Drug Dosing for Liver Disease in Single Ventricle Patients

(IMPROVE-FALD Trial)

Overseen By Jonthan Wagner, DO

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Mercy Hospital Kansas City

Must not be taking: Sildenafil, Pravastatin

Disqualifiers: Pregnancy, Non-fasting, MRI unsafe, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Single dose

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how liver issues affect drug processing in individuals with Fontan circulation, a specific heart condition. Researchers are testing two medications: Pravastatin, a cholesterol-lowering drug, and Sildenafil, used for erectile dysfunction and pulmonary hypertension. They aim to understand how these drugs move through and are metabolized by the liver. The study targets those who have undergone Fontan surgery, have not taken these drugs in the last two months, and can fast overnight. Eligible participants are encouraged to join to help advance understanding of drug processing in similar conditions. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

Will I have to stop taking my current medications?

The trial requires that you stop taking Sildenafil and Pravastatin at least 2 months before participating. Also, if you are on medications that interact with these drugs, you may need to stop those as well. The protocol does not specify other medications, so it's best to discuss with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pravastatin is usually well-tolerated and less likely to harm the liver compared to some other similar medications. Liver function tests are recommended before starting pravastatin, especially for individuals with liver issues, to ensure safety and monitor any potential liver effects.

Studies indicate that sildenafil is generally safe, though a few reports of liver problems exist. Importantly, no cases of severe liver failure have been linked to sildenafil. However, it is not recommended for individuals with serious liver issues.

Both treatments have undergone research and are considered safe for many people, but monitoring remains important, particularly for those with liver concerns. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using pravastatin and sildenafil for liver disease in single ventricle patients because these drugs, while traditionally used for different purposes, offer a novel approach to treating this condition. Pravastatin, commonly used to lower cholesterol, might help reduce liver inflammation due to its anti-inflammatory properties. Sildenafil, known for treating erectile dysfunction and pulmonary hypertension, could improve blood flow to the liver, potentially enhancing organ function. This combination targets the liver in ways current standard treatments do not, offering hope for more effective management of liver disease in this unique patient population.

What evidence suggests that this trial's treatments could be effective for liver disease in single ventricle patients?

Research has shown that pravastatin can alleviate liver problems by reducing pressure in the liver's blood vessels, potentially improving survival rates for individuals with liver issues. Additionally, pravastatin may lower the risk of heart disease, benefiting overall health. In this trial, participants will receive a single dose of oral pravastatin.

Studies also indicate that sildenafil can enhance heart function in individuals with certain heart defects, such as a single ventricle. It widens blood vessels in the lungs, reducing pressure there. This can be particularly beneficial for those with congenital heart conditions. Participants in this trial will also receive a single dose of oral sildenafil. ^{6 7 8 9 10}

Who Is on the Research Team?

Jonathan B Wagner, MD

Principal Investigator

Children's Mercy

Are You a Good Fit for This Trial?

This trial is for children, adolescents, and young adults with a unique heart condition called Single Ventricle Heart and Fontan Circulation who also have liver disease. Specific eligibility details are not provided but typically include certain age ranges and health status requirements.

Inclusion Criteria

I am older than 8 years.

I have completed the Fontan procedure.

Fasting overnight (~8 hours)

Exclusion Criteria

I am not taking medication that affects Sildenafil or Pravastatin.

I have not had diarrhea in the past 24 hours.

I have taken Sildenafil or Pravastatin in the last 2 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of oral sildenafil and oral pravastatin to assess hepatic drug metabolism and transport

Single dose

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Pravastatin
• Sildenafil

Trial Overview The study is testing the effects of two medications, Sildenafil (in doses depending on weight) and Pravastatin (doses vary by age), on how the liver processes drugs in patients with Fontan circulation-related liver issues.

How Is the Trial Designed?

Group I: Assessment Arm Experimental Treatment 2 Interventions

Assessment group will receive a single dose of oral sildenafil and oral pravastatin.

Pravastatin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Pravachol for:

• High Cholesterol
• Hyperlipoproteinemia
• Myocardial Infarction - Prophylaxis
• Revascularization Procedures - Prophylaxis

Approved in European Union as Pravastatin for:

• Hypercholesterolaemia
• Mixed dyslipidaemia
• Prevention of cardiovascular events

Approved in Canada as Pravastatin for:

• Hypercholesterolemia
• Mixed dyslipidemia
• Prevention of cardiovascular events

Approved in Japan as Pravastatin for:

• Hypercholesterolemia
• Familial hypercholesterolemia

Who Is Running the Clinical Trial?

Children's Mercy Hospital Kansas City

Lead Sponsor

Trials

261

Recruited

941,000+

Indiana Clinical and Translational Sciences Institute

Collaborator

Trials

20

Recruited

4,400+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Pravastatin effectively lowers total cholesterol and LDL cholesterol levels in elderly patients, demonstrating significant reductions compared to baseline or placebo, making it a valuable treatment for hypercholesterolemia.

In large clinical trials, pravastatin significantly reduced coronary events in elderly patients at risk for coronary heart disease, and it is well tolerated with minimal adverse effects, supporting its use as a first-line treatment for older individuals with heart disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pravastatin: a review of its use in elderly patients. Bang, LM., Goa, KL.[2018]

Pitavastatin is effective in reducing low-density lipoprotein (LDL) levels similarly to other statins like simvastatin and atorvastatin, making it a viable option for treating hypercholesterolemia and combined dyslipidemia.

Despite its efficacy, pitavastatin has not demonstrated improved clinical outcomes in high-risk patients compared to cheaper alternatives, and its higher cost may limit its use in practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pitavastatin: a new 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor for the treatment of hyperlipidemia. Baker, WL., Datta, R.[2012]

Pravastatin is an effective cholesterol-lowering medication that works by inhibiting HMG-CoA reductase, primarily in the liver, and has shown about 70% absorption in rats and 50% in dogs.

The drug is selectively taken up by the liver and excreted mainly unchanged through bile, with its enterohepatic circulation helping maintain its presence in the liver, which is crucial for its therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition and metabolism of pravastatin sodium in rats, dogs and monkeys. Komai, T., Kawai, K., Tokui, T., et al.[2018]

A new, reliable method for measuring pravastatin plasma concentrations was developed, which can be used in routine clinical settings, showing linearity in the range of 5 to 200 microg/l with a low coefficient of variation.

In a study involving five healthy subjects, peak plasma concentrations of pravastatin were observed between 60 and 120 minutes after a 60 mg dose, with elimination half-lives ranging from 95 to 165 minutes, confirming the pharmacokinetics of pravastatin align with previous studies using more complex methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of pravastatin by high performance liquid chromatography. Siekmeier, R., Gross, W., März, W.[2019]

Pravastatin selectively inhibits the enzyme HMG-CoA reductase in liver cells due to its uptake through a specific transport system, which is crucial for its effectiveness as a cholesterol-lowering medication.

It competes with bile acids for uptake in liver cells, but requires high concentrations to affect sodium-dependent transporters, indicating its targeted action and limited interaction with other liver transport systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue-selective action of pravastatin due to hepatocellular uptake via a sodium-independent bile acid transporter. Ziegler, K., Stünkel, W.[2019]

In a study of 942 elderly patients (average age 70) with high cholesterol, pitavastatin (1-4 mg) significantly reduced LDL cholesterol more than pravastatin (10-40 mg), with reductions of 31.4-44.3% compared to 22.4-34.0% for pravastatin (p < 0.001).

Pitavastatin also led to greater improvements in total cholesterol, apolipoprotein B, and HDL cholesterol levels, while both medications were well tolerated with no serious side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pitavastatin shows greater lipid-lowering efficacy over 12 weeks than pravastatin in elderly patients with primary hypercholesterolaemia or combined (mixed) dyslipidaemia. Stender, S., Budinski, D., Gosho, M., et al.[2013]

Pravastatin is an effective HMG-CoA reductase inhibitor that significantly lowers total cholesterol by 15-30% and LDL cholesterol by 15-40% in patients with hypercholesterolemia, including those with diabetes, when taken in doses of 10-40 mg/day.

It is generally well tolerated with fewer reported adverse effects compared to similar medications like lovastatin, suggesting it may be a safer option for lipid-lowering therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pravastatin: a new drug for the treatment of hypercholesterolemia. Jungnickel, PW., Cantral, KA., Maloley, PA.[2013]

Pravastatin has been shown to have a favorable safety profile in over 15,000 patients, with common withdrawal reasons being mild side effects like rash and gastrointestinal issues, but no significant adverse effects on eye health were noted.

The drug effectively lowers serum cholesterol levels regardless of patient demographics, and it is well tolerated when used in combination with other cholesterol-lowering therapies, indicating its potential for long-term use in preventing coronary heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term experience with pravastatin in clinical research trials. McGovern, ME., Mellies, MJ.[2022]

A sustained release formulation of pravastatin was successfully developed using hydroxy methyl propyl cellulose (HPMC) and sodium carboxy methyl cellulose, with formulation F5 showing optimal release characteristics similar to the marketed product Pravachol.

Formulation F5 demonstrated effective drug release kinetics, following Higuchi's model and non-Fickian diffusion, indicating a controlled and prolonged release of pravastatin, which is beneficial for maintaining therapeutic levels in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statistical Design and Optimization of Sustained Release Formulations of Pravastatin. Gunda, RK., Manchineni, PR.[2022]

The study developed enteric surface-coated nanocubosomal dispersions of pravastatin sodium (PVS) that significantly improved its oral bioavailability in rats compared to traditional aqueous solutions, indicating a more effective delivery method.

The optimized E-F8 system demonstrated controlled-release characteristics, with a delayed peak absorption time and prolonged drug presence in the body, enhancing the potential for better therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions. Tayel, SA., El-Nabarawi, MA., Tadros, MI., et al.[2017]

Pravastatin sodium is an effective lipid-regulating drug that works as an HMG-CoA reductase inhibitor, which helps lower cholesterol levels in the body.

The comprehensive profile includes various methods for synthesizing and analyzing pravastatin, including physical characterization techniques and pharmacokinetic data, ensuring its quality and efficacy as a medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pravastatin sodium. Al-Badr, AA., Mostafa, GA.[2014]

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