Enantiomeric pharmacokinetics of methylphenidate and processing speed measures in adults with ADHD and substance use disorders

The overall aim of this thesis was to investigate the interindividual variability in the enantioselective pharmacokinetics of methylphenidate (MPH) in healthy adults as well as in adults with attention deficit hyperactivity disorder (ADHD) and substance use disorder. This research is significant due to the prevalent discrepancies in existing dosage guidelines, the common practice of exceeding maximum recommended MPH doses, and findings from original studies regarding effective and clinically beneficial plasma concentration levels.

MPH is a chiral compound composed of molecules that exist as mirror images, d- and l-enantiomers, like a left and right hand. Of these, d-MPH is considered responsible for most of the drug's effects. The metabolism of the two MPH enantiomers is stereoselective.

Study I involved 12 healthy subjects to assess the enantiomeric pharmacokinetics of MPH with repeated sampling after a single oral dose of Ritalin¨. The study aimed to determine the concentration-time profiles of d- and l-MPH and its metabolite, d- and l-ritalinic acid (RA), in plasma, oral fluid, and exhaled breath while also exploring the relationship between MPH plasma concentrations and the metabolic ratios (d-RA/d-MPH) as a potential marker of CES1 activity. Oral fluid concentrations of dl-MPH mirrored the biphasic plasma profile but were, on average, 1.8 times higher. MPH was detected in 87% of all exhaled breath samples; however, no consistent concentration-time pattern was observed. As expected, due to the galenic profile of Ritalin¨, d-MPH was detectable in plasma for at least 15 hours in all subjects, exhibiting a biphasic profile. Findings revealed a strong correlation between the d-RA/d-MPH plasma concentration ratio in single plasma samples drawn at 1.5Đ12 hours post-dose and the corresponding area under the curve ratio. Some subjects exhibited significant plasma concentrations of the pharmacologically less active l-enantiomer, potentially impacting total MPH plasma concentrations.

Study II included 28 patients diagnosed with both substance use disorder and ADHD, undergoing treatment at the Stockholm Centre for Dependency Disorders. These individuals were prescribed doses of MPH that exceeded the recommended levels. The primary aim of this study was to assess intra- and interindividual variability of the enantiomers of MPH and its metabolite, RA, in plasma. Additionally, the study aimed to relate the variability in dosage and exposure to the MPH metabolic ratios (d-RA/d-MPH) and CES1 genotypes. Venous blood samples were drawn before MPH intake and approximately five hours post-dose for drug concentration analysis; 12 subjects were sampled repeatedly (1-2 weeks apart). Post-dose d-MPH plasma levels ranged from 8 to 472 ng/mL. In 12 subjects, l-MPH plasma concentrations were measurable, ranging from 1.2 to 389 ng/mL, constituting up to 48% of the total MPH concentration. A notable correlation (rs = 0.94) between the total (d+l) RA/MPH metabolic ratio and the d-RA/d-MPH metabolic ratio suggests that the non-enantioselective analysis may serve as a valuable approach for estimating CES1 activity, despite the complexities arising from the varying contributions of enantiomers to the plasma concentrations of drugs. There was no consistent pattern regarding how the d-MPH plasma concentrations fluctuated with either high or low MPH doses.

Study III evaluated perceptual and cognitive processing speed measures, specifically AQT (A Quick Test of cognitive speed), to monitor the effects of MPH in adults with ADHD and substance use disorder. A significant finding was that perceptual speed (Color, Form) was normalized with MPH in two-thirds of the respondents. In Study IV, we examined if the AQT scores were associated with plasma concentrations of d-MPH. All 21 subjects showed improvement in AQT Color from pre-dose to post-dose. The observation that nine subjects showed improvement across all tests despite exhibiting highly variable d-MPH plasma concentrations ranging from 13 to 277 ng/mL underscores the lack of a direct relationship between AQT performance and d-MPH plasma levels.

The findings of this thesis emphasize the complexity and challenges of making clinical decisions based solely on the MPH dosage.

List of scientific papers

I. Pharmacokinetics of MPH and ritalinic acid in plasma correlations with exhaled breath and oral fluid in healthy volunteers. Michel Arvidsson, Marja-Liisa Dahl, Olof Beck, Gerd Ackehed, Karin Nordin, Staffan Rosenborg. European Journal of Clinical Pharmacology. Volume 76 (2), pages 229-237, 2020.
https://doi.org/10.1007/s00228-019-02787-x

II. Plasma concentrations of MPH enantiomers in adults with ADHD and substance use disorder, with focus on high doses and relationship to carboxylesterase activity. Michel Arvidsson, Johan Franck, Gerd Ackehed, Madeleine Pettersson Bergstrand, Lena Ekstršm, Staffan Rosenborg, Marja-Liisa Dahl. Basic & Clinical Pharmacology & Toxicology. Volume 130 (4), pages 492-500, 2022.
https://doi.org/10.1111/bcpt.13707

III. MPH effects on processing speed in a clinical sample of adults with ADHD and substance use disorder: a pilot study. Michel Arvidsson, Marja-Liisa Dahl, Johan Franck, Elisabeth Wiig, Niels Peter Nielsen. Nordic Journal of Psychiatry. Volume 73 (2), pages 118-124, 2019.
https://doi.org/10.1080/08039488.2019.1573922

IV. Plasma Concentrations of d-MPH and AQT in Adults with ADHD and Substance Use Disorder. Michel Arvidsson, Marja-Liisa Dahl, Johan Franck, Elisabeth Wiig, Niels Peter Nielsen. [Manuscript]