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.

and thereby reduces quality of life. 1,2Afamelanotide, an α-melanocyte-stimulating hormone analog and melanocortin-1 receptor agonist, is administered subcutaneously as an implant and is the only treatment currently approved to increase sunlight tolerance in adults with EPP. 2,3An effective oral treatment option for patients with EPP or XLP has remained elusive, bringing to light a great medical need for safe and effective orally administered treatments.][6] Dersimelagon is being investigated to increase light tolerance for individuals with EPP and XLP, and for the treatment of diffuse cutaneous systemic sclerosis.A phase 1, first-in-human pharmacokinetic (PK)/pharmacodynamic study (ClinicalTrials.gov:NCT02834442) in healthy adults showed an acceptable safety profile for dersimelagon single doses of 1-600 mg and for multiple ascending daily doses of 30-450 mg received for 14 days. 7Following multiple oral doses ranging from 30 to 450 mg, dersimelagon had terminal elimination half-life (t 1/2 ) values ranging from 10.56 to 18.97 hours on Day 14. 7 In a mass balance clinical study in healthy adults (ClinicalTrials.gov:NCT03503266), the primary route of [ 14 C]-dersimelagon (chemical structure of the drug and labeling position described by Tsuda et al 8 ) excretion following a single oral dose (100 mg) was via the feces (92.2%), with minor elimination of radioactivity in the urine (0.3% of the dose) up to 264 hours after dosing. 8In plasma, dersimelagon and the metabolites dersimelagon glucuronide and bis-oxidized desmethyl dersimelagon represented 87.3%, 2.0%, and 2.2% of total drug-related exposure, respectively. 8Based on findings of in vitro and nonclinical studies indicating, respectively, that dersimelagon is mainly metabolized to dersimelagon glucuronide and that dersimelagon glucuronide is excreted via bile as a major component, the authors concluded that dersimelagon is predominantly metabolized to glucuronide in the liver, excreted in bile, and undergoes hydrolysis in the gut to unchanged dersimelagon. 8ndividuals with EPP and XLP may have some degree of liver dysfunction causing mild elevation of liver enzymes (serum aminotransferases) and minor abnormalities of liver function. 1In a small subset (1.0%-5.0%) of patients with EPP, hepatic complications can progress to advanced liver disease (cholestatic liver failure) requiring transplantation. 1 Because of the risk of liver disease and life-threatening hepatic complications in a subset of patients with EPP and XLP, it is important to consider whether liver impairment may affect the PK properties of dersimelagon.This is a particu-larly important consideration because dersimelagon is metabolized in the liver.
In contrast, patients with EPP/XLP do not experience an increased risk of renal dysfunction.Furthermore, only a minor fraction of dersimelagon is eliminated via urine, 8 and it appears unlikely that renal impairment would markedly impact the renal clearance of dersimelagon.Nonetheless, the possibility exists that renal impairment could alter the pharmacokinetics of dersimelagon through an indirect mechanism altering drug absorption, metabolism, or transport. 9,10Oral dersimelagon is intended to be administered chronically in patients with EPP/XLP, and PK studies should be conducted to ensure safety in patients with renal impairment when a drug is intended for ongoing use. 11his article summarizes the results of 2 open-label studies designed to evaluate the effect of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability.The objective of the hepatic impairment study (ClinicalTrials.gov:NCT04116476) was to assess the pharmacokinetics of a single oral dose of dersimelagon 100 mg in participants with varying degrees of hepatic impairment relative to participants with normal hepatic function.The objective of the renal impairment study (ClinicalTrials.gov:NCT04656795) was to compare the pharmacokinetics of a single oral dose of dersimelagon 300 mg in participants with varying degrees of renal impairment to that of participants with normal renal function.Secondary objectives of the studies were to assess the safety and tolerability of dersimelagon in participants with hepatic or renal impairment.Data from these studies are intended to guide clinicians in potential dose adjustments when administering dersimelagon to patients with hepatic or renal impairment.

Methods
This investigation was conducted as 2 separate Phase 1 open-label clinical trials.One study was conducted in participants with varying degrees of hepatic function and the other in participants with varying degrees of renal impairment.Institutional review boards reviewed and approved the study protocols, amendments, and consent procedures.The trials were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice according to the International Conference on Harmonization Tripartite Guideline.Participants provided written informed consent before participating in the study.

Study Design
Effect of Hepatic Impairment.This was a Phase 1, single-center, open-label, parallel-group (University of Miami Clinical Pharmacology Unit, Miami, FL; responsible independent ethics committee: University of Miami Human Subject Research Office, Miami, FL) study designed to assess the pharmacokinetics, safety, and tolerability of a single oral dose (100 mg) of dersimelagon in otherwise healthy participants with varying degrees of hepatic impairment (Figure S1).The 100-mg dose was selected because dersimelagon is believed to undergo glucuronidation in the liver, and it was expected to be tolerated even if participants with hepatic impairment experienced higher exposure than those with normal hepatic function.
Men and women aged 18 years or older and 75 years or younger, weighing at least 50 kg, and having a body mass index of 18-35 kg/m 2 were eligible to participate.Eligible participants with normal hepatic function were in good general health based on medical history, physical examination, clinical laboratory tests, and 12-lead electrocardiogram (ECG) measurements.Participants with normal hepatic function were matched on demographics such as race, age (±10 years), weight (±10 kg), smoking status, and sex to participants with hepatic impairment.Participants with normal hepatic function were excluded if they were positive for hepatitis A virus, hepatitis B surface antibody (except in those who had received hepatitis B virus vaccination), hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C virus; and with aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, or total bilirubin levels more than 1.5 times the upper limit of normal.
Child-Pugh classification was used to define hepatic function groups with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment (Table S1).After review of the safety and PK data of participants with normal hepatic function and moderate hepatic impairment, participants with mild hepatic impairment were enrolled.
Participants stayed in the study site from Study Day -1 to Day 4 (Figure S1).On the morning of Day 1, participants received a single oral dose of dersimelagon 100 mg after an overnight fast.On Day 4, a 72-hour blood sample for pharmacokinetics was collected, and safety assessments were performed.A safety follow-up visit was conducted on Day 8 (±2 days).
Effect of Renal Impairment.This was a Phase 1, nonrandomized, open-label, parallel-group, singlecenter (Clinical Research Services Kiel GmbH.Kiel, Germany; responsible independent ethics committee: Ethik-Kommission bei der Ärztekammer, Schleswig-Holstein, Germany) study designed to characterize the pharmacokinetics, safety, and tolerability of a single dose of dersimelagon 300 mg in otherwise healthy participants with varying degrees of renal impairment (Figure S1).The 300-mg dose was selected because this is the maximum dose expected to be assessed in efficacy studies.There is little elimination of dersimelagon via the kidney; therefore, a significant increase in exposure was not anticipated in participants with renal dysfunction, and the 300-mg dose was expected to be tolerated.
Men and women aged 18 years or older and 80 years or younger, weighing at least 50 kg, and having a body mass index of 18-35 kg/m 2 were eligible to participate.Similar to the design of the hepatic impairment study, eligible participants with normal renal function were in good general health and were matched on demographic characteristics to participants with renal impairment.Participants receiving dialysis and with clinically significant 12-lead ECG abnormalities were excluded.
Participants were classified by renal function based on absolute estimated glomerular filtration rate (eGFR) as determined using the Modification of Diet in Renal Disease equation, multiplied by the individual's body surface area (BSA; according to the DuBois and DuBois equation) and divided by 1.73 m 2 .The absolute eGFR was not standardized to a BSA of 1.73 m 2 but used the individual's BSA.The study groups included normal renal function and mild, moderate, and severe renal impairment (Table S1).Study procedures were first conducted for participants with normal renal function and severe renal impairment.After review of safety and PK findings in these groups, participants with mild and moderate renal impairment were enrolled.
The schedule for the renal impairment study is shown in Figure S1.On the morning of Day 1, each participant received a single oral dose of 300 mg of dersimelagon (as 3 × 100-mg tablets; free base form).

Pharmacokinetic Analysis
Blood samples for dersimelagon PK analysis was collected before dosing and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 24, 48, and 72 hours after dosing (Figure S1).Samples were prepared using the following methods: To determine the concentrations of dersimelagon, plasma samples were analyzed using validated high-performance liquid chromatography coupled with tandem mass spectrometry with a lower limit of quantification of 0.1 ng/mL.Deuterium-substituted free base of dersimelagon (D 6 -MT-7117) was used as the internal standard.Chromatographic separation was achieved with a high-performance liquid chromatography column (Waters Acquity BEH C18, 50 mm × 2.1 mm, 1.7 μm; Waters Corporation) with a gradient program, which combined 2 mobile phases (A and B) at 40°C.In the hepatic study, mobile phase A consisted of 10 mM of ammonium acetate, and mobile phase B consisted of acetonitrile.The opposite is true for the renal study.Samples were analyzed using an AB Sciex Triple Quad 5500 mass spectrometer for PK analysis of the hepatic impairment study and an AB Sciex API 5000 mass spectrometer for PK assessments of the renal impairment study.Detection was performed using multiple reaction monitoring.The m/z values of dersimelagon and its internal standard are 676 > 413 and 682 > 416, respectively.Cumulative accuracy and coefficient of variation (CV) for sample analyses for PK analysis of the hepatic impairment study were 1.5%-4.6%and 5.8% or less, respectively.Cumulative accuracy and CV for sample analyses for PK analysis of the renal impairment study were −10.0% to −4.1% and 8.1% or less, respectively.
Unbound fraction in plasma (f u ) values were calculated using in vitro plasma protein-binding studies via the same method in each study.Three concentrations (0.3, 1, and 3 μg/mL) of radiolabeled free-form dersimelagon ([ 14 C]3131950) were added to predose plasma of each patient.Samples were fractionated by rapid equilibrium dialysis (rapid equilibrium dialysis [RED] device; Thermo Scientific).After the insert tube was placed on a well base plate of a RED device, the test plasma sample (300 μL), prewarmed at 37°C, was added into the sample chamber and phosphate-buffered saline (500 μL), prewarmed similarly, was added into the buffer chamber.The RED device plate was covered with the plate seal (BMBF-400) and incubated at 37°C, 10% CO 2 for 9 hours (shaking: 180 cycles/min).After the incubation, the samples in the buffer chamber were processed.The reconstituted solutions obtained in the sample processing were analyzed by liquid scintillation counter.F u values were calculated.
Maximum observed plasma concentration (C max ), area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC 0-last ), and AUC from time 0 extrapolated to infinity (AUC 0-∞ ) were summarized by each hepatic or renal function group with n, mean, standard deviation (SD), median, range, CV%, geometric mean, and geometric CV%.Additional PK end points included t 1/2 , time to peak drug concentration, apparent oral clearance, and f u .

Statistical Analysis
In the first-in-human study with dersimelagon, the interparticipant CV was estimated at approximately 30% for AUC 0-last , AUC 0-∞ , and C max of dersimelagon (300 mg) for healthy participants.For the hepatic impairment study, the SD of the log (AUC 0-last , AUC 0-∞ , or C max ) was assumed to be 0.3, and therefore 8 participants per group would provide an estimation of the AUC 0-last , AUC 0-∞ , or C max (geometric mean) of dersimelagon for each group with a 2-sided 95% confidence interval (CI) after transformation to the original scale within 30% of the geometric mean (71.6% and 139.7%).For the renal impairment study, 7 partic-ipants per group were considered enough to provide at least 80% power to achieve the 95% CI of the geometric mean AUC 0-∞ and C max within 60% and 140% of each geometric mean estimate.
For both the hepatic and renal impairment studies, log-transformed C max, AUC 0-last , and AUC 0-∞ of dersimelagon were used for the analysis.An analysis of variance model that included hepatic or renal function as fixed effects was used to estimate the least squares (LS) means and interparticipant variance.These estimated LS means and interparticipant variance were used to construct the point estimate and 90% CIs for the difference in means on a log scale between the impaired and normal function groups in each study.The limits of the CIs were retransformed using antilogarithms to obtain 90% CIs for the ratios of the mean C max , AUC 0-last , and AUC 0-∞ of dersimelagon between each hepatic impairment category and the normal hepatic function group and between each renal impairment category and the normal renal function group.
Each PK study end point was calculated for each participant using a noncompartmental model by Phoenix WinNonlin version 6.3 (Certara LP) and summarized by hepatic function group or by renal function group (based on absolute eGFR).For the renal impairment study, scatter plots of absolute eGFR versus C max , AUC 0-last , and AUC 0-∞ with regression lines were produced.Corresponding P values were calculated to test the null hypothesis that the slope parameter of absolute eGFR was equal to 0.

Safety Evaluations
For each study, safety was assessed by measuring the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), vital signs, 12-lead ECGs, physical examination, and clinical laboratory tests.The safety population included all participants who were enrolled in the study and who received at least 1 dose of the study drug.

Effect of Hepatic Impairment on Pharmacokinetics of Dersimelagon
Demographics/Participant Disposition.A total of 23 participants were enrolled, received a single oral dose of dersimelagon (100 mg), and completed the hepatic impairment study (Table 1).Mean Child-Pugh scores were 5.9 and 7.9 for participants in the mild (n = 7; Class A) and moderate (n = 8; Class B) hepatic impairment groups, respectively.All participants in the hepatic impairment groups had hepatobiliary disorders, most commonly hepatic cirrhosis and alcoholic cirrhosis.Vascular disorders (most commonly hypertension) were reported for 5 (71.4%), 7 (87.5%),and 2 (25.0%) participants in the mildly impaired, moderately impaired, and normal hepatic function groups, respectively.
Pharmacokinetics.Following a single oral dose, dersimelagon was absorbed with a median time to peak drug concentration of 5.00 hours among participants with normal hepatic function and 4.50 and 5.00 hours among participants with moderate and mild hepatic impairment, respectively (Table 2; Figure 1).Plasma t 1/2 values and systemic exposure (based on C max and AUC values) of dersimelagon were similar in participants with mild hepatic impairment or normal hepatic function (Table 2; Figure S2).However, plasma t 1/2 values and exposure were higher in participants with moderate hepatic impairment than in participants with normal hepatic function (Table 2; Figure S2).No clear difference was found in f u values based on hepatic function (Table 2).
The geometric LS means for dersimelagon C max , AUC 0-last , and AUC 0-∞ were comparable between participants with normal hepatic function and mild hepatic impairment (Table 3).However, in the moderate hepatic impairment group, geometric LS means were 1.56fold higher for C max and 1.70-fold higher for AUC 0-∞ than corresponding values in the normal hepatic function group (Table 3).Analyses using unbound PK parameters show the same trend as the results of total PK parameters (Table S2).
Safety and Tolerability.Of the 23 individuals who participated in the hepatic impairment study, none experienced a TEAE or TESAE.No participants discontinued from the study, and no deaths occurred.There were no clinically significant changes in vital signs, ECGs, or any laboratory parameter.

Effect of Renal Impairment on Pharmacokinetics of Dersimelagon
Demographics/Participant Disposition.A total of 32 participants were enrolled, received a single oral dose of dersimelagon (300 mg), and completed the renal impairment study (Table 1).All participants were White, and the 4 renal function groups were evenly matched for male:female ratios (5:3).All participants in the renal impairment groups had renal/urinary disorders (most commonly chronic kidney disease) and vascular disorders (most commonly hypertension).Absolute eGFR and creatinine clearance values showed a gradual decrease with increasing severity of renal impairment among the 3 impairment groups (mild, moderate, and severe renal impairment) in comparison with the normal renal function group.
Pharmacokinetics.The profiles of plasma concentration of dersimelagon over time were similar by renal function group (Figure 2).Plasma t 1/2 values increased with increasing levels of renal impairment (Table 2).The arithmetic mean f u values indicated that approximately 99% of dersimelagon in plasma is bound to plasma proteins and that f u values were independent of renal function (Table 2).
Dersimelagon C max , AUC 0-last , and AUC 0-∞ values were comparable in participants with moderate renal impairment and normal renal function (Tables 2 and 3; Figure S3).In contrast, systemic exposure of dersimelagon was higher (C max , 1.86-fold higher; AUC 0-∞ , 1.87-fold higher) in participants with mild renal impairment compared with participants with normal renal function (Table 3).For participants with severe renal impairment, C max and AUC 0-∞ were 1.17-and 1.45-fold higher, respectively, than for participants with normal renal function (Table 3; Figure S3).Individual participant values for key PK parameters by renal function group and against absolute eGFR are shown in Figure S3.The slopes of the regression lines for C max , AUC 0-last , and AUC 0-∞ versus absolute eGFR were not statistically significant, and no obvious trend was observed in the relationship between PK parameters of dersimelagon and measures of renal function (data not shown).Analyses using unbound PK parameters show the same trend as the results of total PK parameters (Table S2).
Safety and Tolerability.TEAEs reported during the renal impairment study are summarized in Table S3.Overall, 12 (37.5%)participants experienced at least 1 TEAE during the study (a total of 26 TEAEs).The frequency of TEAEs was higher in the mild renal impairment (5 of 8, 62.5%) and the normal renal function groups (4 of 8, 50%) than in the severe renal impairment (2 of 8, 25%) and moderate renal impairment groups (1 of 8, 12.5%) (Table S3).TEAEs included headache, nausea, vomiting, hypertension, diarrhea, atrial fibrillation, and supraventricular tachyarrhythmia (Table S3).All TEAEs were mild or moderate in severity.The most common treatment-related adverse event was headache, reported by 3 of 8 (37.5%) participants in the mild renal impairment group and one of 8 (12.5%) participants in each of the severe renal impairment, moderate renal impairment, and normal renal function groups.TEAEs of hypertension were mild to moderate in severity and occurred in 1 participant in each of the severe and moderate renal impairment groups and 2 participants in the mild renal impairment group.No participant in the normal renal function group experienced hypertension.No TESAEs were reported.

Discussion
In the first-in-human Phase 1 study, dersimelagon showed an acceptable safety and tolerability profile following single doses between 1 and 600 mg and multiple doses between 30 and 450 mg. 7The systemic exposure to dersimelagon in plasma, based on C max and AUC 0-∞ , appeared to increase in a more-thandose-proportional manner. 7Additional studies were undertaken to assess effects of hepatic or renal impairment on the pharmacokinetics of dersimelagon.In these studies, reported here, results for participants with moderate hepatic impairment or severe renal impairment, who were enrolled first, did not indicate a significant increase in dersimelagon exposure relative to participants with normal function in each study.However, participants with mild hepatic impairment and with mild and moderate renal impairment were enrolled to obtain additional detail to further enrich the understanding of dersimelagon pharmacokinetics in individuals with hepatic or renal impairment.

Hepatic Impairment
The objectives of the hepatic impairment study were to assess the pharmacokinetics, safety, and tolerability of a single oral dose of dersimelagon (100 mg) in participants with hepatic impairment relative to participants with normal hepatic function.Single-dose administration was selected because dersimelagon showed mostly linear pharmacokinetics, and PK parameters after multiple administrations are expected to be predictable from single-dose data.Participants with mild or moderate hepatic impairment were enrolled to safely evaluate the effect of hepatic function on the PK profile of dersimelagon.
Results of a mass balance study indicated that dersimelagon is metabolized to dersimelagon glucuronide in the liver, which is eliminated in bile. 8Furthermore, individuals with EPP and XLP may have some degree of liver dysfunction that can cause mild elevations of the liver enzymes and minor abnormalities of liver function. 1With the risk of liver disease and lifethreatening hepatic complications in patients with EPP and XLP, it is important to consider whether liver impairment may affect the PK profile of dersimelagon.
Because dersimelagon is mainly eliminated by hepatic metabolism and biliary excretion, a 100-mg dose was selected for the hepatic impairment study to avoid unexpected increases in exposure in participants with hepatic impairment.There, the half-life of dersimelagon did not vary considerably based on hepatic impairment.Systemic exposure to plasma dersimelagon was 1.56-and 1.70-fold higher for C max and AUC 0-∞ , respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function.C max and AUC 0-∞ values, however, were comparable in participants with normal hepatic function and mild hepatic impairment.As previously reported, dersimelagon showed an acceptable safety profile for single doses of 1-600 mg and for multiple doses of 30-450 mg for 14 days in healthy participants. 7Furthermore, most adverse events observed in the Phase 2 study in which dersimelagon was administered at doses of 100 or 300 mg for 16 weeks were mild or moderate in severity and resolved within the trial period. 5Based on the acceptable safety profile and manageable adverse events of dersimelagon, it is unlikely for patients with mild and moderate hepatic impairment to require dose adjustment despite the 1.7-fold increase in systemic exposure.
The increase in exposure in participants with moderate hepatic impairment may be associated with a decrease in first-pass elimination at the gut or liver rather than a decrease in plasma clearance (apparent oral clearance), but the detailed mechanism remains unclear due to the complicated elimination profile of dersimelagon, including glucuronidation, biliary excretion, deconjugation in the gastrointestinal tract, and enterohepatic circulation. 8The f u values indicated that approximately 99% of dersimelagon is bound to plasma proteins regardless of hepatic function.

Renal Impairment
The earlier mass balance study showed that elimination of orally administered [ 14 C]-dersimelagon radioactivity in urine was negligible. 8Considering the limited contribution of kidneys to the elimination of dersimelagon, renal impairment is unlikely to markedly increase dersimelagon exposure by altering renal clearance of dersimelagon.However, it is possible that renal impairment could lead to changes in dersimelagon pharmacokinetics through an indirect mechanism, as reported with other drugs. 12,13Therefore, a separate study was conducted to evaluate the impact of renal impairment on drug exposure in otherwise healthy participants administered a single dose of dersimelagon.Renal impairment was not expected to increase dersimelagon exposure, so a 300-mg dose was selected in the renal impairment study to explore safety at the highest possible clinical dose.The reduced study design included in the first instance participants representing the "worst-case scenario" (ie, those with severe renal impairment).To provide more detailed analysis, participants with mild and moderate renal impairment were also included.In this study, systemic exposure of dersimelagon was higher (although less than 2-fold, based on C max and AUC values) in participants with mild and severe renal impairment compared with participants with normal renal function.However, there was substantial variation in PK parameters, especially in the mild impairment group.As shown in the individual plot of PK parameters by renal function group (Figure S3), the data for 1 participant with mild renal impairment plotted far from the range of mean (±SD).No obvious specific factors elevating systemic exposure of dersimelagon were identified in this participant.The geometric mean ratios of C max and AUC in patients with mild renal impairment decrease from 186% (1.86-fold) to 159% (1.59fold) and from 187% (1.87-fold) to 154% (1.54-fold), respectively, by excluding outliers from the analysis.Even though the increase in patients with mild renal impairment was smaller by excluding outliers, exposure was largest in patients with mild renal impairment compared with other groups.Reasons for the exposure increase in patients with mild renal impairment are still unclear.However, there are no consistent trends of exposure increase with renal impairment severity nor is there a clear trend between eGFR and renal impairment, which is not driving the increase in the exposure.The increase in AUC observed in the severe renal impairment group may be due to an indirect mechanism affecting the absorption, metabolism, and transport of dersimelagon that has yet to be elucidated.
Results of regression analyses indicated no obvious trend in the relationship between PK parameters of dersimelagon and absolute eGFR (data not shown).The f u values indicated that approximately 99% of dersimelagon in plasma is bound to plasma proteins, independent of renal function.In summary, excretion of dersimelagon is mainly nonrenal, 8 and renal function was shown to have minor effects on dersimelagon exposure in this study.

Safety
Dersimelagon was generally well tolerated by participants with moderately impaired, mildly impaired, and normal hepatic function.No participant in the hepatic function study experienced a TEAE.The frequency of TEAEs was higher in the mild renal impairment and normal renal function groups than in the severe and moderate renal impairment groups.The most commonly reported TEAE was headache, and all TEAEs were mild or moderate in severity.In both studies, there were no deaths, TESAEs, or discontinuations, and TEAEs were mostly mild in severity.

Limitations
A limitation of the hepatic study was that it did not include the evaluation of participants with severe hepatic impairment: This study had a reduced design, comprising patients with mild and moderate hepatic impairment.Patients with severe hepatic impairment were not included given that the targeted disease progression is associated with hepatic impairment in some patients and dosing in the severe hepatic impairment category would typically be contraindicated.Additionally, (1) small sample sizes may have resulted in large CIs, especially for groups with renal and hepatic impairment; (2) all participants in the renal study were White; and (3) all participants in the hepatic study were men.Of note, participants did not have EPP or XLP and received only 1 dose of the drug, which represents a limitation for the safety analyses.It is also worth noting that dersimelagon pharmacokinetics include the hepatic glucuronidation, biliary excretion as glucuronide conjugates, deconjugation to unchanged form in the gastrointestinal tract, and reabsorption.The detailed mechanism of the nonproportional increase in plasma concentration of dersimelagon has not yet been clarified.Considering the limited effect of hepatic impairment and the limited increase in pharmacokinetics more than dose proportional, we think that applying the results from a dosing regimen of 100 mg to that of 300 mg does not represent a significant issue.

Conclusions
Systemic exposure to dersimelagon was higher in participants with moderate hepatic impairment than in participants with normal hepatic function and was higher in participants with mild and severe renal impairment than in participants with normal renal function (although small sample size and data variability may have skewed findings in the mild renal impairment group).Exposure was comparable between participants with moderate renal impairment and normal renal function.A single oral dose of dersimelagon was generally tolerated by all participants regardless of hepatic or renal function.The increased systemic exposure observed in participants with mild to moderate hepatic or any level of renal dysfunction is considered to have a small effect on the safety of dersimelagon based on the safety and tolerability of dersimelagon in the first-in-human study. 6

Figure 1 .
Figure 1.Mean plasma concentration of dersimelagon over time by hepatic function (dersimelagon 100 mg).Data are displayed as mean on (A) linear and (B) semilogarithmic scales.

Figure 2 .
Figure 2. Mean plasma concentration of dersimelagon over time by renal function (dersimelagon 300 mg).Data are displayed as mean on (A) linear and (B) semilogarithmic scales.

Table 1 .
Demographics and Baseline Characteristics in the Hepatic Impairment Study (Dersimelagon 100 mg) and Renal Impairment Study (Dersimelagon 300 mg) , body mass index; CL cr , creatinine clearance; eGFR, estimated glomerular filtration rate; NA, not applicable/available; SD, standard deviation.a For the hepatic impairment study, eGFR (mL/min/1.73m 2 ) is reported.For the renal impairment study, absolute eGFR (mL/min) is reported and was calculated using the individual participant's body surface area. BMI

Table 2 .
Summary of Pharmacokinetic Parameters for Plasma Dersimelagon in Participants With Varying Degrees of Hepatic Impairment (Dersimelagon 100 a All pharmacokinetic parameters are presented as arithmetic mean (SD) except for t max , which is presented as median (range).

Table 3 .
Ratios for Pharmacokinetic Parameters for Plasma Dersimelagon in Participants With Varying Degrees of Hepatic Impairment (Dersimelagon 100 a Ratio for impaired/normal within hepatic or renal groups, expressed as percentage.