Evaluation of Plasma Pharmacokinetics of Leniolisib in Subjects with Impaired Hepatic Function and Normal Hepatic Function in Activated Phosphoinositide 3-Kinase Delta Syndrome

The primary objective of this study is to investigate the effect of **hepatic impairment** on the plasma pharmacokinetics (PK) of leniolisib following oral administration, compared to subjects with normal hepatic function. This is clinically relevant as it aims to understand how liver function affects the metabolism and distribution of leniolisib, a small molecule oral inhibitor of p110δ, which is crucial for optimizing dosing regimens in patients with varying degrees of liver function, particularly those with Activated Phosphoinositide 3-Kinase Delta Syndrome.

Secondary objectives include evaluating the safety profile of a single 70 mg oral dose of leniolisib in patients with hepatic impairment. This assessment is essential to ensure the safe use of leniolisib in this patient population, identifying any potential adverse effects associated with its administration.

The clinical trial involves participants diagnosed with **Activated Phosphoinositide 3-Kinase Delta Syndrome**. The study population includes both male and female subjects, aged between 18 and 79 years, who are of non-childbearing potential. Participants are either control subjects with no known hepatic impairment or those with moderate to severe hepatic impairment, as classified by the Child-Pugh Classification. The trial does not include a vulnerable population. Participants are required to have a stable health status, with no significant changes in their hepatic condition within the last 30 days. Lifestyle considerations include a body mass index (BMI) between 18.0 and 34.9 kg/m² and a total body weight of more than 50 kg. Participants may be light smokers or non-smokers, and those with a history of alcohol abuse are eligible if they test negative for alcohol at screening and comply with lifestyle guidelines. The sponsor has not provided information on the total number of participants in the trial.

The clinical trial is designed as an **open-label**, single-dose, parallel-group study to evaluate the plasma pharmacokinetics of **leniolisib** in subjects with impaired hepatic function compared to those with normal hepatic function. The primary objective is to investigate the effect of hepatic impairment on the plasma pharmacokinetics of leniolisib following oral administration. The trial is categorized as a Phase 1 pharmacokinetic study and is not considered low intervention. The study is expected to commence recruitment on January 1, 2024, and conclude by September 30, 2024.

Participants will be involved in the study for a duration that includes a screening visit, dosing, and follow-up assessments. The inclusion visit will involve a comprehensive screening process to ensure participants meet the eligibility criteria, which include being between the ages of 18 and 79, having a stable hepatic impairment, and meeting specific demographic-matching criteria. The study will include subjects with moderate to severe hepatic impairment as classified by the Child-Pugh Classification, as well as control subjects with no known hepatic impairment.

Following the screening, participants will receive a single oral dose of leniolisib, and pharmacokinetic parameters such as maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) will be assessed. Secondary endpoints include time of occurrence of Cmax, apparent terminal phase half-life, and other pharmacokinetic measures. Study visits will include assessments at various time points post-dose to monitor these parameters and any adverse events. The end-of-study visit will conclude the participant's involvement, with a final assessment of safety and pharmacokinetic data.

Participants are expected to comply with all scheduled visits and study procedures. Conditions that may lead to early termination from the study include non-compliance with study requirements, significant adverse events, or any changes in the participant's health status that may affect study outcomes. The study aims to provide valuable insights into the pharmacokinetics of leniolisib in individuals with varying degrees of hepatic function, contributing to the understanding of its safety and efficacy profile in this population.

The clinical trial involves the administration of **CDZ173/Leniolisib**, a pharmaceutical product developed by Pharming Technologies BV. The active substance in this medication is **leniolisib phosphate**, a chemical compound. The medication is formulated as a **film-coated tablet** and is administered orally. Leniolisib functions as a small molecule oral inhibitor of p110δ, which is relevant in the context of the study's objective to evaluate its pharmacokinetics in subjects with impaired hepatic function compared to those with normal hepatic function. The trial does not involve a pediatric formulation, and the product has been designated as an orphan drug under the designation number EU/3/0/2339.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of the experimental medication, CDZ173/Leniolisib. The trial is designed as an open-label, single-dose, parallel-group study, which implies that all participants will receive the experimental treatment without blinding or placebo control. The dosing schedule and participant compliance monitoring details are not specified in the provided data.

Efficacy in this clinical trial will be assessed through a series of pharmacokinetic parameters. The primary endpoints include the **maximum observed concentration (Cmax)** and the **area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC0-infinity)**. These endpoints will provide critical insights into the plasma pharmacokinetics of leniolisib in subjects with impaired hepatic function compared to those with normal hepatic function.

Secondary endpoints will further evaluate the pharmacokinetic profile of leniolisib. These include the **time of occurrence of Cmax (Tmax)**, **apparent terminal phase half-life (t1/2)**, **apparent clearance/bioavailability (CL/F) following oral dosing**, and **apparent volume of distribution after extravascular administration (Vz/F)**. Additional measures such as the **area under the concentration-time curve from time zero to the last time of quantifiable concentration (AUC0-t)**, **terminal elimination rate constant (λz)**, and **percentage of AUC0-inf obtained by extrapolation (AUC%extrap)** will be analyzed. Unbound concentration and fraction in plasma of leniolisib at specified time points (1, 2, 3, 24, 36, and 48 hours post-dose) will also be assessed, along with the **lag time before observation of drug concentrations in the sampled matrix (tlag)**.

Data collection will occur at multiple time points, ensuring a comprehensive analysis of leniolisib's pharmacokinetics. The trial will also monitor the number of subjects experiencing adverse events and those using concurrent medications over a 120-hour timeframe. These assessments will be conducted using validated laboratory tests and methodologies appropriate for pharmacokinetic studies.