Statin Distribution

NCT02360826 | Completed Phase 1 DMC

• 1 other identifier: 13CRP1711002
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief Summary

Anticipating an increased use of statins in children and adolescents, it is imperative that we understand the genetic and developmental characteristics affecting the pharmacokinetics and pharmacodynamics of statins in childhood and adolescence. Simply extrapolating pediatric dosing guidelines from adult dose-exposure-response relationships fails to recognize the potential impact of growth and development in pediatric patients, which may have important clinical implications for drug efficacy or toxicity. Current evidence indicates that genetic variation in the SLCO1B1 transporter is important for statin disposition and toxicity in adults. The ontogeny of SLCO1B1 during human growth and development has not been well characterized, and limited pediatric data indicate that the genotype-phenotype relationship in children is the opposite of that observed in adults. Therefore, investigating the relative roles of SLCO1B1 ontogeny and genetic variation in statin disposition and response is key to determining the age at which the statin dose-exposure-response relationship mimics adults, and has important implications for other medications transported by the SLCO1B1 protein. As the first step in this process, our specific aims for the current investigation are 1) to determine the effect of genetic variation of SLCO1B1 on the pharmacokinetics of pravastatin and simvastatin by comparing Cmax, AUC and elimination between children and adolescents with 2 functional SLCO1B1 alleles and those with one or more variant alleles, and 2) to determine if the magnitude of the genetic effect on pravastatin pharmacokinetics (defined as Cmax, AUC and elimination) is equivalent to the effect on simvastatin pharmacokinetics. As a secondary aim, Cmax and AUC of pravastatin and simvastatin will be compared between children and adolescents for each genotype group. These results will be utilized to determine the sample size necessary to adequately power future studies characterizing the role of ontogeny on statin disposition. The ultimate goal of this proposed investigation is to establish the role of genetic variation in key transporters on the dose-exposure relationship of two commonly used statin drugs in children. This study is the first step in a series of investigations aimed at determining the mechanisms behind variations in physiologic response, clinical efficacy and significant adverse effect risk that surround the statin drugs in children and adolescents.

Conditions

Drug Distribution

Outcome Measures

Primary Outcomes (4)

• Evaluate effect of genotype (SLCO1B1) on Cmax pravastatin

  2 years

• Evaluate effect of genotype (SLCO1B1) on AUC pravastatin

  2 years

• Evaluate effect of genotype (SLCO1B1) on Cmax Simvastatin

  2 years

• Evaluate effect of genotype on AUC Simvastatin

  2 years

Secondary Outcomes (24)

• Evalaute the effect of age on Cmax of pravastatin

  2 years

• Evalaute the effect of gender on Cmax of pravastatin

  2 years

• Evalaute the effect of race Cmax of pravastatin

  2 years

• Evaluate the effect of sexual maturity on Cmax of pravastatin based

  2 years

• Evaluate the effect of age on Cmax of simvastatin

  2 years

Study Arms (2)

Pravastatin

EXPERIMENTAL

Pravastatin 20mg tablet (age 8-13 years), 40mg tablet (\>14 years); 1 time dose given per oral at at the start of the study day.

Drug: Pravastatin

Simvastatin

EXPERIMENTAL

Simvastatin 10mg tablet (ages 8-13 years), 20mg tablet (\>14 years); 1 time dose given per oral at the start of the study day.

Drug: Simvastatin

Interventions

Pravastatin DRUG

Pravastatin

Simvastatin DRUG

Simvastatin

Eligibility Criteria

• Age: 8 Years - 21 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children 8-21 years of age
• LDL cholesterol \>130mg/dl (\>95% percentile)
• Successfully genotyped for SLCO1B1
• Willing to sign the assent/permission/consent form

You may not qualify if:

• Underlying structural heart disease including congenital heart disease or acquired heart disease.
• History or laboratory evidence of an underlying intestinal, metabolic, autoimmune, or renal disease that could alter the disposition of simvastatin or pravastatin.
• Underlying pathology of the gastrointestinal tract or recent surgery which would be expected to alter the rate and/or extent of drug absorption
• Evidence of previous hypersensitivity to statin medications
• Unwillingness or inability to have screening labs drawn
• Refusal to participate in the study
• Unwillingness or inability to participate in an overnight fast
• Subjects taking drugs with interactions with statins (CYP3A4 inducers/inhibitors, OATP1B1 inducers/inhibitors)
• Inability to swallow a tablet drug
• For females, a positive urine beta-human chorionic gonadotropin pregnancy test result
• Evidence of hepatic abnormality as determined by values \> 3 times the age-specific upper limit of normal for AST, ALT, total and conjugated bilirubin, serum albumin, Alkaline Phosphatase, and GGT.
• Abnormal red blood cell morphology and/or a hemoglobin less than 9 gm/dl

Sponsors & Collaborators

• Children's Mercy Hospital Kansas City: lead
• American Heart Association: collaborator

Study Sites (1)

Children's Mercy Hospital

Kansas City, Missouri, 64108, United States

Location

Related Publications (1)

• Wagner JB, Abdel-Rahman S, Van Haandel L, Gaedigk A, Gaedigk R, Raghuveer G, Kauffman R, Leeder JS. Impact of SLCO1B1 Genotype on Pediatric Simvastatin Acid Pharmacokinetics. J Clin Pharmacol. 2018 Jun;58(6):823-833. doi: 10.1002/jcph.1080. Epub 2018 Feb 22.

  PMID: 29469964 DERIVED

MeSH Terms

Interventions

Pravastatin; Simvastatin

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Lovastatin

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: DO

Study Record Dates

• First Submitted: September 3, 2013
• First Posted: February 11, 2015
• Study Start: June 17, 2014
• Primary Completion: July 5, 2016
• Study Completion: July 5, 2016
• Last Updated: July 19, 2017

Record last verified: 2017-07

Locations

US (1)