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Exposure–response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults

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Abstract

The aim of the study was to evaluate the exposure–response (E–R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E–R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E–R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.

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Acknowledgements

This research was supported by Division of Clinical Pharmacology I funding from the U.S. Food and Drug Administration. This project was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

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Authors and Affiliations

  1. Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Liang Li, Ramana S. Uppoor, Mehul U. Mehta & Hao Zhu

  2. Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Yaning Wang

  3. Division of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Tiffany Farchione & Mitchell V. Mathis

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  1. Liang Li
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Correspondence to Hao Zhu.

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Li, L., Wang, Y., Uppoor, R.S. et al. Exposure–response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults. J Pharmacokinet Pharmacodyn 44, 245–262 (2017). https://doi.org/10.1007/s10928-017-9513-5

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