Abstract
Background and Objective
Mitiperstat (AZD4831) is a novel irreversible oral myeloperoxidase inhibitor in clinical development for heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and chronic obstructive pulmonary disease. This study evaluated the pharmacokinetics, safety and tolerability of multiple ascending doses of mitiperstat in healthy male Japanese and Chinese volunteers.
Methods
Three cohorts of eight Japanese participants were randomized to receive once-daily oral doses of mitiperstat 2.5, 5 or 10 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo, per cohort). One cohort of eight Chinese participants was randomized to receive mitiperstat 5 mg or matching placebo for 10 days (six receiving mitiperstat and two receiving placebo).
Results
Mitiperstat was rapidly absorbed, with a time to maximum plasma concentration of 1–2 h. Exposure was dose proportional over the investigated dose range, as assessed by area under the concentration–time curve and maximum and trough plasma concentrations. Steady state was reached within 10 days, and accumulation was observed, consistent with the observed long elimination half-life of mitiperstat (50.2–57.8 h). Except for a few events of maculopapular rash, mitiperstat up to 5 mg was well tolerated in participants of Japanese or Chinese origin.
Conclusions
The pharmacokinetics of mitiperstat were similar among Japanese and Chinese participants. These characteristics were similar to those in a previous multiple ascending-dose study in healthy primarily white and Black/African American volunteers. Therefore, the pharmacokinetics of mitiperstat do not affect dosing regimens in these different populations.
Trial Registration
NCT04232345 (03/01/2020).
Supplementary Information
The online version contains supplementary material available at 10.1007/s40261-024-01402-x.
Key Points
| The oral myeloperoxidase inhibitor mitiperstat was shown to have similar pharmacokinetics in healthy male Japanese and Chinese volunteers and was generally well tolerated at doses up to 5 mg in these participants. |
| The pharmacokinetics in Japanese and Chinese participants were similar to previously reported pharmacokinetics in primarily white and Black/African American participants, indicating no requirement for differing dosing regimens in these populations. |
Introduction
Myeloperoxidase is an abundant microbicidal enzyme present in the azurophilic granules of neutrophils and makes up approximately 5% of the dry weight of cells [1]. Myeloperoxidase is secreted upon degranulation and generates reactive chlorinating species, such as hypochlorous acid, with bactericidal and viricidal properties [2]. Myeloperoxidase is primarily active in phagolysosomes within the neutrophils but can also be released extracellularly by degranulation or in the context of neutrophil extracellular traps, causing tissue damage and dysfunction due to generation of reactive oxygen species (hypohalous acid). These are processes implicated in the pathogenesis of atherosclerosis [2–4].
Mitiperstat (AZD4831) is a mechanism-based myeloperoxidase inhibitor that acts as a substrate for myeloperoxidase and forms a covalent bond with the heme moiety in the enzyme, thereby inhibiting the enzymatic activity [5]. In preclinical models, myeloperoxidase inhibition can improve both macro- and microvascular function, suggesting that mitiperstat may be effective in treating patients with cardiovascular disease, including heart failure [4]. From in vitro pharmacology data, therapeutic concentrations of mitiperstat are predicted to inhibit primarily extracellular myeloperoxidase rather than the intragranular enzyme [3]. Mitiperstat treatment is therefore not expected to interfere with host defence against infections.
The safety, tolerability, pharmacokinetics and pharmacodynamics of mitiperstat have previously been investigated in single-ascending-dose (SAD; 5–405 mg) and multiple-ascending-dose (MAD; 5–45 mg) studies in healthy participants and in the phase IIa SATELLITE study (up to 5 mg) in patients who had heart failure with preserved ejection fraction (HFpEF) or with mildly reduced ejection fraction (HFmrEF) [6–8]. In the SAD study, participants received mitiperstat 5, 15, 45, 135 or 405 mg under fasted conditions (n = 6 per group) or 45 mg under fed conditions (n = 4) [6]. A pooled placebo group of 10 participants was also included. Exposure, measured as average area under the plasma concentration–time curve (AUC), increased proportionally with mitiperstat dose [6]. In the MAD study, participants received mitiperstat 5 mg (n = 8), 10 mg (n = 8), 15 mg (n = 8), 45 mg (n = 5) or placebo (n = 8, pooled) [8]. The AUC and maximum plasma concentration (Cmax) were approximately proportional to dose on the last day of dosing [8].
Mitiperstat is currently being investigated in the phase IIb/III ENDEAVOR study in patients with HFpEF/HFmrEF [9] and in patients with metabolic dysfunction-associated steatohepatitis [10] and chronic obstructive pulmonary disease [11].
Mitiperstat pharmacokinetics in healthy participants are characterised by rapid absorption, with a time to Cmax of approximately 1 h, followed by apparent biphasic elimination [8]. Following once-daily dosing to steady state, an approximately 2- to 3-fold accumulation of mitiperstat was observed owing to its long terminal half-life of between 38 and 50 h in the SAD study and between 53 and 73 h in the MAD study [6, 8].
Elimination of mitiperstat occurs via both renal and metabolic clearance [6, 8, 12, 13]. Renal clearance is the primary elimination pathway for the parent compound [12]. A human absorption, distribution metabolism and excretion study showed that mitiperstat accounts for approximately 7% of drug-related exposure in plasma [12]. The predominant circulating metabolite of mitiperstat, accounting for 75–80% of drug-related exposure, is a carbamoyl conjugate (M7) formed mainly by UGT1A1, but only small amounts of M7 are found in human excreta, primarily because of hydrolyzation and potentially enterohepatic recycling [12]. Several metabolites of mitiperstat, including the carbamoyl conjugate and another metabolite formed via N-acetyl transferase 2 (NAT2), were identified in varying amounts in plasma, urine and faeces, indicating different metabolic clearance pathways for individual metabolites [12]. Despite high systemic exposures, the circulating metabolites are considered to have little or no contribution to overall myeloperoxidase inhibition. To further investigate the elimination pathways, the pharmacokinetics of mitiperstat were investigated in separate studies in patients with hepatic impairment (NCT05751759, pending results) and severe renal impairment. The exposure to mitiperstat in participants with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min) was approximately 2-fold higher than in matched control participants with healthy renal function (eGFR > 90 mL/min) [14].
Because it is eliminated both renally and metabolically by several different pathways, no pharmacokinetic variability in mitiperstat metabolism between populations of different racial backgrounds is expected, although enzymes such as NAT2 and UGT1A1 are known to be polymorphic [12, 13, 15]. Additionally, although rapid NAT2 acetylators are more common in Asian populations than in those of non-Asian origin [16], the metabolic clearance of mitiperstat via NAT2 acetylation accounts for only a small proportion of the overall elimination [12]. Therefore, the contribution of various polymorphic enzymes to overall mitiperstat elimination and disposition in ethnically different populations is difficult to predict and quantify without a dedicated clinical trial.
Apart from maculopapular rash, mitiperstat was generally well tolerated in healthy participants and patients with HFpEF/HFmrEF in previous studies [6–8]. Following single and multiple dosing in healthy volunteers, the frequency of maculopapular rash increased with mitiperstat dose [6, 8]. In the SATELLITE study, maculopapular rash occurred in 1/27 participants with HFpEF/HFmrEF receiving mitiperstat 5 mg [7]. All doses up to 405 mg in the SAD study were considered well tolerated; however, because the incidence of rash increased disproportionately at the highest dose levels, no further dose increases were delivered, and the study was stopped before reaching the predefined exposure stopping criteria [6].
To aid dose selection for phase III studies, it is important to investigate potential pharmacokinetic variability in different populations. The main purpose of this Japanese and Chinese MAD study was to determine the potential for differences in pharmacokinetics in an Asian population compared with a non-Asian population. The study was designed to investigate the safety, tolerability and pharmacokinetics of mitiperstat following once-daily MAD administration in healthy Japanese and Chinese volunteers. The results were compared with previously published data on multiple ascending doses of mitiperstat in healthy volunteers who were mainly white or Black/African American [8].
Methods
Study Design
This was a randomized, single-blind, placebo-controlled, phase I, sequential MAD study in healthy Japanese and Chinese volunteers conducted at a single study centre in the USA. The study included three cohorts of Japanese participants, randomized 3:1 to receive once-daily oral mitiperstat 2.5, 5 or 10 mg or placebo for 10 days, and one cohort of Chinese participants, randomized 3:1 to receive once-daily oral mitiperstat 5 mg or placebo for 10 days. The design was similar to that of a previous MAD study of mitiperstat 5, 10, 15 and 45 mg in healthy volunteers [8].
Participants
Eligible participants were healthy Japanese and Chinese volunteers (both parents and four grandparents who were ethnically Japanese or Chinese) of male sex, aged 18–50 years, with a body mass index of 18–30 kg/m2 and bodyweight of 50–100 kg. The Chinese cohort was enrolled after the Japanese cohorts. Key exclusion criteria were history of any clinically important disease or disorder; history or presence of gastrointestinal, hepatic or renal disease; presence of infection (particularly fungal infection); history of or current thyroid disease; ongoing skin disorder; and history of or ongoing clinically significant allergy or hypersensitivity. Full exclusion criteria are provided in the supplementary material.
Planned enrolment was eight participants per cohort: six to receive mitiperstat and two to receive placebo. No formal sample size estimation was performed. The planned sample size was considered adequate to meet the study objectives.
Conduct
All participants provided written informed consent before entering the study. The study was performed in accordance with ethical principles that had their origins in the Declaration of Helsinki and were consistent with the International Conference on Harmonisation Good Clinical Practice and the AstraZeneca policy on Bioethics and Human Biological Samples.
Mitiperstat Formulation and Dose Selection
At the time of the study, no tablet formulation of mitiperstat was available to provide planned doses. Therefore, an oral suspension was used per the previous global MAD study [8]. Given the small number of subjects in the current study, it was considered essential to minimize differences between the two study protocols to facilitate cross-study comparisons that might reveal any potential pharmacokinetic differences between the ethnically different cohorts.
The mitiperstat doses used in the current study were selected based on the results of the previous phase I study in healthy, mainly white and Black/African American volunteers [8]. This allowed for a gradual escalation of mitiperstat dose with intensive safety monitoring. Before subjects proceeded to the next dose level, the safety review committee evaluated all available safety, tolerability and pharmacokinetic data and applied strict pre-specified criteria for continued, sequentially increasing doses or halting further dose escalation.
The introduction of the mitiperstat 2.5 mg dose group in the current study allowed for the assessment of a broad dose range in Japanese participants. The mitiperstat 2.5 mg dose was anticipated to have a better safety profile than the 5 mg and 10 mg doses, while still producing myeloperoxidase inhibition at a level associated with beneficial clinical effects [17]. The highest dose of mitiperstat in the current study (10 mg) was much lower than the 405 mg tested in the SAD study [6] and lower than the 45 mg in the MAD study [8]. Based on the results in the SAD/MAD studies [6, 8], and in consideration of safety, mitiperstat 10 mg was considered most suitable for the Japanese cohorts in the current study. Safety was evaluated in the Japanese cohorts before the Chinese cohort was enrolled and revealed the occurrence of rash with mitiperstat 10 mg. Consequently, mitiperstat 5 mg was selected for the Chinese cohort.
Procedures
Screening took place during a 28-day period before the start of the study. Enrolled participants resided at the study centre from the day before dosing (day − 1) until at least 48 h after the final dose on day 10 and were discharged on day 12. Participants received mitiperstat or placebo as oral suspensions once daily in the morning under fasted conditions (≥ 10 h). Participants then visited the study centre on days 14, 16, 20 and 24.
Blood samples were collected into tubes containing K2EDTA as anticoagulant for plasma pharmacokinetic analyses before dosing and subsequently at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 h post-dose on days 1 and 10. Blood samples were also collected before dosing and at 24, 36, 48, 96, 144, 240 and 336 h post-dose. Spot urine was collected pre-dose on day 1, and pooled urine was collected at 0–3, 3–6, 6–9, 9–12 and 12–24 h post-dose on day 10. Plasma was prepared by centrifugation at 1500g, 4 °C for 10 min and transferred to a 1.8 mL polypropylene tube and frozen within 70 min of sample collection. Plasma and urine pharmacokinetic samples were stored frozen at − 50 to − 90 °C until sample analysis.
Safety
Safety was evaluated at every study visit in all randomized participants who received at least one dose of mitiperstat or placebo. Evaluations included the incidence and severity of adverse events and serious adverse events, vital signs, electrocardiograms, safety laboratory assessments and the occurrence of skin rash.
Pharmacokinetics
Plasma and urine samples were analysed by Covance (LabCorp) Laboratories Ltd (Harrogate, UK) using validated assays [6, 8, 12]. The methods employed liquid–liquid extraction for plasma and sample dilution for urine followed by reversed-phase liquid chromatography with tandem mass spectrometric detection in the positive ion mode. The method for determination of mitiperstat in plasma was validated in the range 2.0 (lower limit of quantification [LLOQ]) to 2000 nmol/L, and the method for urine was validated in the range 20.0 (LLOQ) to 20,000 nmol/L using 25 μL sample volume [6, 8, 12].
Intra- and inter-batch biases were well within the accepted 15% (± 20% at LLOQ) of the nominal concentration at all levels [6, 8, 12]. The recoveries were consistent across the validated concentration ranges. The average mean recovery of mitiperstat and its [13C315N2] stable, labelled internal standard was 61.7% and 56.8% in plasma and 91.3% and 105.7% in urine, respectively. Results from in-study quality control samples, calibration standards and incurred re-analysis samples indicated acceptable assay performance during the study sample analysis. It was observed that 95.5% (84/88) of the repeat results and original results in plasma were within 20% of the mean of the two values, which is well within the acceptance criteria in the current regulatory guidance. All study samples were analysed within the known stability period of 438 and 439 days for plasma and urine, respectively.
Mitiperstat plasma and urine pharmacokinetic parameters were derived using non-compartmental methods using Phoenix® WinNolin® V8.1 or higher (Certara Inc., Princeton, NJ, USA). Parameters included Cmax, trough plasma concentration (Ctrough), time to Cmax, elimination half-life associated with terminal slope of a semi-logarithmic concentration–time curve, AUC within the dosing interval (AUCτ) and from time zero to infinity, apparent total clearance from plasma (CL/F), apparent volume of distribution and the accumulation ratios of AUC and Cmax. Urinary parameters included renal clearance and excretion of unchanged mitiperstat.
The pharmacokinetic analysis set included all participants who received mitiperstat who had at least one quantifiable post-dose concentration and no protocol deviations that might have affected the pharmacokinetic data. AUC values were calculated using the linear trapezoidal approach for increasing concentrations and the logarithmic trapezoidal method for decreasing concentrations. All parameters were assessed using descriptive statistics. Figures and tables were produced using R V4.4.0 (R Foundation for Statistical Computing, Vienna, Austria).
The pharmacokinetic characteristics for Japanese and Chinese patients reported in this study were compared with those of the participants of the phase I, randomized, single-blind, placebo-controlled, MAD study in participants who were mainly white and Black/African American (one participant was Asian) [8]. Because only one Asian participant was included in the earlier study, contrast analysis excluding the Asian patient from the reference database was not considered helpful or meaningful.
Descriptive analysis using visual assessment was the principal method of analysis to compare the dose proportionality and associated components of pharmacokinetics. This was also the case for the comparison of the two MAD studies (mainly white and Black/African American [8] and the participants in this study). For assessment of dose proportionality, visual inspection was considered most suitable because of the relatively low variability in pharmacokinetics and the narrow range of doses studied. Limited statistical analyses were conducted, but the small numbers of participants limited their reliability. Ad hoc unpaired two-sample t tests were performed assuming that variance among samples were either equal or unequal. However, the study was not powered to draw any inferences based on statistical results.
Results
Participants
In total, 32 participants were enrolled in the study: 24 Japanese participants and eight Chinese participants. Mean age was 35 and 36 years in Japanese and Chinese participants, respectively, and mean body mass index was 24 kg/m2 in both groups (Table 1). Mean eGFR at baseline was 114 and 106 mL/min/1.73 m2 in Japanese and Chinese participants, respectively. All participants received at least one dose of mitiperstat or placebo, with 23/24 (95.8%) Japanese participants and 7/8 (87.5%) Chinese participants completing the study. One participant receiving mitiperstat 5 mg in the Japanese cohort withdrew from the study after experiencing an adverse event and one Chinese participant withdrew during follow-up.
Table 1.
Baseline demographics and characteristics of Japanese and Chinese participants receiving mitiperstat or placebo
| Characteristics | Japanese | Chinese | Total (n = 32) | |||||
|---|---|---|---|---|---|---|---|---|
| Placebo (n = 6) | Mitiperstat 2.5 mg (n = 6) | Mitiperstat 5 mg (n = 6) | Mitiperstat 10 mg (n = 6) | Total mitiperstat (n = 18) | Placebo (n = 2) | Mitiperstat 5 mg (n = 6) | ||
| Age, years | 34 (6.5) | 34 (8.2) | 31 (8.7) | 40 (6.3) | 35 (8.3) | 38 (11.3) | 36 (3.7) | 35 (7.2) |
| Height, cm | 173 (7.6) | 171 (2.9) | 171 (3.2) | 173 (3.7) | 172 (4.9) | 170 (1.4) | 178 (7.4) | 173 (5.6) |
| Weight, kg | 72 (13.3) | 70 (7.8) | 64 (8.0) | 73 (10.8) | 69 (9.4) | 78 (2.7) | 72 (10.2) | 71 (10) |
| BMI, kg/m2 | 24 (3.1) | 24 (2.9) | 22 (2.8) | 24 (2.7) | 23 (2.9) | 27 (0.50) | 23 (1.6) | 24 (2.8) |
| eGFR, mL/min/1.73 m2 | 116 (4.2) | 114 (21) | 116 (16) | 112 (8.6) | 114 (15) | 101 (1.1) | 106 (18) | 112 (14) |
All data are presented as mean (standard deviation). eGFR data were calculated on day 1 using the Chronic Kidney Disease Epidemiology Collaboration formula
BMI body mass index, eGFR estimated glomerular filtration rate
Safety and Tolerability
Adverse events were reported in 9/24 (37.5%) participants receiving mitiperstat (seven Japanese and two Chinese) and 1/6 (16.7%) participants receiving placebo (Japanese) (Table 2). Rash was the most frequently reported adverse event, occurring in 5/24 (20.8%) participants receiving mitiperstat (four Japanese and one Chinese).
Table 2.
Adverse events in Japanese and Chinese participants receiving mitiperstat or placebo
| Adverse events | Japanese | Chinese | Total (N = 32) | |||||
|---|---|---|---|---|---|---|---|---|
| Placebo (n = 6) | Mitiperstat 2.5 mg (n = 6) | Mitiperstat 5 mg (n = 6) | Mitiperstat 10 mg (n = 6) | Total mitiperstat (n = 18) | Placebo (n = 2) | Mitiperstat 5 mg (n = 6) | ||
| Any AE | 1 (16.7) | 1 (16.7) | 2 (33.3) | 4 (66.7) | 7 (38.9) | 0 (0.0) | 2 (33.3) | 10 (31.3) |
| Maculopapular rash | 0 (0.0) | 0 (0.0) | 1 (16.7) | 3 (50.0) | 4 (22.2) | 0 (0.0) | 1 (16.7) | 5 (15.6) |
| Any SAE | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Death | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Any AE leading to discontinuation | 0 (0.0) | 0 (0.0) | 1 (16.7) | 3 (50.0) | 4 (22.2) | 0 (0.0) | 1 (16.7) | 5 (15.6) |
| Any possibly related AE | 0 (0.0) | 0 (0.0) | 1 (16.7) | 3 (50.0) | 4 (22.2) | 0 (0.0) | 2 (33.3) | 6 (18.8) |
All data are presented as n (%)
AE adverse event, SAE serious adverse event
Four adverse events of rash were of moderate intensity (maculopapular rash, Common Terminology Criteria for Adverse Events [CTCAE] grade 2; three Japanese participants receiving mitiperstat 10 mg, one Chinese participant receiving mitiperstat 5 mg) and one was of mild intensity (maculopapular rash, CTCAE grade 1; one Japanese participant receiving mitiperstat 5 mg). Rash occurred at day 4 in the Japanese participant receiving mitiperstat 5 mg and on day 9 in the other four participants who experienced rash. All cases of rash were resolved within 1 month of occurrence. All adverse events of rash were considered by the investigator to be related to mitiperstat, and all led to discontinuation per predefined criteria in the protocol. In addition, one Chinese patient elected to withdraw from the study for personal reasons unrelated to occurrence of rash and was subsequently lost to follow-up.
All other adverse events were mild in intensity. In the Japanese cohort receiving mitiperstat, contact dermatitis, dyspnoea, dry throat, throat irritation, dyspepsia, vomiting, pyrexia, back pain and headache were reported in one participant each. One event of contact dermatitis was reported in a participant receiving placebo in the Japanese cohort. In the Chinese cohort, axillary pain, dry throat, nasal dryness, nasopharyngitis, pruritus and pyrexia were reported in one participant each. There were no serious adverse events or deaths. No clinically significant trends or shifts from baseline were reported for laboratory results, vital signs or electrocardiograms.
Pharmacokinetics
Japanese Participants
Mitiperstat was rapidly absorbed followed by apparent biphasic elimination in Japanese participants (Fig. 1). Exposure to mitiperstat increased proportionally with dose over the 2.5–10 mg range tested, as assessed by AUC, Ctrough and Cmax (Fig. 2 and Figures S2 and S3 in the supplementary material). Interparticipant variability for AUCτ and Cmax was generally low for the mitiperstat 2.5 mg and 5 mg dose groups but was high for the 10 mg dose group on day 10 (geometric coefficient of variation > 40%; Table 3).
Fig. 1.
Plasma concentration–time curves on A day 1 (normal scale) and B day 10 (log scale) in Japanese participants receiving multiple ascending doses of mitiperstat. Data are presented as geometric mean ± geometric standard deviation (n = 6 per treatment group)
Fig. 2.
Dose proportionality of exposure in Japanese participants receiving multiple ascending doses of mitiperstat on A day 1 and B day 10. Data (translucent dots) are shown for individual participants. AUCτ area under the concentration–time curve within the dosing interval
Table 3.
Pharmacokinetic parameters of mitiperstat in Japanese and Chinese participants
| Parameters | Japanese | Chinese | ||||||
|---|---|---|---|---|---|---|---|---|
| Mitiperstat 2.5 mg, day 1 (n = 6) | Mitiperstat 2.5 mg, day 10 (n = 6) | Mitiperstat 5 mg, day 1 (n = 6) | Mitiperstat 5 mg, day 10 (n = 5) | Mitiperstat 10 mg, day 1 (n = 6) | Mitiperstat 10 mg, day 10 (n = 3) | Mitiperstat 5 mg, day 1 (n = 6) | Mitiperstat 5 mg, day 10 (n = 5) | |
| AUCτ, nmol·h/L | 100.3 (8.2) | 234.5 (16.3) | 217.1 (19.8) | 572.7 (10.9) | 415.6 (25.5) | 1082 (41.2) | 238.6 (14.5) | 607.9 (20.4) |
| Cmax, nmol/L | 8.43 (27.1) | 16.9 (18.0) | 17.0 (33.8) | 37.4 (5.7) | 43.8 (38.5) | 80.6 (49.1) | 21.8 (26.6) | 39.7 (14.5) |
| Cmax/dose, nmol/L/mg | 3.37 (27.1) | 6.77 (18.0) | 3.39 (33.8) | 7.47 (5.73) | 4.38 (38.5) | 8.06 (49.1) | 4.36 (26.6) | 7.95 (14.5) |
| tmax, h | 1.00 (1.00–3.00) | 1.77 (0.50–3.02) | 1.50 (1.00–3.00) | 2.00 (0.50–4.00) | 0.51 (0.50–3.00) | 1.50 (1.48–2.00) | 1.50 (1.00–2.00) | 1.02 (0.50–3.00) |
| t½λz, h | NE | 50.2 (29.3) | NE | 57.8 (27.6) | NE | 56.4 (24.3) | NE | 55.4 (19.1) |
| CLR, L/h | NE | 14.9 (29.6) | NE | 12.9 (32.6) | NE | 16.9 (17.8) | NE | 12.0 (11.4) |
| CL/F, L/h | NE | 31.8 (16.3) | NE | 26.1 (10.9) | NE | 27.6 (41.2) | NE | 24.6 (20.4) |
| Vz/F, L | NE | 2304 (40.2) | NE | 2173 (25.7) | NE | 2246 (16.7) | NE | 1962 (20.7) |
| RacAUC | NE | 2.34 (16.82) | NE | 2.48 (19.20) | NE | 2.74 (10.97) | NE | 2.59 (6.16) |
| RacCmax | NE | 2.01 (21.36) | NE | 1.95 (19.02) | NE | 1.89 (28.38) | NE | 1.84 (19.62) |
| Ae(0–last), mg | NE | 1.20 (0.29) | NE | 2.56 (0.72) | NE | 6.29 (1.77) | NE | 2.48 (0.53) |
| fe(0–last), % | NE | 47.94 (11.55) | NE | 51.14 (14.31) | NE | 62.94 (17.71) | NE | 49.59 (10.62) |
Data are presented as geometric mean (geometric coefficient of variation; %), except for tmax, which is presented as median (minimum–maximum)
Ae(0–last) cumulative amount of analyte excreted at the last sampling interval, AUC area under the concentration–time curve, AUCτ AUC within the dosing interval, CL/F apparent total clearance from plasma, CLR renal clearance, Cmax maximum plasma concentration, Cmaxdose dose-normalised maximum plasma concentration, fe(0–last) fraction of dose excreted unchanged in urine from time 0 to the last measured time point, NE not estimated, RacAUC accumulation ratios of AUC, RacCmax accumulation ratios of Cmax, t½λz elimination half-life associated with terminal slope of a semi-logarithmic concentration–time curve, tmax time to maximum plasma concentration, Vz/F apparent volume of distribution
Japanese and Chinese Participants
Exposure to mitiperstat 5 mg was numerically similar between Japanese and Chinese participants (Fig. 3). However, a small concentration rebound was observed at 5 h (day 1) or 50 h (day 10) after administration in Chinese participants. Cmax and AUCτ were higher in Chinese than in Japanese participants (129% and 110% higher on day 1; both 106% higher on day 10). The median time to Cmax of mitiperstat on day 10 was 1.02–2.00 h (range 0.50–4.00) and was similar among Japanese and Chinese participants (Table 3). The half-life of mitiperstat on day 10 was also similar among Japanese and Chinese participants: 57.8 and 55.4 h, respectively. The long half-life of mitiperstat resulted in accumulation between day 1 and day 10 (Fig. 4). By visual interpretation, steady state was reached after approximately 7 days, and elimination of mitiperstat was slow. Renal clearance of mitiperstat accounted for approximately 50% of apparent total clearance in both Japanese and Chinese participants.
Fig. 3.
Plasma concentration–time curves on A day 1 (normal scale) and B day 10 (log scale) in Japanese and Chinese participants receiving mitiperstat 5 mg daily. Data are presented as geometric mean ± geometric standard deviation (n = 6 per treatment group)
Fig. 4.
Trough mitiperstat concentrations on A day 1 (normal scale) and B day 10 (log scale) in Japanese and Chinese participants. Date are presented as geometric mean ± geometric standard deviation (n=6 per treatment group)
An ad hoc, unpaired, two-sample t test, assuming equal variance for both populations, of the logarithm of individual pharmacokinetic parameter data for Japanese and Chinese participants receiving mitiperstat 5 mg on day 10 gave non-significant p values for AUCτ Cmax and Ctrough (p > 0.05). Similar results were obtained assuming variance not to be equal.
Mitiperstat Pharmacokinetics in Healthy Asian Versus Mainly Non-Asian Volunteers
The plasma–concentration profiles for mitiperstat in healthy Japanese participants observed
in this study were similar to those seen in mainly white and Black/African American
participants in a previous phase I study (Fig. 5) [8]. However, a potential trend of lower mean exposure in Japanese participants was observed, as assessed by CL/F. The mean CL/F on the last study day was 25.3 L/h in Japanese and Chinese cohorts receiving mitiperstat 5 mg and 22.8 L/h in mainly white and Black/African American participants [8]. Corresponding values for the 10 mg dose were 27.6 L/h and 20.6 L/h, respectively.
Fig. 5.
Plasma concentration–time curves on A day 1 (normal scale) and B day 10 (log scale) in Asian and mainly non-Asian participants receiving multiple ascending doses of mitiperstat. Data are presented as geometric mean ± geometric standard deviation for plasma concentrations in Japanese and Chinese participants in the current study (Japanese/Chinese multiple ascending dose [JCMAD]) and for mainly white and Black/African American participants in a previous study (multiple ascending dose [MAD]) [8]. In the previous study, the last dose was administered on day 10 for participants randomized to mitiperstat 5 mg and on day 14 for patients randomized to mitiperstat 10 mg. Thin and thick horizontal dashed lines indicate peak mean plasma mitiperstat concentration after 10 mg and 5 mg doses, respectively, in the first MAD study [8]
Pharmacokinetics and Maculopapular Rash
Because the incidence of mitiperstat-related maculopapular rash was highest in the 10 mg group, the association of rash and mitiperstat exposure was investigated (Fig. 6). No clear differences were observed in mitiperstat plasma concentration–time profiles between participants who experienced rash and those who did not.
Fig. 6.
Individual plasma concentration–time profiles for participants who did and did not experience rash. Data are shown for individual participants
Discussion
Mitiperstat is a novel oral myeloperoxidase inhibitor currently in clinical development for treatment of HFpEF/HFmrEF, metabolic dysfunction-associated steatohepatitis and chronic obstructive pulmonary disease. There are currently no approved HF treatments targeting myeloperoxidase inhibition. Despite recent approvals of sacubitril/valsartan (Entresto, Novartis Pharmaceuticals) [18] and sodium-glucose transport protein-2 inhibitors [19] for HFpEF, a large unmet medical need persists in patients with HFpEF or HFmrEF. Mitiperstat may have an important role in meeting this need, subject to demonstration of clinical effect and regulatory approval.
In this study, mitiperstat up to 5 mg was generally well tolerated in healthy Japanese and Chinese volunteers. Mitiperstat pharmacokinetics are characterised by rapid absorption, followed by biphasic slow elimination resulting in accumulation. The pharmacokinetic profiles of mitiperstat were similar between healthy Japanese and Chinese volunteers and to those previously reported in healthy volunteers who were mainly white or Black/African American [8].
Although rapid NAT2 acetylators are more common in Asian populations than in non-Asian populations [16], their role in mitiperstat metabolic clearance is small [12]. Likewise, the M7 carbamoyl conjugate formed via UGT1A1 is only excreted in small amounts [12]. Therefore, pharmacokinetic differences between Asian and non-Asian populations is expected to be minor. This is consistent with the results of this study, which indicated that the pharmacokinetic characteristics of mitiperstat in healthy Japanese and Chinese volunteers were similar to those previously reported in healthy, mainly white and Black/African American volunteers. The apparent concentration rebound at 5 h (day 1) or 50 h (day 10) after dosing in Chinese participants is interesting but difficult to explain. A possible explanation could be hydrolysis of the carbamoyl metabolite back to mitiperstat following enterohepatic cycling, as discussed previously [12]. However, given the overlapping error bars and limited number of participants, a continued decrease over time seems most likely. The effect of reduced metabolic capacity on the pharmacokinetics and elimination of mitiperstat and its metabolites has been evaluated in a phase I study enrolling participants with various degrees of hepatic impairment (NCT05751759).
Mitiperstat is intended to be a lifetime treatment, so requires a high level of safety and tolerability. The mitiperstat doses used in the current study were selected based on the results of the previous phase I study in healthy, mainly white and Black/African American volunteers [8]. In this study, mitiperstat was generally well tolerated at doses up to 10 mg. Events of maculopapular rash were reported in the mitiperstat 15 mg and 45 mg dose groups only, so these doses were not included in the current study. Events of rash in the current study increased with dose, and no rash was reported in the mitiperstat 2.5 mg dose group. However, four events of moderate rash (maculopapular rash, CTCAE grade 2) were reported in one Chinese participant receiving mitiperstat 5 mg and three Japanese participants receiving mitiperstat 10 mg. In addition, a single event of mild rash (maculopapular rash, CTCAE grade 1) was reported in one Japanese participant receiving mitiperstat 5 mg. All events of rash were considered by the investigator to be related to the administration of mitiperstat. The skin rash in healthy Asian volunteers was seen at lower doses than in previous findings from non-Asian participants. However, the small numbers of participants and cross-study nature of the comparison makes conclusions about the relationship between dose and frequency of rash hard to draw at this stage. Overall, mitiperstat was considered generally well tolerated in participants receiving mitiperstat 2.5 mg and 5 mg.
The current study has a number of limitations. All participants were male because information on potential reproductive toxicity was limited at the time of the study. Only a single cohort of Chinese participants was included in the study, receiving mitiperstat 5 mg. However, the observed pharmacokinetics for mitiperstat 5 mg were similar between Chinese and Japanese participants, so similar pharmacokinetic profiles can be anticipated for mitiperstat 2.5 mg and 10 mg. Finally, mitiperstat was administered as an oral suspension because no suitable tablet formulation was available at the time of the study and the previous global MAD study used the oral suspension. Therefore, because of the need to minimize differences between the two studies to detect potential ethnic pharmacokinetic differences, the oral suspension was used. It should be noted that later studies have used a tablet formulation. This is noteworthy because the results of an in vivo bioavailability study showed similar pharmacokinetic profiles following administration of either the tablet or the suspension formulations (unpublished data, AstraZeneca).
Conclusions
Multiple ascending doses of mitiperstat were generally well tolerated in healthy Japanese and Chinese volunteers, apart from a few events of mild and moderate rash. The pharmacokinetics of mitiperstat following single and once-daily dosing to steady state were similar in Japanese and Chinese participants. The pharmacokinetic profiles were also similar to those observed in healthy, mainly white and Black/African American volunteers. The comparable safety and pharmacokinetic profiles of mitiperstat in populations of different racial backgrounds support the further development of mitiperstat in multiple patient populations.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Under the direction of the authors, Susie Eaton, MBio, from Oxford PharmaGenesis, provided medical writing support, which was funded by AstraZeneca.
Declarations
Funding
This study was funded by AstraZeneca.
Conflicts of interest
MS, CB, KN, MA, MH, AC, MT and HE are employees and stockholders of AstraZeneca. PG and JH were employees and stockholders of AstraZeneca when the study was conducted. DH is an employee of PAREXEL, which received funding from AstraZeneca for the conduct of this study.
Ethics approval
The study was performed in accordance with ethical principles that had their origins in the Declaration of Helsinki and were consistent with the International Conference on Harmonisation Good Clinical Practice and the AstraZeneca policy on Bioethics and Human Biological Samples. The study was approved by Aspire IRB, LLC, 11491 Woodside Avenue, Santee, CA 92071, USA (ASPIRE® Protocol #2019336727, 27 December 2019).
Consent to participate
All participants provided written informed consent before entering the study.
Consent for publication
All participants provided written informed consent for their anonymised data to be published.
Data availability
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Code availability
Not applicable.
Author contributions
Substantial contributions to study conception and design: HE, PG, KN. Substantial contributions to analysis and interpretation of the data: MS, JH, MT, DH, PG, CB, HE. Drafting the article or revising it critically for important intellectual content: all authors. Final approval of the article to be published: all authors.
Footnotes
Julie Holden and Pavlo Garkaviy: Affiliation at the time the study was performed.
References
- 1.Khan AA, Alsahli MA, Rahmani AH. Myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives. Med Sci (Basel). 2018;6(2):33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005;25(6):1102–11. [DOI] [PubMed] [Google Scholar]
- 3.Inghardt T, Antonsson T, Ericsson C, Hovdal D, Johannesson P, Johansson C, et al. Discovery of AZD4831, a mechanism-based irreversible inhibitor of myeloperoxidase, as a potential treatment for heart failure with preserved ejection fraction. J Med Chem. 2022;65(17):11485–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Björnsdottir H, Welin A, Michaëlsson E, Osla V, Berg S, Christenson K, et al. Neutrophil NET formation is regulated from the inside by myeloperoxidase-processed reactive oxygen species. Free Rad Biol Med. 2015;89:1024–35. [DOI] [PubMed] [Google Scholar]
- 5.Tidén AK, Sjögren T, Svensson M, Bernlind A, Senthilmohan R, Auchère F, et al. 2-Thioxanthines are mechanism-based inactivators of myeloperoxidase that block oxidative stress during inflammation. J Biol Chem. 2011;286(43):37578–89. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gan LM, Lagerström-Fermér M, Ericsson H, Nelander K, Lindstedt EL, Michaëlsson E, et al. Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo-controlled, phase I study in healthy volunteers. Br J Clin Pharmacol. 2019;85(4):762–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Lam CSP, Lund LH, Shah SJ, Voors AA, Erlinge D, Saraste A, et al. Myeloperoxidase inhibition in heart failure with preserved or mildly reduced ejection fraction: SATELLITE trial results. J Card Fail. 2024;30(1):104–10. [DOI] [PubMed] [Google Scholar]
- 8.Nelander K, Lagerstrom-Fermer M, Amilon C, Michaëlsson E, Heijer M, Kjaer M, et al. Early clinical experience with AZD4831, a novel myeloperoxidase inhibitor, developed for patients with heart failure with preserved ejection fraction. Clin Transl Sci. 2021;14(3):812–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lund LH, Lam CSP, Pizzato PE, Gabrielsen A, Michaëlsson E, Nelander K, et al. Rationale and design of ENDEAVOR: a sequential phase 2b–3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. Eur J Heart Fail. 2023;25(9):1696–707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.NCT05638737. A study in participants with non-cirrhotic NASH with fibrosis (COSMOS). https://clinicaltrials.gov/study/nct05638737. Accessed 30 May 2024.
- 11.NCT05492877. An efficacy and safety study of mitiperstat (AZD4831) (MPO inhibitor) vs placebo in the treatment of moderate to severe COPD. (CRESCENDO). https://clinicaltrials.gov/study/nct05492877. Accessed 30 May 2024.
- 12.Bhattacharya C, Sandinge AS, Bragg RA, Heijer M, Yan J, Andersson LC, et al. Application of accelerator mass spectrometry to characterize the mass balance recovery and disposition of AZD4831, a novel myeloperoxidase inhibitor, following administration of an oral radiolabeled microtracer dose in humans. Drug Metab Dispos. 2023;51(4):451–63. [DOI] [PubMed] [Google Scholar]
- 13.Jurva U, Weidolf L, Sandinge AS, Leandersson C, Ekdahl A, Li XQ, et al. Biotransformation of the novel myeloperoxidase inhibitor AZD4831 in preclinical species and humans. Drug Metab Dispos. 2023;51(4):464–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bhattacharya C, Pizzato PE, Heijer M, Sunnåker M, Holden J, Trebski M, et al. The effect of severe renal impairment on the pharmacokinetics, safety, and tolerability of mitiperstat. Br J Clin Pharmacol. 2024. 10.1111/bcp.16205. (online ahead of print). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Conway LP, Rendo V, Correia MSP, Bergdahl IA, Sjöblom T, Globisch D. Unexpected acetylation of endogenous aliphatic amines by arylamine N-acetyltransferase NAT2. Angew Chem Int Ed Engl. 2020;59(34):14342–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ramachandran G, Swaminathan S. Role of pharmacogenomics in the treatment of tuberculosis: a review. Pharmgenom Pers Med. 2012;5:89–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Rudolph TK, Wipper S, Reiter B, Rudolph V, Coym A, Detter C, et al. Myeloperoxidase deficiency preserves vasomotor function in humans. Eur Heart J. 2012;33(13):1625–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Nicolas D, Kerndt CC, Patel P, Reed M. Sacubitril-Valsartan [updated 2024 Feb 29]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK507904/. Accessed 25 Oct 2024. [PubMed]
- 19.McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2023;44(37):3627–39. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data-sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.