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A first‐in‐human oral dose study of mesdopetam (IRL790) to assess its safety, tolerability, and pharmacokinetics in healthy male volunteers

Abstract The management of Parkinson's disease (PD) is frequently compromised by complications induced by dopaminergic treatment such as involuntary movements (dyskinesias) and psychosis. Mesdopetam (IRL790) is a novel dopamine D3 receptor antagonist developed for the management of complications of therapy in PD. This study evaluated the safety, tolerability, and pharmacokinetics of escalating single and multiple doses of mesdopetam. We conducted a prospective, single‐center, randomized, double‐blind, placebo‐controlled phase I, and first‐in‐human (FIH) study with mesdopetam administered to healthy male subjects. Overall, mesdopetam was well‐tolerated up to a 120 mg single dose and up to 80 mg upon multiple dosing. Adverse events (AEs) were mainly related to the nervous system and were dose‐dependent. No serious adverse events occurred and no AEs led to withdrawal. The results of the single‐ascending‐dose and multiple‐ascending‐dose parts indicated dose‐ and time‐independent pharmacokinetics with rapid absorption and maximum plasma levels that were generally reached within 2 h after dosing. No accumulation was observed upon multiple dosing. It is concluded that mesdopetam was safe and well‐tolerated in healthy male volunteers. Pharmacokinetic analysis indicated rapid absorption and dose‐linear pharmacokinetics of mesdopetam, with a plasma half‐life of around 7 h, upon single and repeated dosing. The pharmacokinetics of mesdopetam supports twice‐daily use in patients.

The study comprised two parts.
Part 1 was designed as a partial cross-over single-ascending-dose (SAD) study with ascending dose levels of mesdopetam and one food interaction cohort. Sixteen (16) subjects were included in one of the two cohorts, eight subjects in each cohort (six active treatments and two placebos), and the cohorts were dosed in a zig-zag manner (5 mg-40 mg-160 mg and 15 mg-80 mg-food/80 mg) with a washout period of at least 1 week between doses. A follow-up visit was performed 5-10 days after the last dose.
Part 2 examined multiple-ascending-dose (MAD) cohorts with study treatment once daily for 10 consecutive days. Twenty-four (24) subjects were included, 12 subjects in each dose cohort (nine on active treatment, three on placebo), and the cohorts were dosed with 40 and 80 mg, respectively. A follow-up visit was performed 5-10 days after the last dose.
This study was approved by the Ethics Review Board in Uppsala, Sweden and conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. All subjects provided written informed written consent before participating in any study procedures.

| Dose selection
Based on preclinical results in experimental animal models, a clinically relevant plasma concentration of IRL790 is around 1 μM. The NOAEL in dogs given twice-daily oral doses IRL790 is 18 mg/kg/day (9 mg/kg orally twice daily), corresponding to C max of about 9 μM.
Calculations based on oral administration in dogs suggested that the starting dose in humans, 5 mg, would yield a peak plasma concentration of about 0.12 μM and 1.3% of the plasma concentration of the NOAEL in the most sensitive species studied. The dose selection in the SAD part of the study was based on sub-and supra-clinical doses. Hence, the 40 mg dose was calculated to yield peak plasma concentrations of about 1 μM and the top dose, 160 mg, 4 μM, well below the NOAEL level in dogs. Since dose-limiting AEs were expected to be central nervous system (CNS) related, it was our experience that humans could be more sensitive to such AEs, doses selected for the study did not a priori aim for an maximum tolerated dose level following single oral administration, but rather to cover a relevant plasma concentration range.
The partial cross-over design in the present study enabled each subject to receive maximum of three doses of IRL790; 5, 40, and 160 mg or 15, 80 (fasted), and 80 mg (fed). The advantage of this two-cohort design was the ability to assess the dose-dependency of potential AEs in individual subjects but also to enable a sufficient number of subjects to evaluate the variability in pharmacokinetics (PK) properties.
Depending on the outcome of each dosing step, the investigational Safety Review Committee had the choice to decide to escalate the dose as planned, reduce, or increase the dose-escalation step, repeat the dose, reduce the dose, or terminate the study.
The MAD part of the study examined the effect of repeated once-daily dosing of a clinically relevant dose estimated to be in the range of 40-80 mg and a higher dose estimated to be in the range of 80-160 mg. The selection of the doses administered was determined depending on the results from the SAD part of the study. The maximum allowed exposure was to not exceed a C max of 4.5 μM and an AUC 0-24 of 42 μM/h. IRL790 is rapidly absorbed with a t max of about 30-60 min in experimental animals. Adverse effects are dose-dependent and CNSrelated, and appear to be most prominent around C max . The 60 min interval between dosing in the SAD part of the study would allow the investigator to adjust the schedule in case of intolerability in the higher dose groups. Moreover, since this was an FIH study, a 60 min interval between subjects would allow additional safety precautions upon initial dosing.

| Subjects
Healthy male subjects 18-50 years of age, weighing at least 50 kg, with a body mass index between 18 and 30 kg/m 2 were eligible for the study. Good health was determined by medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory tests at screening. Main exclusion criteria included: history of any clinically significant disease which, in the opinion of the investigator, could either put the subject at risk because of participation in the study or influence the results or the subject's ability to participate in the study.

| Primary objectives and endpoints (safety and tolerability)
In both the SAD and MAD part of the study, safety assessments included: frequency, seriousness, and intensity of adverse events (AEs), physical examination, 12-lead ECGs, Columbia Severity Suicidal Rating Scale, vital sign measurements, and laboratory measurements (clinical chemistry, hematology, and urinalysis). The SAD part also included telemetry.

| Secondary objectives and endpoints (pharmacokinetic parameters)
In the SAD part, blood samples for the measurement of plasma concentrations of mesdopetam and its metabolites IRL902 and IRL872 were collected at predetermined time points: predose, 20, 40 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after the intake of mesdopetam (up to 8 h only in the food interaction cohort). In the MAD part, blood samples were collected predose, 20, 40 min, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after the first and last dose of mesdopetam. A 48-h sample was also taken after the first dose, and on day 4, sampling was performed predose, 1, 2, and 3 h postdose.

| Bioanalytical methods
Plasma samples were analyzed for mesdopetam and the metabolites IRL872 and IRL902 using ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) performed by the National Veterinary Institute, Department of Chemistry, Environment and Feed Hygiene Section of Chemical Analysis, Uppsala, Sweden. A deuterated analog of each molecule was used as the internal standard. The method was validated according to EMA guidelines 7 and the bioanalytical experiments performed in accordance with the OECD Principles of Good Laboratory Practice. The validated concentration range was 6.00-6000 nmol/L for mesdopetam, and 3.00-1000 and 1.00-1000 nmol/L for IRL872 and IRL902, respectively.

| Statistical analysis
No formal sample size calculation was performed for this study and therefore no hypothesis testing. The sample size was considered sufficient to provide adequate information for the study objectives.
The full analysis set, comprising all subjects who received randomized study treatment and have available data, has been used for the safety and tolerability assessments. Evaluations have been performed according to the actual treatment regardless of randomization.
The per-protocol (PP) analysis set comprises data from all randomized subjects who have received study treatment and have evaluable PK parameter data with no major protocol deviations with an impact on the PK data. All protocol violations were presented and discussed at the clean file meeting. The PP set has been used for the presentation of PK endpoints.
All statistical calculations were performed using the SAS ® pro-

| Pharmacokinetic calculations
The pharmacokinetic parameters were calculated by noncompartmental analysis (NCA) using the software Phoenix WinNonlin ® version 6.3 or later (Pharsight Corporation). Plasma concentration values below the lower limit of quantitation and missing values (e.g., no blood sample collected, or no value obtained at analysis) were excluded from the NCA. Actual time-points for blood sampling were used in the calculations of the individual parameters, while nominal time points were denoted for summary statistics. Dose proportionality of AUC and C max was estimated using a non-linear power model. As an estimate of the accumulation ratio (AR), the quotient of the AUC 0-24 h for the first and the last dose for each subject was calculated.

| Subject demographics
A total of 40 subjects (17 subjects in part 1 and 23 subjects in part 2) were randomized to the study. All subjects were male Caucasians.
One subject in part 1 discontinued after 5 mg and was replaced for the subsequent dose levels, and one subject in part 2 withdrew consent before randomization and was not replaced. The treatment groups within each study part were comparable with respect to demographic parameters as well as concomitant medication and medical history.

| Safety and tolerability
All 40 subjects were included in the safety analysis. There were no serious adverse events (SAEs) in the study and no AEs led to withdrawal.
The first subject administered a single dose at the highest predefined dose level, 160 mg, experienced adverse CNS symptoms of antidopaminergic character such as disturbance in attention, dizziness, tremor, restlessness, nervousness, and cold sweat. The main symptoms disappeared within 7 h postdose and the subject was fully recovered after 1 day. Due to these AEs, the dose was reduced to 120 mg for the remaining subjects.
All AEs were coded according to MedDRA version 19.0. A detailed account of AEs occurring after the first administration of investigational medical product (IMP) (Treatment-Emergent AEs, TEAEs) is presented by the SAD cohort (part 1) in Table S1 and by the MAD dose group (part 2) in Table S2. During single-dose escalation (part 1), the AEs most frequently represented were Infections and infestations

| Single-dose pharmacokinetics All available mesdopetam concentration values for all subjects in
all dose groups were included in the PK calculations. Following oral single-dose administration of mesdopetam, the plasma concentration increased rapidly to reach a maximum of 0.7 to 3 h after dosing, with a subsequent log-linear decline (Figure 1). The single-dose PK parameter results are presented in Table S3. In brief, for dose TA B L E 1 Median plasma levels of prolactin (µg/L) at baseline (predose) and 2, 6, and 12 h and following single doses of mesdopetam with the highest median value after 15 mg mesdopetam.
• Mean C max from 73.6 ± 18.4 nmol/L to 1940 ± 326 nmol/L with the highest mean value after 120 mg mesdopetam.
• Mean CL/F from 23.8 ± 4.3 L/h to 32.5 ± 6.2 L/h with the highest mean value after 80 mg mesdopetam.
• Mean V z /F from 223 ± 41.7 L to 328 ± 59.0 L with the highest mean value after 80 mg mesdopetam.

| Relative bioavailability after fed and fasting conditions
For the four subjects receiving mesdopetam both under fasting and fed conditions, a small food interaction was observed. The geometric mean ratio (fed/fasted) was 110.7% for AUC 0-8 h and 109.0% for C max . t max was also delayed after food intake compared to fasting.
For the metabolites IRL902 and IRL872, the geometric mean ratio (fed/fasting) was 82.5% and 84.5% for AUC 0-8 h and 95.9% and 117.8% for C max essentially reflecting the results for mesdopetam.

| Dose proportionality after single dose
The analysis of dose linearity for AUC t , AUC 0-∞ , and C max showed a linear relationship with a proportionality constant (b) close to 1, indicating dose proportionality for the parent compound mesdopetam and the metabolite IRL902.  (Table S4).

| Multiple-dose pharmacokinetics
After the first and last dose of 80 mg mesdopetam, a mean

| Dose proportionality after multiple doses
The proportionality constant for AUC ss and C max of mesdopetam, for the last MAD dose, indicated dose proportionality for AUC ss (1.06) and supra-proportional increases of C max (1.3).

| AR after multiple doses
The mean AR for mesdopetam and IRL902 was close to 1 for

| DISCUSS ION
Mesdopetam (formerly IRL790) is a novel compound for the treatment of dyskinesia and psychosis in PD. This was an FIH study investigating the safety, tolerability, and pharmacokinetics after single and repeated oral administrations of mesdopetam.
During the initial single-dose escalation, five escalating doses of IRL790 were tested in 16 male subjects included in two alternating cohorts with eight subjects in each. At each dose level, two subjects were given placebo and six subjects were given IRL790, using a partial cross-over design.
The multiple-dose escalation included 23 healthy male subjects.
IRL790 was administered as once-daily doses for 10 consecutive days in doses 40 and 80 mg.
Overall, IRL790 was well-tolerated up to 120 mg single dose and up to 80 mg multiple doses although an increased frequency of AEs  In conclusion, mesdopetam was generally safe and well-

ACK N OWLED G M ENTS
The authors would like to acknowledge all investigators and staff involved at the study center. We also would like to direct our specific acknowledgments to Rikard Sandström for his excellent contributions to this manuscript. Unfortunately, he was unable to see the final result due to his unexpected and early death.

D I SCLOS U R E
The following co-authors (SW, BL, CS, NW, and JT) have been supported by the sponsor (salary), Integrative Research Laboratories AB, Gothenburg, Sweden.

AUTH O R CO NTR I B UTI O N
All the authors contributed to conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing, and provided final approval of the manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data will be available from the first author on reasonable request.