Clinical Evaluation of Simcyp-Guided Simvastatin Dosing in Patients With Liver Cirrhosis

Kafrelsheikh University22 enrolled

Overview

This prospective open-label parallel pilot clinical study evaluated the efficacy and safety of physiologically based pharmacokinetic (PBPK)-guided simvastatin dosing in Child-Pugh A and B cirrhotic patients with portal hypertension over a 3-month period. Twenty-two patients were enrolled following screening, and portal hemodynamic, laboratory, and safety parameters were assessed.

This was a prospective, open-label, parallel interventional clinical study conducted over a three-month period in Egyptian cirrhotic patients with portal hypertension. Thirty patients were screened for eligibility. Eight patients were excluded as they did not meet the predefined inclusion criteria. A total of 22 patients were enrolled and completed the study. Adult patients aged ≥18 years with confirmed liver cirrhosis and portal hypertension without a history of variceal bleeding were eligible for inclusion. Patients with severe renal impairment, pregnancy, known hypersensitivity to statins, active malignancy within the previous two years, or recent use of strong CYP3A4 inhibitors were excluded. Patients were stratified according to Child-Pugh (CP) classification into CP class A and CP class B groups. Simvastatin doses were determined using physiologically based pharmacokinetic (PBPK) modeling via the Simcyp® Simulator to account for hepatic impairment-related changes in drug exposure. CP class A patients received simvastatin 15 mg once daily, while CP class B patients received simvastatin 5 mg once daily. Clinical evaluation included Doppler ultrasonographic assessment of portal and hepatic hemodynamics, including portal vein diameter, portal vein velocity, congestion index, and hepatic artery resistive index. Laboratory investigations included liver function tests (ALT, AST, total bilirubin, and serum albumin), renal function tests (serum creatinine and BUN), complete blood count, and creatine kinase for safety monitoring. Patients were followed monthly throughout the 3-month study period, with systematic documentation of adverse events.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Liver Cirrhosis Portal Hypertension Related to Cirrhosis

Interventions

Simvastatin 15 mgDRUG

Simvastatin is an HMG-CoA reductase inhibitor that improves endothelial nitric oxide bioavailability and reduces intrahepatic vascular resistance, thereby potentially lowering portal pressure.

Simvastatin 5 mgDRUG

Simvastatin is an HMG-CoA reductase inhibitor that improves endothelial nitric oxide bioavailability and reduces intrahepatic vascular resistance, thereby potentially lowering portal pressure.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adult patients aged ≥ 18 years * Confirmed diagnosis of liver cirrhosis (clinical, laboratory, or imaging evidence) * Evidence of portal hypertension (clinical findings and/or Doppler ultrasound measurements) * No previous history of variceal bleeding * Child-Pugh class A or B Exclusion Criteria: * Active hepatocellular carcinoma * Severe renal impairment (eGFR \< 30 mL/min/1.73 m²) * Baseline creatine kinase (CK) \> 3 × upper limit of normal * Known hypersensitivity to simvastatin * Current therapy with strong CYP3A4 inhibitors * Any active malignancy in the last 2 years * Pregnancy or lactation

Locations (1)

Kafrelsheikh University

Cairo, Egypt

Outcomes

Primary Outcomes

Change in Portal Vein Diameter (mm)

Portal vein diameter will be measured as a Doppler ultrasound parameter to evaluate changes related to portal hypertension

Time frame: 3 months

Change in Portal Vein Velocity (cm/s)

Portal vein velocity will be assessed as an indicator reflecting changes in portal hypertension

Time frame: 3 months

Change in Hepatic Artery Resistance Index (HARI)

The Hepatic Artery Resistance Index will be measured as a Doppler-based marker associated with changes in portal hypertension

Time frame: 3 months

Change in Congestion Index (CI) (cm/ [cm/s2])

The congestion index will be evaluated as a Doppler-derived surrogate marker for portal hypertension severity

Time frame: 3 months

Change in Modified Vascular Liver Index (MVLI) (cm/s)

MVLI will be measured as part of the Doppler assessment reflecting changes in portal hypertension

Time frame: 3 months

Change in Platelet Count (×10⁹/L)

Platelet count will be assessed as a hematologic surrogate marker associated with portal hypertension.

Time frame: 3 months

Secondary Outcomes

Incidence of adverse effects related to Simvastatin

Adverse effects will be monitored throughout the study period, including clinical evaluation and laboratory investigations such as liver function tests (ALT, AST), creatine kinase (CK), and documentation of any muscle-related or gastrointestinal symptoms.

Data from ClinicalTrials.gov

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