title: Exposure-response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults.
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.
authors.affiliation: Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Yaning
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Ramana S
authors.initials: RS
authors.lastname: Uppoor
authors.affiliation: Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Mehul U
authors.initials: MU
authors.lastname: Mehta
authors.affiliation: 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.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Farchione
authors.affiliation: 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.
authors.forename: Mitchell V
authors.initials: MV
authors.lastname: Mathis
authors.affiliation: Division of Clinical Pharmacology I, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. hao.zhu@fda.hhs.gov.
authors.forename: Hao
authors.identifier: 0000-0002-3858-2048
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination / Q000379:methods; D002940:Circadian Rhythm / Q000187:drug effects; D002986:Clinical Trials as Topic; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D003692:Delayed-Action Preparations; D008774:Methylphenidate
keywords: Attention-deficit/hyperactivity disorder (ADHD); Diastolic blood pressure (DBP); Heart rate (HR); Methylphenidate (MPH); Modeling and simulation; Systolic blood pressure (SBP)