A New Once Daily Product for ADHD
A New Once Daily Product for ADHD
Upon oral administration of MPH-MLR, plasma methylphenidate concentrations rise rapidly, with an initial peak at 2 hours followed by a gradual decline over the next 4 to 6 hours. A second increase in methylphenidate concentrations begins at 6 hours, with a second peak at approximately 7 to 8 hours. The relative bioavailability of the product is 100%.
The pharmacokinetic profile of MPH-MLR was evaluated in a randomized, open-label cross-over study conducted in 26 healthy adults. All subjects received each of the three treatment arms: an 80 mg capsule whole, an opened 80 mg capsule sprinkled onto applesauce, and methylphenidate 25 mg immediate-release (IR) given three times daily. Under fasting conditions, the capsule provided a maximum concentration (Cmax) of 23.5 ± 11.4 ng/mL at 2 hours, with an area under the concentration time curve (AUC) of 258.1 ± 94.2 ng•hr/mL and a half-life of 5.1 ± 1.6 hours. The results when the beads were sprinkled on applesauce were similar to those with the capsule, with a Cmax of 21.8 ± 9.5 ng/mL, an AUC of 258.0 ± 84.4 ng•hr/mL and a half-life of 5.4 ± 2.5 hours. For comparison, IR methylphenidate produced a Cmax of 29.1 ± 14.9 ng/mL, an AUC of 281.7 ± 171.6 ng•hr/mL and a half-life of 3.4 ± 0.7 hrs.
Administration of MPH-MLR with a high fat meal produced an increase in the Cmax of 28% and an 18% increase in AUC, but resulted in a decrease in the second peak concentration, suggesting a shift towards a slightly greater percentage of the dose was released earlier. The variation produced with administration of MPH-MLR with food was not considered clinically significant. Methylphenidate is metabolized via deesterification to α-phenyl-piperidine acetic acid. The effects of hepatic or renal insufficiency on the elimination of MPH-MLR have not been studied.
A pediatric pharmacokinetic study of MPH-MLR conducted in 2007 provided similar results to those obtained in adults. The crossover study was conducted in 14 children (13 males, 1 female) with ADHD, ranging in age from 6 to 12 years (mean 9.6 ± 2.5 years). Patients were randomized to receive either MPH-MLR or IR methylphenidate given twice daily with a 14-day washout before receiving the other treatment. Doses ranged from 20 to 80 mg/day, with a mean dose of 38.6 mg/day. Pharmacokinetic parameters were comparable between the two products, with the exception of a 60% higher Cmax with the immediate-release product compared to MPH-MLR (20.41 ± 8.5 ng/mL versus 12.12 ± 5.76 ng/mL) which was expected. The results for AUC were similar: 155.11 ± 71.16 ng•hr/mL for MPH-MLR and 144.95 ± 53.89 ng•hr/mL for IR methylphenidate. The half-life for MPH-LR was 5.07 ± 1.47 hrs, compared to 2.86 ± 0.41 hrs for IR methylphenidate.
Data obtained in these studies, as well as the initial pediatric clinical trial have been used to create a pharmacokinetic/pharmacodynamic model to predict dose response. The one-compartment, first-order elimination population pharmacokinetic model was used for simulations of response to doses between 10 and 80 mg. The model demonstrated a positive correlation between maximum concentration and improvement in symptoms. An unexpected relationship was found between increasing body weight and reduced symptom control. Traditionally methylphenidate has not been dosed by weight, but this model suggests that weight may need to be factored into dosing considerations for older children and adolescents in order to maximize patient response.
Pharmacokinetics and Pharmacodynamics
Upon oral administration of MPH-MLR, plasma methylphenidate concentrations rise rapidly, with an initial peak at 2 hours followed by a gradual decline over the next 4 to 6 hours. A second increase in methylphenidate concentrations begins at 6 hours, with a second peak at approximately 7 to 8 hours. The relative bioavailability of the product is 100%.
The pharmacokinetic profile of MPH-MLR was evaluated in a randomized, open-label cross-over study conducted in 26 healthy adults. All subjects received each of the three treatment arms: an 80 mg capsule whole, an opened 80 mg capsule sprinkled onto applesauce, and methylphenidate 25 mg immediate-release (IR) given three times daily. Under fasting conditions, the capsule provided a maximum concentration (Cmax) of 23.5 ± 11.4 ng/mL at 2 hours, with an area under the concentration time curve (AUC) of 258.1 ± 94.2 ng•hr/mL and a half-life of 5.1 ± 1.6 hours. The results when the beads were sprinkled on applesauce were similar to those with the capsule, with a Cmax of 21.8 ± 9.5 ng/mL, an AUC of 258.0 ± 84.4 ng•hr/mL and a half-life of 5.4 ± 2.5 hours. For comparison, IR methylphenidate produced a Cmax of 29.1 ± 14.9 ng/mL, an AUC of 281.7 ± 171.6 ng•hr/mL and a half-life of 3.4 ± 0.7 hrs.
Administration of MPH-MLR with a high fat meal produced an increase in the Cmax of 28% and an 18% increase in AUC, but resulted in a decrease in the second peak concentration, suggesting a shift towards a slightly greater percentage of the dose was released earlier. The variation produced with administration of MPH-MLR with food was not considered clinically significant. Methylphenidate is metabolized via deesterification to α-phenyl-piperidine acetic acid. The effects of hepatic or renal insufficiency on the elimination of MPH-MLR have not been studied.
A pediatric pharmacokinetic study of MPH-MLR conducted in 2007 provided similar results to those obtained in adults. The crossover study was conducted in 14 children (13 males, 1 female) with ADHD, ranging in age from 6 to 12 years (mean 9.6 ± 2.5 years). Patients were randomized to receive either MPH-MLR or IR methylphenidate given twice daily with a 14-day washout before receiving the other treatment. Doses ranged from 20 to 80 mg/day, with a mean dose of 38.6 mg/day. Pharmacokinetic parameters were comparable between the two products, with the exception of a 60% higher Cmax with the immediate-release product compared to MPH-MLR (20.41 ± 8.5 ng/mL versus 12.12 ± 5.76 ng/mL) which was expected. The results for AUC were similar: 155.11 ± 71.16 ng•hr/mL for MPH-MLR and 144.95 ± 53.89 ng•hr/mL for IR methylphenidate. The half-life for MPH-LR was 5.07 ± 1.47 hrs, compared to 2.86 ± 0.41 hrs for IR methylphenidate.
Data obtained in these studies, as well as the initial pediatric clinical trial have been used to create a pharmacokinetic/pharmacodynamic model to predict dose response. The one-compartment, first-order elimination population pharmacokinetic model was used for simulations of response to doses between 10 and 80 mg. The model demonstrated a positive correlation between maximum concentration and improvement in symptoms. An unexpected relationship was found between increasing body weight and reduced symptom control. Traditionally methylphenidate has not been dosed by weight, but this model suggests that weight may need to be factored into dosing considerations for older children and adolescents in order to maximize patient response.
