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.

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.

Single-Dose Pharmacokinetics of HLD200, a Delayed-Release and Extended-Release Methylphenidate Formulation, in Healthy Adults and in Adolescents and Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Current extended-release (ER) formulations of psychostimulants used for treatment of attention-deficit/hyperactivity disorder (ADHD) provide an extended duration of ADHD symptom control; however, the onset of efficacy can be protracted and variable, leaving the early morning untreated. The primary objective was to characterize the single-dose pharmacokinetics and tolerability of HLD200, an evening-dosed, delayed-release (DR) and ER formulation of methylphenidate (MPH), in healthy adults and in adolescents and children with ADHD. METHODS: The pharmacokinetics and tolerability of a single, oral evening dose of HLD200 (54 mg) were evaluated in two single-center open-label studies: the first in healthy adults (n = 12) and the second in adolescents (n = 18) and children (n = 11) with ADHD. Primary pharmacokinetic endpoints were the rate and extent of MPH absorption (Cmax and area under the curve [AUC]) and time to peak concentration (Tmax). These parameters were calculated using noncompartmental analysis. RESULTS: HLD200 produced a pharmacokinetic profile characterized by an 8- to 10-hour delay in MPH release, followed by a period of extended controlled release, resulting in an ascending absorption profile that coincided with the early morning and afternoon. Mean values (coefficient of variation [CV]%) of weight-adjusted pharmacokinetic parameters were similar in adults and in adolescents and children with ADHD: Cmax ([ng/mL]/[mg/kg]) was 9.1 (35.2), 8.8 (34.5), and 7.4 (30.1); AUC0-t ([ng · h/mL]/[mg/kg]) was 126.5 (35.5), 129.4 (34.8), and 129.7 (27.3); and Tmax (hours) was 15.6 (11.1), 17.1 (14.5), and 17.7 (14.1), respectively. Intersubject variability in the mean time to achieve ascending plasma MPH concentrations of 2, 3, 4, and 5 ng/mL was low (CV: 7.8%-17.7%). CONCLUSIONS: Evening-dosed HLD200 produces the intended DR and ER pharmacokinetic profile that provides a consistent predictable delay in initial MPH release until the early morning, followed by extended release across the day. The body weight-adjusted pharmacokinetics of HLD200 were similar between adults and adolescents and children with ADHD.

Component rotational alignment in unexplained painful primary total knee arthroplasty.

BACKGROUND: Rotational malalignment of the components in total knee arthroplasty (TKA) can be a factor in poor outcomes but has yet to be defined. This study compares the rotational alignment of components in a cohort of 56 patients with unexplained pain following total knee arthroplasty with a matched control cohort of 56 patients with cemented Nex Gen Legacy posterior stabilised (LPS) flex fixed bearing TKA between March 2006 and May 2010. The aim of the study was to define an acceptable limit of rotation in total knee replacement. METHODS: Rotational alignment was calculated using the Berger protocol with post operative computerised tomography scanning. The alignment parameters measured were tibial and femoral component rotations and the combined component rotations and the component rotational mismatch. RESULTS: The two cohorts were demographically matched. Excessive internal rotation of the components was defined using the tenth percentile of rotations in the control cohort. Values of excessive internal rotation were 5.8° of the tibial component, 3.9° of the femoral component, 8.7° of combined rotation and 5.6° of the component mismatch. No significant difference was identified in excessive external rotation in any of the parameters. A significant difference in the mean rotations between the two cohorts was identified with internal rotation of the components in the painful cohort and external rotation on the control cohort. CONCLUSIONS: We identified internal rotation malalignment of the tibial (p=0.0003) and femoral (p=0.014) components individually as well as the combined component rotation (p=0.0003) and component rotation mismatch (p=0.0001) to be a factor in pain following TKA. External rotation of any of the component parameters was not identified to be a factor in painful TKA. This study adds to the understanding of rotational alignment in TKA and suggests limits of internal rotation alignment associated with painful Nex Gen Legacy posterior stabilised (LPS) flex fixed bearing TKA. LEVEL OF EVIDENCE: Level III.

Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules.

OBJECTIVE: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels. PATIENTS AND METHODS: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3, 6, or 9 h late, or when two doses are taken at one time. RESULTS: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 microg/ml only to 4 microg/ml after 24 h without medication, and only to 2.5 microg/ml after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 microg/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ. CONCLUSIONS: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

STUDY OBJECTIVES: To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. DESIGN: Randomized, open-label, crossover study. SETTING: Clinical research unit. PATIENTS: Forty-one healthy adults. INTERVENTIONS: Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. MEASUREMENTS AND MAIN RESULTS: The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. CONCLUSION: SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.