Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

Sponsor

Icahn School of Medicine at Mount Sinai (Other)

Overall Status

Recruiting

CT.gov ID

NCT03781752

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), University of Florida (Other), Children's Hospital Medical Center, Cincinnati (Other), Seattle Children's Hospital (Other)

500

Enrollment

Locations

Arm

64.9

Anticipated Duration (Months)

125

Patients Per Site

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The study team will determine the association between d,l-methylphenidate (MPH) therapeutic outcomes in ADHD patients and genetic variants of CES1 and reveal key associations between CES1 genotypes and the PK and PD of MPH.

Condition or Disease	Intervention/Treatment	Phase
ADHD Attention Deficit Hyperactivity Disorder	Drug: Methylphenidate	Phase 4

Detailed Description

Psychostimulants are the first-line pharmacotherapy for Attention deficit-hyperactivity disorder (ADHD), and MPH accounts for approximately 50% of all stimulant usage. There has been an ~10-fold increase in MPH prescribing since 1990, with 18 million prescriptions dispensed in 2010, including 1.9 million new starts on MPH, making it the 5th most commonly prescribed medication to children ages 2 -11 and the single most frequently prescribed medication of any type in those aged 12-17 years. The annual exposure of pediatric patients to MPH is extremely high and MPH is among the most commonly prescribed chronic use oral medications for US children. Despite nearly 60 years of accrued clinical experience with MPH, the significant inter-individual variability in MPH pharmacokinetics (PK), pharmacodynamics (PD) and adverse effects is inadequately explained and unpredictable. Up to 35% of ADHD patients do not respond satisfactorily to MPH therapy, and an even larger percentage discontinues treatment despite persistent ADHD. During clinical trials of MPH in treatment-naïve patients, a significant number suffer from adverse effects that are severe and persistent enough to require dose decreases or even study withdrawal. Moreover, some severe adverse drug reactions (ADRs) - including sudden cardiac death - have been associated with MPH, although the precise reasons for these associations remain elusive and controversial. Research efforts have been made to identify genetic biomarkers associated with MPH therapeutic outcomes, almost exclusively focusing on genes related to MPH PD (e.g., dopamine transporter gene [DAT1, SLC6A3]). Unfortunately, findings from these studies have been somewhat inconsistent, equivocal or even contradictory, and they do not explain the variability in the PK of MPH. Pharmacogenomic studies in MPH-treated children have not assessed the influence of genes associated with individual variability in PK in relation to clinical response. Carboxylesterase-1 (CES1), an abundant hepatic enzyme encoded by the polymorphic CES1 gene, is the sole hepatic enzyme catalyzing the metabolism (i.e., hydrolytic deactivation) of MPH. CES1 expression and activity are known to vary substantially among individuals. The first clinically significant CES1 variant G143E (rs71647871), discovered in the study team's lab during the course of a healthy volunteer MPH PK study, led to gross impairments in MPH metabolism. This variant has been unequivocally shown in vitro and in clinical studies to lead to significantly impaired metabolism of MPH and other known CES1 substrates. The study team has established the minor allele frequency (MAF) of the G143E variant as 3-4% in the general population. Accordingly, with ~1.9 million new starts of MPH annually, an estimated 133,000 pediatric patients (i.e. G143E carrier's frequency 6-8%) with a genetically impaired ability to metabolize/deactivate the drug will receive it - exposing them to high systemic concentrations of MPH and any attendant risks or toxicities. In addition, the study team's in vitro studies have revealed that another common CES1 variant D203E (rs2307227) exhibited significantly impaired activity on MPH metabolism, although the effects on D203E on clinical response are in need of further elucidation. Furthermore, despite recent intensive research on CES1 pharmacogenetics, the functions of a large number of additional CES1 variants remain undetermined.

The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can significantly alter the expression and/or activity of CES1, thereby influencing the metabolism and disposition of MPH. These influences will be directly investigated in relation to MPH therapeutic response and tolerability in ADHD patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Youth will NOT be randomized to drug for this PD study, but will receive MPH from their treatment providers in clinical care either before or after being invited to participate in the PK procedure. Their treatment data will be collected from their providers to augment the study team's analyses. The study team is performing a pharmacokinetic (PK) study using a single dose of methylphenidate (MPH) among youth identified as having specific variants of the CES1 gene. Youth will be identified by cheek swabs for CES1 variants. They will be provided . MPH for the PK procedure.Youth will NOT be randomized to drug for this PD study, but will receive MPH from their treatment providers in clinical care either before or after being invited to participate in the PK procedure. Their treatment data will be collected from their providers to augment the study team's analyses. The study team is performing a pharmacokinetic (PK) study using a single dose of methylphenidate (MPH) among youth identified as having specific variants of the CES1 gene. Youth will be identified by cheek swabs for CES1 variants. They will be provided . MPH for the PK procedure.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

Actual Study Start Date :

Mar 4, 2018

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Jul 31, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methylphenidate Youth with ADHD	Drug: Methylphenidate study to determine dose Other Names: d,l-methylphenidate MPH

Arm

Intervention/Treatment

Experimental: Methylphenidate

Youth with ADHD

Drug: Methylphenidate

study to determine dose

Other Names:

d,l-methylphenidate

MPH

Outcome Measures

Primary Outcome Measures

Maximum methylphenidate plasma concentration (Cmax), [up to 8 Hours]
The maximum plasma concentration achieved after dosing.

Secondary Outcome Measures

Time to maximum concentration (Tmax) [up 8 hours]
The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.
Area under the plasma concentration curve (AUClast) [up to 8 hours]
Area under the plasma concentration-time curve from time zero to the last measurable concentration.
Area under the plasma concentration curve (AUCinf) [up to 8 hours]
Area under the plasma concentration-time curve from time zero to infinity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 26 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Youth ages 6-26 years with ADHD as a primary diagnosis
For former participants of MPH trials to be invited back for PK procedures.

Exclusion Criteria:

Participants that do not have ADHD as a primary diagnosis
Participants that do not want, require, or are not healthy enough for medication treatment with MPH for ADHD per the clinical judgment of the treating and study clinicians
Participants that are smokers or, are pregnant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610
2	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
3	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
4	Seattle Children's Hospital	Seattle	Washington	United States	98105

Sponsors and Collaborators

Icahn School of Medicine at Mount Sinai
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Florida
Children's Hospital Medical Center, Cincinnati
Seattle Children's Hospital

Investigators

Principal Investigator: Jeffrey Newcorn, MD, Icahn School of Medicine at Mount Sinai
Principal Investigator: Mark Stein, PhD, University of Washington
Principal Investigator: Tanya Froehlich, MD, Children's Hospital Medical Center, Cincinnati