Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate

Patrick, Kennerly S.; Straughn, Arthur B.

doi:10.1124/dmd.115.067975

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…44 Guidance from the Food and Drug Administration explicitly addresses concern over the potential influence of concomitant ethanol on the gastric formulation dissolution rate, 66 in the context of dose dumping. 67 Accordingly, the present study avoided any such potential confounds to the interpretation of results in view of ethanol being administered 4 hours after MR-MPH dosing.…”

Section: Discussionmentioning

confidence: 99%

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Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

Zhu

Patrick

Straughn

et al. 2017

J Clin Psychopharmacol

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Background/Purpose Ethanol co-administered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on: (1) inhibition of post-absorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, Spheroidal Oral Drug Absorption Systems of dl-MPH and d-MPH. Methods/Procedures In a randomized, 4-way crossover study, fourteen healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. Findings/Results Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01), and the partial area under the curve (pAUC4–8h) by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for co-exposure. Ethanol significantly potentiated stimulant responses to either formulation. Implications/Conclusions These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent co-abuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid ADHD-alcohol use disorder.

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Section: Discussionmentioning

confidence: 99%

“…40–43 In addition to ethanol influencing d-MPH PK, formulation differences between IR-dl-MPH and IR-d-MPH have also been reported to markedly alter early exposure to d-MPH. 44 …”

Section: Introductionmentioning

confidence: 99%

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

Zhu

Patrick

Straughn

et al. 2017

J Clin Psychopharmacol

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“…Further, the d‐enantiomer of MPH has been reported to inhibit the extent to which l‐MPH is subject to first‐pass metabolism . This enantioselective inhibition by l‐MPH of d‐MPH may not generalize to l‐MPH inhibiting d‐MPH deesterification, vis‐à‐vis, the absorption of d‐MPH following one‐half the mg dose of dexMPH, when compared to equimolar dl‐MPH, resulted in significantly higher early exposure to d‐MPH for oral dexMPH . In the interest of mass balance, MPH and ritalinic acid are also eliminated as their lactams to account for most of the remaining 10% of an oral MPH dose (Figure ).…”

Section: Metabolic Fate Of Mph and Dexmphmentioning

confidence: 99%

“…It is noted in Table that IR‐dexMPH provides significantly greater early exposure than IR‐MPH. Hypothetical explanations for this difference have recently been advanced . The distinctly biphasic, high IR percentage (50%) of the spheroidal oral delivery absorption system (SODAS) MPH and dexMPH products exhibit pAUC 0–3 hours values nearly identical to the respective twice‐daily IR doses they were developed to mimic (e.g., the IR‐MPH pAUC 0–3 hrs of 33%, equals approximately 2 times the 17% pAUC 0–3 hrs for one daily SODAS‐MPH).…”

Section: Distinguishing Mr‐mph Products For Individualized Therapymentioning

confidence: 99%

Drug Regimen Individualization for Attention‐Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations

et al. 2018

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In 2000, the first biphasic modified-release (MR) formulation of methylphenidate (MPH) was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). An immediate-release (IR) MPH pulse (22% of the dose) facilitates rapid onset of stimulant action, while the remaining MR portion of the dose provides for day-long duration of efficacy. A wide array of oral MR-MPH products has subsequently been approved that also allows for once-daily dosing, though each product is characterized by distinctive exposure time courses. This review compares each member of the current MPH armamentarium to assist in the rational selection of a specific MPH regimen for the individualized treatment of patients with ADHD. The IR portion of biphasic MPH formulations now ranges from 15%, 20%, 22%, 25%, 30%, and 37% IR-MPH, as well as a 50% IR-MPH product whose distinctly pulsatile time course closely resembles that of the pre-century "gold standard" twice-daily IR-MPH regimen. Further, transdermal, suspension, and orally disintegrating tablet products are now available to overcome any solid dosage form swallowing difficulties. Most of these formulations are racemic, though in 2001, a chiral switch drug IR-dexmethylphenidate (dexMPH) was approved, followed by biphasic MR-dexMPH (50% IR) in 2005. New U.S. Food and Drug Administration (FDA) partial area under the curve (pAUC) bioavailability metrics have improved discrimination between specific generic MR-MPH products. This has resulted in two Orange Book MR-MPH products being recoded from "AB" (i.e., meets necessary bioequivalence requirements) to "BX" (i.e., insufficient data to confirm bioequivalence). The metabolic drug interaction between MPH and alcohol, which increases MPH bioavailability, potentiates euphoric effects, and heightens abuse liability, is discussed. This review concludes with brief considerations of pharmacogenomic predictors of ADHD first-line drug selection, carboxylesterase allelic variants influencing interindividual MPH metabolism, and novel MPH formulations in the regulatory pipeline. KEY WORDS methylphenidate, dexmethylphenidate, attention-deficit/hyperactivity disorder, pharmacokinetics, partial area under the curve, early exposure, relative bioavailability, carboxylesterase 1, bioequivalence.Estimates of attention-deficit/hyperactivity disorder (ADHD) global prevalence generally range from 5% to 7% in the pediatric population. 1,2 Recognition that ADHD often persists into adulthood has become well established, a

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“…The following discussion is intended to better define the pharmacokinetics (PK) of oral IR-dl-MPH. In addition, in this letter we offer a rationale for considering selection of less-complex, cost-curtailing bioanalytical methods that obviate chromatographic chiral discriminators when monitoring the psychoactive d-methylphenidate (d-MPH) isomer component of this racemate (Patrick et al, 1987;Patrick and Straughn, 2016). Understanding the PK of IR-dl-MPH underpins rational study designs of new modifiedrelease (MR) dl-MPH formulation technologies (at least six unique branded MR-dl-MPH products have been approved in the last 5 years, with a seventh tentatively approved (Drugs@FDA: FDA Approved Drug Products; https://www.accessdata.fda.gov/scripts/cder/daf/); others are in the regulatory pipeline (Patrick et al, 2019).…”

mentioning

confidence: 99%

Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization/Gas Chromatography

Patrick

Rodriguez

2019

Drug Metab Dispos

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A tenable hypothesis is presented which explains disparities between older oral dl-MPH bioavailability data generated using chiral derivatization-gas chromatography versus more recent findings using chiral liquid chromatography. These disparities persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-MPH is 23% and that of l-MPH is 5% (i.e., 82% as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. Older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent yields the (R,R,R)-MPH-prolyl diastereomer which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimation of the percent l-MPH at the expense of underestimating d-MPH. Unless compelling reasons exist to justify use of any chiral discriminators, less complex and less costly achiral analysis of plasma MPH appears appropriate for d-MPH quantitation since 99% exists as d-MPH. However, simultaneous plasma monitoring of d-MPH and l-MPH may be warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For example, (a) with transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which elevates l-MPH and d-MPH concentrations; (d) in forensic studies of intravenous or intranasal dl-MPH abuse; (e) were dl-MPH to be formulated as a free base sublingual product; or (f) as emerging advances in dl-MPH gene-dose effects warrant isomer correlations.

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Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate

Cited by 9 publications

References 22 publications

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers

Drug Regimen Individualization for Attention‐Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations

Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization/Gas Chromatography

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