Pravastatin for Endothelial Injury in Pediatric Patients

Overseen By Ormarie Vazquez Silva

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: Pravastatin

Must not be taking: OATP1B1/OATP1B3 substrates

Disqualifiers: Anaphylaxis to pravastatin, Renal impairment, Neuromuscular disorders, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 weeks

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if pravastatin, a cholesterol-lowering drug, can protect blood vessel linings in children with high BMI undergoing bone marrow transplants. The goal is to see if it can prevent serious complications by keeping these blood vessels healthy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking drugs that interact with certain transporters (OATP1B1 and OATP1B3).

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking drugs that interact with certain transporters (OATP1B1 and OATP1B3).

How is the drug pravastatin unique for treating endothelial injury in pediatric patients?

Pravastatin is unique because it is a statin that has been shown to be safe and effective in lowering cholesterol levels in children with familial hypercholesterolemia, and it has a specific mechanism of action that inhibits HMG-CoA reductase, an enzyme involved in cholesterol production. Its use in pediatric patients is novel due to its ability to lower LDL cholesterol and increase HDL cholesterol, which may help in managing endothelial injury. ^{1 2 3 4 5}

How is the drug pravastatin unique for treating endothelial injury in pediatric patients?

Pravastatin is unique because it is a statin that has been shown to be safe and effective in lowering cholesterol levels in children with familial hypercholesterolemia, and it has a specific genetic consideration (SLCO1B1 genotype) that affects its systemic exposure, which may be relevant for personalized treatment in pediatric patients. ^{1 2 3 4 5}

Research Team

Jane Koo, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for pediatric patients aged 2-25 with an elevated BMI who are scheduled for a stem cell transplant. It's open to all diagnoses, but not for those with kidney issues, taking certain drugs, allergic to pravastatin, unable to take oral medication, or have specific muscle disorders.

Inclusion Criteria

My condition does not limit my eligibility based on diagnosis.

My BMI classifies me as overweight or obese according to CDC guidelines.

I am between 2 and 25 years old.

Exclusion Criteria

My kidney function is reduced.

I am currently taking medication that affects liver transport proteins.

Patients with documented anaphylaxis to pravastatin

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pravastatin as a prophylactic treatment to reduce endothelial injury after bone marrow transplant

5 weeks

Weekly monitoring visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

9 weeks

Long-term follow-up

Participants are monitored for graft failure and primary disease relapse

100 days

Treatment Details

Interventions

• Pravastatin

Trial Overview The study tests if Pravastatin can prevent damage to the endothelial lining in blood vessels after bone marrow transplants in young patients with high body weight. The goal is to see if it reduces complications like GVHD and VOD.

Participant Groups

Group I: Pravastatin Prophylactic Treatment Experimental Treatment 1 Intervention

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 Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Findings from Research

The study found that the SLCO1B1 genotype significantly influences the systemic exposure to pravastatin in children and adolescents with hypercholesterolemia, with specific variants (521TC and 521CC) showing different levels of drug exposure compared to wild-type controls (521TT).

Despite the genetic influence, there was considerable variability in pravastatin exposure among individuals within the same genotype group, suggesting that other demographic and physicochemical factors also play a role in how the drug is processed in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia. Wagner, JB., Abdel-Rahman, S., Gaedigk, R., et al.[2020]

In a study involving 20 children aged 4.9 to 15.6 years with familial hypercholesterolemia, a single 10 mg dose of pravastatin showed a pharmacokinetic profile similar to that in adults, with a peak plasma concentration reached in about 1.4 hours.

After 8 weeks of daily treatment, pravastatin significantly reduced total cholesterol by 18% and low-density lipoprotein (LDL) cholesterol by 21%, indicating its effectiveness in lowering cholesterol levels in children, with few transient side effects and no significant liver or muscle enzyme increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia. Hedman, M., Neuvonen, PJ., Neuvonen, M., et al.[2013]

A 12-week study involving 72 children with heterozygous familial hypercholesterolemia showed that pravastatin was well tolerated, with mild adverse events evenly distributed across treatment groups.

Pravastatin significantly reduced plasma total and LDL cholesterol levels in all treatment groups compared to placebo, indicating its efficacy in managing cholesterol levels in children with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Knipscheer, HC., Boelen, CC., Kastelein, JJ., et al.[2013]

In a study of 24 children aged 8-16 with familial hypercholesterolemia, pravastatin showed a 27% reduction in low-density lipoprotein cholesterol after 14 days, indicating its efficacy in lowering cholesterol levels in this age group.

Pharmacokinetic analysis revealed that prepubertal children had a higher maximum plasma concentration (C(max)) of pravastatin compared to adolescents, suggesting that dosing may need to be adjusted for younger children, potentially starting at half the adult dose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetics of pravastatin in children with familial hypercholesterolaemia. Wiersma, HE., Wiegman, A., Koopmans, RP., et al.[2018]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Impact of Genetic Variation on Pravastatin Systemic Exposure in Pediatric Hypercholesterolemia. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of pravastatin in children with familial hypercholesterolemia. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. [2013]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Steady-state pharmacokinetics of pravastatin in children with familial hypercholesterolaemia. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions. [2017]