Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder

Abstract

This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.