Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate: Evaluation of Dose Proportionality, Food Effect, Multiple-Dose Modeling, and Comparative Bioavailability with Immediate-Release Methylphenidate in Healthy Adults
| Autor: | Angus McLean, Jogarao V. S. Gobburu, Tao Liu, Michelle D. Po, Bev Incledon, Norberto J. DeSousa, Floyd R. Sallee |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Biological Availability methylphenidate Pharmacology attention-deficit/hyperactivity disorder 03 medical and health sciences Young Adult 0302 clinical medicine Dose proportionality Pharmacokinetics mental disorders food effect Medicine Attention deficit hyperactivity disorder Humans Pharmacology (medical) dose proportionality Morning FOOD EFFECT Cross-Over Studies business.industry Methylphenidate Delayed release (linguistics) Original Articles Middle Aged relative bioavailability medicine.disease Healthy Volunteers 030227 psychiatry Bioavailability Diet Psychiatry and Mental health Attention Deficit Disorder with Hyperactivity Delayed-Action Preparations Pediatrics Perinatology and Child Health Central Nervous System Stimulants Female business human activities pharmacokinetics 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Child and Adolescent Psychopharmacology |
| ISSN: | 1557-8992 |
| Popis: | Objectives: HLD200, an oral, once-daily, evening-dosed, delayed-release, and extended-release methylphenidate (DR/ER-MPH), was designed to provide efficacy from the early morning, throughout the day, and into the evening to individuals with attention-deficit/hyperactivity disorder. The objectives were to evaluate DR/ER-MPH pharmacokinetic (PK) properties in healthy adults, including dose proportionality, food effect, the potential of accumulation using multiple-dose modeling, and bioavailability compared to an immediate-release MPH (IR MPH). Methods: Three open-label, single-dose, crossover studies were conducted, all with a 7-day washout between treatments. In Study I, 20 subjects received evening-dosed DR/ER-MPH (20 and 100 mg) followed by a medium-fat breakfast; 13 subjects received a subsequent 100-mg dose of DR/ER-MPH followed by a low-fat breakfast. In Study II, 18 subjects were evaluated after receiving evening-dosed DR/ER-MPH (100 mg) under 3 conditions: immediately after a high-fat meal, sprinkled on applesauce, and in a fasted state. In Study III, 11 and 12 subjects received evening-dosed DR/ER-MPH (100 mg) and morning-dosed IR MPH (20 mg), respectively. Results: DR/ER-MPH demonstrated dose proportionality between 20- and 100-mg doses. DR/ER-MPH PK parameters were not significantly affected by breakfast content or by sprinkling capsule contents. A high-fat meal immediately preceding evening dosing did not affect total MPH exposure but lowered peak MPH exposure by 14% and 11% versus fasted and sprinkled states, and time to peak exposure was delayed by ∼2.5 hours; these PK differences are unlikely to be clinically significant. Based on multiple-dose simulations using data from Study I, negligible accumulation of DR/ER-MPH was predicted. The relative bioavailability for DR/ER-MPH compared to IR MPH was 73.9%. No serious adverse events (AEs) were reported, and the observed AEs were consistent with MPH. There were no discontinuations in Studies I and III, but three participants withdrew in Study II due to AEs. Conclusions: Evening-dosed DR/ER-MPH demonstrated dose proportionality and can be administered with or without food. Significant accumulation is unlikely with multiple dosing. |
| Databáze: | OpenAIRE |
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