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Journal of Clinical Pharmacology, 2004; 44:173-178
© 2004 the American College of Clinical Pharmacology

PHARMACOKINETICS AND PHARMACODYNAMICS

A Single-Dose, Two-Way Crossover, Bioequivalence Study of Dexmethylphenidate HCl with and without Food in Healthy Subjects

Steve K. Teo, PhD, Michael R. Scheffler, PhD, Anfan Wu, PhD, David I. Stirling, PhD, Steve D. Thomas, PhD, Daria Stypinski, PhD and Vikram D. Khetani, PhD

From Celgene Corporation, Warren, New Jersey (Dr. Teo, Dr. Scheffler, Dr. Wu, Dr. Stirling, Dr. Thomas, Dr. Khetani) and MDS Pharma Services, Lincoln, BE (Dr. Stypinski).

Address for reprints: Steve K. Teo, Celgene Corporation, 7 Powder Horn Drive, Warren, NJ 07059.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Attention deficit hyperactivity disorder (ADHD) in children is effectively treated by racemic oral methylphenidate (dl-MPH). The d-isomer (d-MPH) has been developed as an improved treatment for ADHD since only half the racemic dose is used. This study, performed in healthy subjects, assessed the effect of food on the pharmacokinetics of dexmethylphenidate hydrochloride (d-MPH HCl) in a single dose (2 x 10-mg tablets), two-way crossover with d-MPH administered to subjects in both a fasting state or after a high-fat breakfast. There were no serious or unexpected adverse events during the course of this study, with most events reported in comparable numbers of fed and fasted subjects. The bioequivalence of d-MPH was similar with or without food, with 90% confidence intervals of 88.2% to 104.6% and 105.9% to 118.2% for ln(Cmax) and ln[(AUC0-{infty})], respectively. There was a marginal but statistically significant 1-hour increase in tmax in the fed versus fasted state, reflecting an absorption delay. The rate of formation of the major metabolite, d-ritalinic acid (d-RA), was marginally decreased (~14%) after food. The extent of exposure to d-RA was similar (within 1.2%) between both treatments. There was a marginal but statistically significant difference in mean tmax for d-RA between fed and fasted conditions, with peak concentration occurring 1.5 hours later after d-MPH administration with food. There was no measurable in vivo chiral inversion of d-MPH to l-MPH in plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA. In summary, food had no substantial effect on the bioavailability of d-MPH, with an equivalent rate and extent of exposure obtained. Therefore, d-MPH can be administered without regard to food intake.

Key Words: Dexmethylphenidate HCl • attention deficit hyperactivity disorder • food-drug interactions

Attention deficit hyperactivity disorder (ADHD) has been estimated to affect 7% to 16% of 8- to 19-year-olds in the United States.1,2 Methylphenidate (methyl-phenyl-2(2'piperidyl)acetate; d,l-MPH HCl) is an effective treatment and was originally marketed as a 80:20 mixture of the erythro- and threo-racemates.3-5 It is the most commonly used stimulant for the disorder, with a response rate approaching 75%.6 More than 90% of all children diagnosed with ADHD are treated with d,l-MPH.7 Studies have shown that only the threo-racemate of d,l-MPH was responsible for the central nervous system (CNS) actions of the racemic mixture, but both racemates were equipotent in producing unwanted hypertensive effects and toxicity.8,9 In an effort to improve the therapeutic index and decrease the toxicity, the erythro-racemate was subsequently removed. The currently marketed d,l-MPH product is therefore a 50:50 racemic mixture of the d-threo-and l-threo-MPH enantiomers and is sold as Ritalin® and other generic versions. d,l-MPH is a mild CNS stimulant structurally and pharmacologically related to amphetamine. Recent studies have shown that d-threo-MPH HCl (d-MPH; dexmethylphenidate hydrochloride) is the pharmacologically active enantiomer.10

Advances in stereospecific manufacturing have allowed for the preparation of optically pure d-MPH in commercial quantities. A preparation containing only this enantiomer could provide a better therapeutic index than a racemic threo-MPH mixture and represents an advance in single-enantiomer technology. d-MPH was therefore developed as an improved treatment for ADHD and was approved by the Food and Drug Administration (FDA) for this indication in November 2001 and is sold under the brand name Focalin®. The current study was performed to determine the effect of food on the pharmacokinetics of d-MPH in healthy subjects.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Fifteen healthy, nonobese subjects (9 males and 6 females) with a mean age of 30 years (range: 20-44), weight of 72 kg (range: 54-100), and height of 1.73 m (range: 1.54-1.91) were enrolled. Fourteen subjects were Caucasian, and 1 was Asian. Eight were smokers. Screening of subjects included a complete medical history, physical examination (height, weight, vital signs, 12-lead electrocardiogram), and clinical laboratory tests (fasting blood chemistry, hematology, urinalysis, HIV antibody, alcohol and drugs of abuse). They were instructed not to take any nonprescription medications and alcohol throughout the study. All subjects read and signed an informed consent form approved by the institutional review board prior to study initiation. All subjects completed the study and were included in the safety and pharmacokinetic analyses.

Study Formulation
d-MPH was 99.8% pure, with an enantiomeric purity of 100%, as determined by high-performance liquid chromatography (HPLC) (Celgene internal document). It was manufactured commercially under cGMP guidelines and formulated as an immediate-release (IR) 10-mg tablet.

Study Design
This was a single-dose, two-way crossover study. The study protocol, informed consent form, and investigator's brochure were reviewed by the institutional review board of MDS Pharma Services prior to initiation of the study. Two 10-mg tablets were administered in a fasting state and following a high-fat meal consisting of 2 eggs fried in butter, 2 pieces of bacon, 2 pieces of white toast with butter, 2 to 4 ounces of hash brown potatoes, and 8 ounces of whole milk. Calories from fat constituted 58% of the total caloric content, followed by carbohydrates and protein at 27% and 15.4%, respectively. The d-MPH dose was the recommended daily maximum therapeutic dose in children. All subjects were enrolled as one cohort group and were dosed on Days 1 and 8. They were prospectively randomized in a Latin square design to either a fasted-then-fed sequence or a fed-then-fasted sequence. Each subject received both treatments separated by a 1-week washout period. Study participation lasted for approximately 9 days, during which subjects remained confined to the clinic for about 2 days on two separate occasions.

Sample Collection
Blood samples were collected in EDTA-coated tubes at the following time points on Days 1 and 2 and Days 8 and 9 after dosing: 30 minutes predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, and 36 hours after dosing. Plasma samples were prepared by centrifugation and then stored at -20°C prior to analysis.

Analytical Methods
Frozen samples were thawed under refrigeration and then brought to room temperature with frequent vortexing. LC/MS/MS methods were developed, validated, and used for the determination of d-MPH and l-MPH and their corresponding major metabolites, d- and l-ritalinic acid (d-RA, l-RA), in human EDTA plasma by MDS Pharma Services (Lincoln, NE). Briefly, samples were spiked with the appropriate deuterated internal standards (d,l-MPH or d-RA) and the compounds extracted from alkalinized plasma into n-pentane. Dried extracts were reconstituted and injected into an LC/MS/MS equipped with a chiral column and using the APCI interface. Positive ions were monitored in the multiple-reaction monitoring mode. The potential for chiral inversion was determined by looking for the appearance of l-MPH after administration of only the d-isomer. The stereospecificity of d-MPH metabolism was also determined by monitoring for the presence of d- and l-RA.

Pharmacokinetic Analysis
Plasma d-MPH and d-RA concentration versus time profiles were analyzed by a noncompartmental pharmacokinetic method (WinNonlin, Version 3.1 Professional, Pharsight, Palo Alto, CA). Cmax and tmax were determined as observed. The terminal rate constant ({gamma}) was determined by linear regression of the terminal linear portion of the ln concentration versus time curve. The terminal half-life was calculated as 0.693/{gamma}. Area under the plasma concentration versus time curve (AUC0-t) from time zero to the last quantifiable concentration (Ct) was calculated by trapezoidal integration. Area with extrapolation to infinity (AUC0-{infty}) was calculated from AUC0-{infty} +Ct/{gamma}. The mean residence time (MRT) was calculated based on the area under the first moment curve (AUMC).

Statistical Analysis
Previous studies by Srinivas et al11,12 describing the pharmacokinetics of d,l-MPH in healthy volunteers were used as the basis for arriving at the proposed sample size. Based on a Cmax and AUC0-{infty} of d-MPH of 18.12 ± 4.34 ng/mL and 120.21 ± 30.68 ngh/mL, respectively, a sample size of 15 was chosen. This size was sufficient for the study to detect, with 80% power, a 20% difference in the Cmax and AUC0-{infty} of d-MPH when given with and without food. Differences in pharmacokinetic parameters (excluding tmax) were evaluated using ANOVA. Differences in tmax were evaluated nonparametrically using the Wilcoxon signed rank test. Bioequivalence was shown if the 90% confidence intervals of the ratio of product means for d-MPH ln(Cmax) and ln(AUC0-{infty}) were within the range of 80% to 125%. Similar parameters were calculated for d-RA and were planned to be calculated for l-MPH and l-RA should their levels be detectable in the plasma.


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Analytical Methods
Extraction recoveries for d-MPH, l-MPH, d-RA, and l-RA averaged 84%, 78%, 44%, and 46%, respectively. Linear ranges were 0.5 to 50 ng/mL for d-MPH, 0.05 to 5 ng/mL for l-MPH, and 5 to 500 ng/mL for both d-RA and l-RA, with correlation coefficients greater than 0.996 for all compounds. No dilutions of plasma samples were required. Limits of quantitation were 0.5 ng/mL for d-MPH, 0.05 ng/mL for l-MPH, and 5 ng/mL for both d-RA and l-RA. Quality control samples analyzed with each analytical run of d-MPH, l-MPH, d-RA, and l-RA had coefficients of variation less than or equal to 6.86%, 11.28%, 6.29%, and 4.55%, respectively. Coefficients of variation for accuracy and precision for intraday and interday variation were less than or equal to 5.56%, 8.27%, 7.1%, and 6.8% for d-MPH, l-MPH, d-RA, and l-RA, respectively. All plasma samples for d-MPH and d-RA were within the linear range of the assay. All plasma samples for l-MPH and l-RA were below the limit of quantitation. No pharmacokinetics could therefore be calculated for l-MPH and l-RA.

Adverse Events
No serious or unexpected adverse events occurred. The majority of all adverse events were mild in intensity. Adverse events were reported by 10 (67%) of the 15 subjects. The most common were dry mouth (6 subjects or 40%), nervousness (5 subjects or 33%), and somnolence (4 subjects or 27%). Most events were reported in comparable numbers of subjects following d-MPH dosing in fed or fasted states. One possible exception was nervousness, reported by 4 subjects in the fasted state (27%) versus 2 subjects in the fed state (13%).

Effect of Food on d-MPH Pharmacokinetics
Comparison of mean ratios of ln-transformed Cmax and AUC0-{infty} at 96.0% and 111.9%, respectively, for the fed relative to the fasted state indicated that the rate and the extent of d-MPH absorption were similar when administered with or without food (Table I, Figure 1). Although comparison of mean tmax showed that there was a marginal but statistically significant increase in tmax in the fed versus fasted state, with food delaying peak concentration levels by about 1 hour, the 90% confidence intervals for ln(Cmax) and ln(AUC0-{infty}) were 88.2% to 104.6% and 105.9% to 118.2%, respectively, and therefore were within the 80% to 125% range required for bioequivalence. Food therefore has no effect on the bioavailability of the 10-mg tablet formulation of d-MPH. Comparison of mean tmax, however, indicated that there was a marginal but statistically significant increase in tmax in the fed versus fasted state. Food therefore delayed the Cmax by 1 hour.


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  		Table I Summary of Plasma Pharmacokinetics of d-MPH in Fed and Fasted Conditions (Mean ± SD)

 


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  		Figure 1. Plasma concentrations of d-MPH and d-RA over time. No l-MPH or l-RA was detected.

 

Effect of Food on d-RA Pharmacokinetics
Comparison of mean ratio of ln-transformed AUC0-{infty} for the fed relative to the fasted state indicated that the extent of exposure to d-RA was similar (101.2%). The rate of formation, however, was marginally decreased in the presence of food, with a mean ratio of ln-transformed Cmax of 86.7% and a marginal but statistically significant 1.5-hour delay in mean tmax between fed and fasted conditions (Table II, Figure 1). The 90% confidence interval for ln(Cmax) and ln[(AUC0-{infty})] were 82.3% to 91.3% and 97.6% to 104.9%, respectively.


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  		Table II Summary of Plasma Pharmacokinetics of d-RA in Fed and Fasted Conditions (Mean ± SD)

 

Chiral Inversion and Stereospecific Metabolism of d-MPH
No in vivo chiral inversion of d-MPH to l-MPH occurred since oral administration of d-MPH did not produce any l-MPH in the plasma. In addition, the metabolism of d-MPH was stereospecific as d-MPH only produced d-RA.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite the numerous studies on the effects of food on the absorption of various drugs, there are still too many variables (e.g., physical/chemical properties of the drug; size, type, and content of meal; size of dose; use of concomitant medications) to predict food-drug interactions for specific compounds. Clinical studies have shown the coadministration of food to delay, decrease, increase, or have no effect on drug absorption.13 Since d-MPH is mainly dosed in the morning, prior to the school day, the effects of a high-fat breakfast could have clinically relevant effects on its absorption, plasma levels, and efficacy. Previous studies using immediate-release formulations of dl-MPH have yielded conflicting results on the effects of food. Two studies reported an effect of food on absorption and suggested dosing before meals, while two others found no effect.14-17 The latter studies, however, were not sufficiently powered for detecting differences.16,17 More recent studies looked at various formulations of dl-MPH. A high-fat breakfast had no effect and did not induce dose dumping from an osmotically controlled release formulation of d,l-MPH.18 In a study using IR and slow-release (SR) formulations, a high-carbohydrate breakfast significantly increased the extent of exposure (AUC) but not the rate (Cmax/AUC and Cmax) of the d-MPH isomer absorption.19 The IR formulation's tmax was prolonged by 0.5 hours, while no difference was seen in the SR formulation. These results suggest that the type of food and formulation can influence dl-MPH and d-MPH pharmacokinetics. The gold standard for food studies has been a high-fat breakfast, so as to maximize any potential food effect. It continues to be recommended by the FDA. A new trend in pediatric food studies is to use a typical high-carbohydrate diet (20% protein, 21% fat, 59% carbohydrate) rather than a high-fat (60% fat) diet.17 Our present studies, however, were performed in adults and used the standard high-fat diet.

The pharmacokinetics of d-MPH has previously been determined indirectly following dosing with IR dl-MPH.19 In that study, a high-carbohydrate breakfast significantly increased the Cmax and tmax of d-MPH by 23% and 0.5 hours, respectively. Food also increased the extent (AUC) of absorption by a modest 15% but not the rate (Cmax/AUC) of absorption. The investigators concluded that dl-MPH should be taken after breakfast, as food increased absorption and decreased the potential for gastric side effects. Food effect studies using SR and osmotic controlled-release formulations of d,l-MPH also showed no effects.20,21

In the present study, subjects were dosed with Celgene's IR d-MPH. In contrast to the IR dl-MPH study, our results only showed a significant increase in the tmax, with no substantial change in the AUC. Similar results after a high-fat meal were also obtained for the osmotic controlled-release formulation of d,l-MPH since fat has a greater effect on delaying gastric emptying than carbohydrate or protein.13,18 Even though our present study used healthy adults, previous studies have shown no difference in the oral pharmacokinetics of dl-MPH in adults and children.22 Presumably, this is also the case for d-MPH. The present results could be different if a high-carbohydrate diet had been used. A recent review of food-effect studies noted significant changes in the bioavailability of various drugs depending on whether the diet is high in fat, protein, or fiber.13

Our present results support earlier studies showing no interconversion in plasma between isomers of MPH after oral administration of d-MPH or l-MPH.12,21 We also confirm the in vivo isomer-selective metabolism of d-MPH to d-RA. While previous studies have shown that d-MPH and l-MPH are metabolized at different rates, we now know this is not a clinically relevant issue.20

In conclusion, food had no substantial effect on the bioavailability of d-MPH. While the magnitude of peak concentrations and the extent of absorption were not affected, tmax was increased by 1 hour, indicating a slower absorption process. In general, d-MPH is taken in the morning before school. Our results indicate that d-MPH can be taken with or without food.


   FOOTNOTES
 
DOI: 10.1177/0091270003261899

Submitted for publication May 20, 2003; Revised version accepted November 14, 2003.


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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