Effect of Food on Early Drug Exposure from Extended-Release Stimulants: Results from the Concerta®, Adderall XR™ Food Evaluation (CAFÉ) Study

Abstract

Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p < 0.0001). By contrast, methylphenidate concentrations over the same 8 h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8 h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS tablet provides a reliable and consistent delivery of methylphenidate HCI, independent of food, for patients with ADHD.

Bioavailability of modified‐release methylphenidate: influence of high‐fat breakfast when administered intact and when capsule content sprinkled on applesauce

“…Metadate 1 capsules contains 30% IR beads and 70% DR beads, and when administered once daily produces a methylphenidate plasma concentration profile similar to that of IR methylphenidate taken twice daily. The bioavailability of methylphenidate was not shown to be altered when the capsules were administered by sprinkling their contents onto a small amount of applesauce [17]. Concerta 1 tablets are coated with IR methylphenidate and contains an osmotic pumop (OROS) that gradually releases the drug over a 10 h period.…”

“…Enrollment of children into clinical studies that require the use of invasive procedures is always a major concern. In this study, a relatively large number of blood samples (17) were required to be taken from each subject over three 24 h periods post administration, and therefore adults were chosen as the subjects of the study.…”

Current Methods for Predicting Human Food Effect

“…However, drug exposure for methylphenidate from the Concerta ® formulation was not affected by food. The authors concluded less variability in drug exposure in patients taking Concerta ® compared to Adderall XR ® particularly if meal intake varied (10). Although these results were challenged because the study compared partial area AUCs as opposed to traditional BE criteria, it illustrates how food effect data can also be used to promote market advantage between drugs in a therapeutic class (11).…”

Lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy and safety in children and adolescents

“…Significant variations in the plasma levels of d-amphetamines were reported when one compared their administration with and without food intake (Adderall XR) 26,27 . It has been demonstrated in vitro that the solubility of LDX is not affected by pH within a physiologically relevant range (pH = 1-8), and is slightly reduced when the pH is substantially increased (pH = 8-13) 20 .…”