Pharmacokinetics of Mitiperstat in Participants With Hepatic Impairment

Study Overview
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Brief Summary
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This study will assess the effect of hepatic impairment on the pharmacokinetics (PK), safety and tolerability of mitiperstat.

Detailed Description
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This is a Phase I, single dose, non-randomised, open-label, parallel group study to examine the PK, safety, and tolerability of mitiperstat in participants with hepatic impairment and participants with normal hepatic function. Participants will be assigned to one of the following cohorts as per Child-Pugh classification: Cohort 1: Eight participants with Mild hepatic impairment (Child-Pugh A) Cohort 2: Eight participants with Moderate hepatic impairment (Child-Pugh B) Cohort 3: Eight participants with Severe hepatic impairment (Child-Pugh C) Cohort 4: Eight to twelve participants with Normal hepatic function A final safety follow-up visit on Day 21 will be there after all procedures are completed on Day 15.

Official Title
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A Phase I Single Dose, Non-Randomised, Open-Label, Parallel Group Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics, Safety and Tolerability of Mitiperstat

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Mitiperstat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥ 18 to ≤ 85 years (inclusive), at the time of signing the informed consent. Weight ≥ 50kg and BMI ≥ 18 kg/m2 up to < 40 kg/m2. Male and/or females. Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Criterion not applicable to this CSP version. Female participants: Female participants must not be lactating. Female participants of childbearing potential who are sexually active with a non-sterilised male partner must agree to use an acceptable method of birth control, from enrolment throughout the study and until at least 4 weeks after the last dose of study intervention. Capable of giving signed informed consent. Participants with hepatic impairment only: Supporting documents confirming that the participant has liver cirrhosis with hepatic impairment must be available. Diagnosis of chronic and stable hepatic impairment. Exclusion Criteria: Any positive result on screening for serum or plasma hepatitis B surface antigen, hepatitis C antibody, and HIV. History of substance dependence or a positive screen for drugs of abuse, likely to impact participant safety or compliance with study procedures. History of alcohol abuse or excessive intake of alcohol in the last 12 months. Abnormal vital signs, after 10 minutes supine rest at screening or Day -1. Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead ECG at screening or Day -1: Vulnerable participants. For female participants only: currently pregnant or breast-feeding. Participants with hepatic impairment only Participants with previous transjugular intrahepatic portosystemic shunt (TIPS). Severe ascites defined as ascites requiring paracentesis and albumin at 4-week intervals or less. Fluctuating or rapidly deteriorating hepatic function, as indicated by strongly varying or worsening of clinical and/or laboratory signs of hepatic impairment within the screening period. Any evidence of additional severe or uncontrolled systemic disease or laboratory finding that makes it unsafe for the participant to participate in the study. Change in dose regimen of medically-required medication within the last 2 weeks before pre-study examination. Biliary obstruction or other causes of hepatic impairment not related to parenchymal disorder and/or disease of the liver. Clinically relevant hepatic encephalopathy. Oesophageal variceal bleeding in prior 3 months. Platelet count < 50 × 109/L and/or neutrophil count < 1.2 × 109/L and/or haemoglobin < 85 g/L. Post liver transplantation. History of acute or chronic pancreatitis, or pancreatic amylase or lipase greater than twice the ULN at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>8 participants with mild hepatic impairment (Child-Pugh A) will be given Dose A of mitiperstat. | Drug: Mitiperstat<br>* Participants receive mitiperstat orally.<br>* Other names: AZD4831;|
| Experimental: Cohort 2<br>8 participants with moderate hepatic impairment (Child-Pugh B) will be given Dose A of mitiperstat. | Drug: Mitiperstat<br>* Participants receive mitiperstat orally.<br>* Other names: AZD4831;|
| Experimental: Cohort 3<br>8 participants with severe hepatic impairment (Child-Pugh C) will be given Dose A of mitiperstat. | Drug: Mitiperstat<br>* Participants receive mitiperstat orally.<br>* Other names: AZD4831;|
| Experimental: Cohort 4<br>8-12 participants with normal hepatic function will be given Dose A of mitiperstat. | Drug: Mitiperstat<br>* Participants receive mitiperstat orally.<br>* Other names: AZD4831;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed plasma concentration (Cmax) | The Cmax of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared. | Day 1 to Day 15 | 
| Area under the concentration-time curve from time zero to infinity (AUCinf) | The AUCinf of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared. | Day 1 to Day 15 | 
| Area under the concentration-time curve from time zero to last time of quantifiable concentration (AUClast) | The AUClast of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated and compared. | Day 1 to Day 15 | 
| Apparent terminal elimination half-life (t½λz) | The t½λz of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Time to Cmax (tmax) | The tmax of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Apparent Clearance (CL/F) | The CL/F of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Volume of distribution (apparent) following extravascular administration [based on terminal phase] (Vz/F) | The Vz/F of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Cumulative amount of unchanged drug excreted into urine (Ae[0-24]) | The Ae(0-24) of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Renal clearance of drug from plasma (CLR) | The CLR of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Non-renal clearance of drug from plasma (CLNR) | The CLNR of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 
| Percentage of dose excreted unchanged in urine from time 0 to time 24 (fe[0-24) | The fe(0-24) of a single dose of mitiperstat in participants with impaired hepatic function and controls with normal hepatic function will be evaluated. | Day 1 to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs), and Serious Adverse Events (SAEs) | The safety, and tolerability of a single dose of mitiperstat in participants with hepatic impairment and controls with normal hepatic function will be assessed. | From time of dose to the final follow-up visit (Day 21 [± 4 days]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic impairment, Liver disease