Safety and Pharmacokinetics of Linzagolix in Female Subjects With Normal and Impaired Renal Function

Study Overview
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Brief Summary
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The primary objective of this study is to assess the pharmacokinetics (PK) of linzagolix in subjects with varying degrees of impaired renal function compared to matched control subjects with normal renal function

Detailed Description
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This is a Phase 1, non-randomized, open label, single-dose study to evaluate the effect of varying degrees of impaired renal function (i.e., mild, moderate, severe Renal Impairment (RI), and End-Stage Renal Disease (ESRD) on hemodialysis) on the PK, safety, and tolerability of linzagolix and its major metabolite, KP017. Up to 40 adult female participants will be enrolled.

Official Title
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Evaluation of the Safety and Pharmacokinetics of a Single Dose of Linzagolix in Female Subjects With Normal and Impaired Renal Function

Conditions
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Renal Impairment, Healthy Participants

Intervention / Treatment
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* Drug: Linzagolix


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Renal Impaired Subjects Adult female, ≥ 18 years of age at screening Has a BMI ≥ 18.0 and ≤ 42.0 kg/m^2 and weight ≥ 40 kg, at screening Aside from RI, be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, electrocardiograms (ECGs), and screening clinical laboratory profiles, as deemed by the Principal Investigator (PI) or designee Subjects with mild, moderate, or severe RI: Has estimated glomerular filtration rate (eGFR) based on Modification of Diet in Renal Disease (MDRD) equation at screening as follows: Severe RI only: ≤ 29 mL/min/1.73m^2 not on hemodialysis Moderate RI only: 30 - 59 mL/min/1.73m^2 Mild RI only: 60 - 89 mL/min/1.73m^2 Has a stable renal function with no clinically significant change in renal status at least 1 month prior to study drug administration and is not currently or has not been previously on hemodialysis for at least 1 year Subjects with ESRD: Subject is maintained on a stable hemodialysis regimen at least 3 times a week for at least 3 months prior to dosing Healthy Subjects Health adult female will be matched to subjects with RI Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee Baseline eGFR ≥ 90 mL/min/1.73m^2 at screening, based on the MDRD equation. Actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of or in conjunction with the MDRD equation at the PI's discretion Key Exclusion Criteria: Renal Impaired Subjects Had any major surgery within 4 weeks prior to dosing Presence of functioning renal transplant Has a surgical (e.g., hepatectomy, nephrectomy, digestive organ resection) or medical condition other than RI which might significantly alter the absorption, distribution, metabolism, or excretion of linzagolix and its metabolites, or which may jeopardize the subject's safety in case of participation in the study, in the opinion of the PI or designee Healthy Subjects Has any clinically significant illness, as judge by the PI or designee, within 4 weeks prior to dosing Has laboratory values at screening or check-in which are deemed to be clinically significant (especially derangement within liver function test), unless agreed in advance by the PI and the Sponsor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Renal Function<br>Healthy participants with Normal Renal Function (estimated Glomerular Filtration Rate (eGFR) ≥ 90 mL/min/1.73m^2) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Mild Renal Impairment<br>Presence of Mild Renal Impairment (eGFR 60-89 mL/min/1.73m^2) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Moderate Renal Impairment<br>Presence of Moderate Renal Impairment (eGFR 30-59 mL/min/1.73m^2) | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: Severe Renal Impairment<br>Presence of Severe Renal Impairment (eGFR ≤ 29 mL/min/1.73m^2), not on hemodialysis | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|
| Experimental: End-Stage Renal Disease<br>Presence of End-Stage Renal Disease (ESRD) requiring hemodialysis | Drug: Linzagolix<br>* A single dose of 200 mg linzagolix (2 tablets of 100 mg) will be administered orally under fasting conditions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetic (PK) parameter Cmax of linzagolix and of KP017 | Measurement of effect of renal impairment on PK of linzagolix and its metabolite KP017 by assessment of the maximum plasma concentration (Cmax). Cmax directly determined from the plasma concentration-time profiles | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter Tmax of linzagolix and of KP017 | Measurement of effect of renal impairment on PK of linzagolix and its metabolite KP017 by assessment of the Time to reach Cmax (Tmax) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter AUC0-t of linzagolix and of KP017 | Measurement of effect of renal impairment on PK of linzagolix and its metabolite KP017 by assessment of the AUC0-t (area under the concentration time curve, from time 0 to the last observed non-zero concentration) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 
| Plasma PK parameter T1/2 of linzagolix and of KP017 | Measurement of effect of renal impairment on PK of linzagolix and its metabolite KP017 by assessment of the T1/2 (Terminal half life) | predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment emergent Adverse Events | Assessment of safety and tolerability of a single dose linzagolix in renal impaired subjects compared with healthy control subjects by assessing the number, frequency and severity of treatment emergent Adverse Events | Day 1 to 14 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linzagolix, OBE2109, Renal impairment, Renal Insufficiency, Kidney Diseases, Clinical pharmacology study