentrations of macrolides immediately before MDZ administration on day 4 were much lower than the IC(50) values for reversible CYP3A inhibition, the persistent effects may be predominantly caused by CYP3A inactivation. These results suggest that the monkey might be a suitable animal model to predict DDIs caused by MBI of CYP3A.

Effect of oral ketoconazole on oral and intravenous pharmacokinetics of simvastatin and its acid in cynomolgus monkeys.

Drugs with potential drug-drug interactions (DDIs) may have a limited scope of use and, at worst, may have to be withdrawn from the market. Therefore, during the drug discovery process it is important to select drug candidates with reduced potential for DDIs. In the present study, we evaluated the pharmacokinetics of simvastatin (SV), a typical substrate for cytochrome P450 (P450) 3A, and examined the DDI between SV and ketoconazole (KTZ), a P450 3A inhibitor, in monkeys. SV metabolism in monkey liver and intestinal microsomes was almost completely inhibited by addition of anti-P450 3A4 antiserum. A similar effect was seen in human microsomes, and the IC(50) values of KTZ for inhibition of SV metabolism were similar in monkey and human samples. In vivo, there were no significant differences in the pharmacokinetic parameters of SV and SVA after i.v. administration of SV in the presence of KTZ compared with those in controls, probably because of the limited systemic exposure to KTZ. In contrast, the pharmacokinetics of SV and SVA after p.o. administration of SV were significantly influenced by the presence of KTZ, and C(max) and area under the plasma concentration-time curve were approximately 5 to 10 times higher than those after p.o. dosing with SV alone. The increases in systemic SV exposure caused by a concomitant p.o. dose of KTZ in monkeys were similar to those observed in clinical studies, which suggests that monkeys might be a suitable animal model in which to predict DDIs involving P450 3A inhibition.

Effect of oral ketoconazole on intestinal first-pass effect of midazolam and fexofenadine in cynomolgus monkeys.

Because the expression of drug-metabolizing enzymes and drug efflux transporters has been shown in the intestine, the contribution of this tissue to the first-pass effect has become of significant interest. Consequently, a comprehensive understanding of the absorption barriers in key preclinical species would be useful for the precise characterization of drug candidates. In the present investigation, we evaluated the intestinal first-pass effect of midazolam (MDZ) and fexofenadine (FEX), typical substrates for CYP3A and P-glycoprotein (P-gp), respectively, with ketoconazole (KTZ) as a potent dual CYP3A/P-gp inhibitor in cynomolgus monkeys. When MDZ or FEX was administered i.v. at doses of 0.3 or 1 mg/kg, respectively, the plasma concentration-time profiles were not influenced by p.o. coadministration of KTZ (20 mg/kg). On the other hand, when MDZ or FEX was administered p.o. at doses of 1 or 5 mg/kg, respectively, concomitant with a dose p.o. of KTZ (20 mg/kg), significant increases were observed in the area under the plasma concentration-time curves of MDZ or FEX (22-fold in MDZ and 3-fold in FEX). These findings indicate that both CYP3A and P-gp play a key role in the intestinal barrier and that inhibition of intestinal CYP3A/P-gp activities contributes exclusively toward the drug-drug interactions (DDI) with KTZ. Additionally, the K(i) values of the antifungal agents, KTZ, itraconazole, and fluconazole, for MDZ 1'-hydroxylation in monkey intestinal and liver microsomes were comparable with those in the respective human samples. These results suggest that monkeys may be an appropriate animal species for evaluating the intestinal first-pass effect of p.o. administered drugs and predicting intestinal DDI related to CYP3A4 and P-gp in humans.