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Pharmacokinetic Variability of Long-Acting Stimulants in the Treatment of Children and Adults with Attention-Deficit Hyperactivity Disorder

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Abstract

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology.

Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmoticrelease formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile.

The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

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Acknowledgements

This review was supported by funding from Shire Development Inc. Although the sponsor was involved in the collection, analysis and interpretation of information, the ultimate interpretation of the information was made by the authors, as was the writing of this manuscript and the decision to submit this manuscript for publication in CNS Drugs. Editorial assistance in the form of proofreading, copy editing and fact checking was provided by Mary Ann McAdams of Ogilvy CommonHealth Scientific Communications (OCSC).

Mr Ermer, Mr Adeyi and Dr Pucci were all extensively involved in the conception and planning of the focus and content of this review, in directing acquisition, analysis and interpretation of the published literature included. They were all involved in drafting and critical revision of the manuscript for important intellectual content and provided approval of the final submitted version of the manuscript.

Mr Ermer and Mr Adeyi are Shire employees and own stocks and/or stock options from Shire. Dr Pucci is an employee of OCSC. OCSC was funded by Shire Development Inc. for support in writing and editing this manuscript.

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  1. Clinical Pharmacology and Pharmacokinetics, Shire Development Inc., Wayne, Pennsylvania, USA

    James C. Ermer

  2. Biostatistics and Statistical Programming, Shire Development Inc., Wayne, Pennsylvania, USA

    Ben A. Adeyi

  3. Medical Affairs, Ogilvy CommonHealth Scientific Communications, Parsippany, New Jersey, USA

    Michael L. Pucci

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Ermer, J.C., Adeyi, B.A. & Pucci, M.L. Pharmacokinetic Variability of Long-Acting Stimulants in the Treatment of Children and Adults with Attention-Deficit Hyperactivity Disorder. CNS Drugs 24, 1009–1025 (2010). https://doi.org/10.2165/11539410-000000000-00000

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