Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

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.