Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions of childhood. The worldwide prevalence of ADHD in children and adolescents is estimated at 7.2% (1). ADHD is characterized by the core symptoms of inattention, hyperactivity, and impulsivity that interfere with social, academic or occupational functioning (2). Successful ADHD management requires a comprehensive multimodal treatment plan, and may include both psychosocial and pharmacological interventions, that is tailored to the individual’s unique needs and preferences (3–6). Psychostimulants, including methylphenidate (MPH) and amphetamines (AMP), are the mainstay of ADHD treatment.
Numerous stimulant formulations are currently marketed, including short- and long-acting formulations. Immediate-release (IR) formulations usually have a short half-life and duration of action and thus often require multiple daily dosing, which is associated with various challenges, including an increased risk of non-compliance, social stigma associated with dosing during school time, and potential for medication misuse/diversion (7). Therefore, once-daily formulations have been developed to eliminate the need for multiple daily dosing.
Currently marketed AMP products include IR and modified-release (MR) formulations containing different AMP salts and enantiomers (7). A tablet formulation of immediate-release dexamphetamine sulfate (Attentin®/Amfexa®/Tentin®, hereinafter referred to as DEX-IR) received market authorization in Germany in 2011 and is currently marketed in several countries. The product is available in strengths of 5 mg, 10 mg, and 20 mg. DEX-IR is indicated as part of a comprehensive treatment program for ADHD in children and adolescents aged 6 to 17 years when response to previous MPH treatment is considered clinically inadequate (8). The effectiveness and safety of DEX-IR in the routine treatment of children and adolescents with ADHD were shown in an observational study. Most participants administered DEX-IR once daily; however, a large proportion of participants (approx. 40%) required twice daily dosing, presumably to extend the duration of action to the late afternoon and evening (9).
Therefore, a novel once-daily MR formulation of dexamphetamine sulfate (DEX-MR) was developed with the aim of achieving a biphasic pharmacokinetic profile mimicking twice-daily dosing of DEX-IR. DEX-MR was formulated to provide an initial rapid release of dexamphetamine followed by a period of prolonged release, thereby combining a rapid onset with an extended duration of action. DEX-MR consists of a hard gelatin capsule containing two types of drug-loaded pellets in a 1:1 ratio: uncoated pellets immediately dissolving in the acidic milieu of the stomach, and enteric-coated pellets dissolving at a pH value above 5.5, i.e., when reaching the duodenum. The DEX-MR formulation was developed in the strengths of 5, 10, 15, and 20 mg to cover the dose range of 5 mg to 20 mg (up to 40 mg in rare cases), as currently approved for DEX-IR tablets, with a single intake of one or two capsules in the morning.
The clinical development program for DEX-MR included three phase I studies that investigated the pharmacokinetic characteristics of DEX-MR in healthy adults. These studies were designed in accordance with applicable regulatory guidelines, specifically the ‘Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms’ of the European Medicines Agency (EMA) (10). The main objective of the PK study program was to establish similar bioavailability between a single dose of DEX-MR given in the morning and the same total dose of DEX-IR split into two equal doses given in the morning and four hours later.
All three studies were conducted in South Africa. The studies enrolled healthy non-smoking males between 18 and 55 years of age, with a body weight of at least 50 kg and a body mass index of 18.5 to 30 kg/m2. Female subjects were excluded to avoid risks to the unborn child in case of pregnancy. Participants were required to be healthy as determined by medical history (participant-reported), vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations. Participants agreed to comply with all study procedures and to use effective contraception during the study and for three months after receiving the last dose of study drug. A summary of exclusion criteria is given in the Supplementary Material. Exclusion criteria included concomitant monoamine oxidase inhibitor treatment within 14 days before and during the study; concomitant treatment with agents that acidify or alkalinize the urinary fluids; treatment with any known cytochrome P450 enzyme altering agents (e.g., barbiturates, phenothiazines, cimetidine) within 30 days before the study; and treatment with any prescription medication within 14 days or over-the-counter or herbal remedies within seven days before first study drug administration, except if this would not affect the outcome of the study in the opinion of the investigator. Participants were not permitted to ingest food and beverages containing grapefruit and/or pomelo for ten days before and during the study, food and beverages containing other citrus fruits and/or apple or pineapple for 72 hours before and during the study, food and beverages containing alcohol and/or methylxanthines, and poppy seeds for 48 hours before and during the study.
The study protocols, including subject information sheets and informed consent forms, were reviewed and approved by an independent ethics committee (Health Sciences Research Ethics Committee, Bloemfontein, South Africa) and by the South African Health Products Regulatory Authority. Participants were recruited from a volunteer database via text message. Compensation of participants was reasonable and related to the nature and degree of inconvenience and discomfort expected to result from participation in the study. Subjects provided written informed consent before screening. All three studies were randomized, open-label, laboratory-blind, crossover studies in healthy males conducted at a single center. In all studies, participants were required to fast overnight for at least ten hours before dosing. The test product DEX-MR and the reference product DEX-IR were both administered at a total daily dose of 20 mg: DEX-MR was administered as a single 20 mg dose (i.e., one capsule of DEX-MR 20 mg or two capsules of DEX-MR 10 mg), whereas the reference product DEX-IR 10 mg was administered twice daily four hours apart. The capsules or tablets were swallowed whole with 240 mL of water. For fed treatment periods, participants consumed a meal within 30 minutes before dosing. Water was allowed as desired except for one hour before and one hour after drug administration. Participants fasted for at least five hours post-morning-dose and received a standardized lunch at 5:15 hours post-dose.
The single-dose study was a six-sequence, six-period crossover study under fasted and fed conditions. The objectives of the single-dose study were 1) to compare bioavailabilities of a single 20 mg dose of DEX-MR (1 × 20 mg or 2 × 10 mg) with DEX-IR 10 mg b.i.d., 2) to compare the bioavailability of DEX-MR 10 mg with 20 mg, and 3) to investigate the influence of food on the bioavailability of DEX-MR. A further objective was to evaluate the safety and tolerability of the study drugs. Participants were randomized to one of six treatment sequences: a single dose of DEX-MR 20 mg, a single dose of DEX-MR 10 mg (2 × 10 mg), and two doses of DEX-IR 10 mg taken four hours apart were administered once under fasted and once under fed conditions. The treatment periods included a profile period of 72 h and were separated by washout periods of seven days. During the fed treatment periods, participants consumed a high-fat, high-calorie breakfast that contained 800–1000 kilocalories, consisting of carbohydrate (~250 kilocalories), protein (~150 kilocalories) and fat (500–600 kilocalories), as recommended for food effect studies (10). The breakfast consisted of an omelet with whole milk and butter/margarine, whole wheat white bread rolls, fried bacon with fat, fried potato croquette/chips, butter, tomatoes and fresh whole milk (see Supplementary Table S1 for the meal composition).
This study was a four-sequence, four-period crossover study under fed conditions. The objective of the study was to investigate the effects of different meal types (normocaloric vs. high-fat, high-calorie breakfast) on the bioavailability of DEX-MR and DEX-IR. The safety and tolerability of the study drugs were also evaluated. Participants were randomized to one of four treatment sequences: a single dose of DEX-MR 20 mg and two doses of DEX-IR 10 mg taken four hours apart were administered once after consumption of a normocaloric breakfast and once after consumption of a high-fat, high-calorie breakfast. The treatment periods included a profile period of 72 h and were separated by washout periods of 7 to 14 days. The high-fat, high-calorie breakfast was identical to the one used in the single-dose study. The normocaloric breakfast contained 500–600 kilocalories, consisting of carbohydrate (45–65% of energy), protein (10–35% of energy) and fat (20–35% of energy), as per FDA recommendations. The breakfast consisted of muesli with nuts, low-fat milk and orange juice (see Supplementary Table S2 for the meal composition).
This study was a multiple-dose, two-sequence, two-period crossover study under fed conditions. The main objective of the study was to compare bioavailabilities of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. at steady-state under fed conditions. A further objective was to evaluate the safety and tolerability of the study drugs. Participants were randomized to one of two treatment sequences: a single dose of DEX-MR 20 mg followed by two doses of DEX-IR 10 mg taken four hours apart, or vice versa. To ensure that steady-state was reached, each treatment period consisted of a run-in period of five days followed by two profile periods of 24 hours each (days 6 and 7). Treatment periods were separated by a washout period of 7 to 14 days. According to the EMA’s recommendations, normocaloric meals should be used throughout a multiple-dose PK study including profile days, if the summary of product characteristics (SmPC) recommends intake under fed conditions, unless different meal conditions are mandated in the SmPC (10). In line with this requirement, normocaloric meals were used in the run-in periods as well as on profile day 6. As it was not known at the time the multiple-dose study was initiated whether the type of breakfast (normocaloric vs. high-fat, high-calorie) would have any decisive impact on the bioavailability of DEX-MR or DEX-IR, a second profile day on which the high-fat, high-calorie breakfast was to be consumed was included. The normocaloric meal consisted of two boiled eggs, two Weet-Bix, rooibos tea, sugar, and low-fat milk (see Supplementary Table S3 for the meal composition). The high-fat, high-calorie meal was identical to the one used in the single-dose and breakfast study.
In the single-dose study, blood samples (2 mL) for PK analysis were collected pre-dose and at 0.33, 0.67, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.33, 4.67, 5, 5.25, 5.5, 5.75, 6, 6.33, 6.67, 7, 7.33, 7.67, 8, 9, 16, 24, 48, 60, and 72 h post-dose. In the breakfast study, samples (4 mL) were collected pre-dose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 12, 24, 36, 48, and 72 h post-dose. In the multiple-dose study, pre-dose samples (4 mL) were collected on days 4 to 7 to assess steady-state achievement by day 6. On days 6 and 7, samples (4 mL) were collected at 0.5, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 10, 12, and 24 h post-dose. An indwelling venous cannula was inserted before dosing on profile days. Blood draws during the run-in period of the multiple-dose study were performed using a syringe and needle.
Blood samples were collected into dipotassium ethylenediaminetetraacetic acid (K2EDTA) plastic tubes. Plasma was separated by centrifugation at 4 °C and stored at −20 °C until analysis. Plasma concentrations of dexamphetamine were measured at FARMOVS Bioanalytical Services Division (Bloemfontein, South Africa) using a validated liquid chromatography with a tandem mass spectrometry (LC-MS/MS) method. The lower limit of quantification (LLOQ) of dexamphetamine was 0.469 ng/mL and the calibration range was 0.469 to 120 ng/mL. Samples were analyzed on a Sciex API4000QTRAP / API4000 using Watson Analyst® (version 1.6.2 / 1.6.3) and LIMS™ (version 7.4.2) software. The within-run (im)precision ranged from 0.6% to 2.1% and the within-run (in)accuracy ranged from −1.9% to 6.0%. The between-run (im)precision ranged from 1.2% to 1.6% and the between-run (in)accuracy ranged from −0.9% to 5.0%.
Concentrations below the LLOQ prior to time to maximum observed plasma concentration (
In the single-dose and breakfast study, PK metrics included the maximum observed plasma concentration (
In the multiple-dose study, PK metrics included the maximum observed concentration at steady-state (
In all studies, assessments of safety and tolerability included monitoring of adverse events (AEs), vital sign measurements, physical examinations, ECGs, and laboratory investigations (hematology, clinical chemistry and urinalysis). Prior and concomitant medications were also recorded. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.0.
PK metrics were calculated for each participant and treatment using non-compartmental analysis based on the actual sampling time points. Statistical analyses were performed using Phoenix® WinNonlin® version 8.3.4. A mixed effects model was fitted to the loge-transformed values of
In the single-dose study, 28 of 30 participants completed the study. One participant withdrew consent after treatment period 1 due to personal reasons. One participant was withdrawn upon admission to treatment period 2 due to a positive cotinine test. In the breakfast study, 19 of 20 participants completed the study. One participant was withdrawn prior to treatment period 4 due to numerous AEs. In the multiple-dose study, 46 of 50 participants completed the study. Four participants were withdrawn by the investigator; two for violating the protocol and two for safety reasons. Demographic and baseline characteristics of the study populations were comparable across the studies. Mean age ranged from 29.7 to 30.3 years; most participants were black (Supplementary Table S4).
Sampling was sufficiently long to obtain reliable estimates of
Geometric mean dexamphetamine plasma concentration-time profiles following single-dose administration of DEX-MR and DEX-IR in (a) fasted and (b) fed state.
Comparative bioavailabilities of DEX-MR (20 mg dose) and DEX-IR 10 mg b.i.d. under fasted and fed conditions (single-dose study), 28 subjects.
PK metric (unit) | Geometric Least Squares Mean | PE (%) | 90% CI | CVintra (%) | CVinter (%) | |
---|---|---|---|---|---|---|
Fasted conditions | ||||||
DEX-MR 10 mg 1×2 | DEX-IR 10 mg b.i.d. | |||||
53.94 | 57.82 | 93.29 | 91.26 – 95.36 | 4.78 | 12.40 | |
914.8 | 884.4 | 103.43 | 99.81 – 107.18 | 7.75 | 15.11 | |
926.2 | 895.6 | 103.41 | 99.66 – 107.30 | 8.03 | 15.39 | |
DEX-MR 20 mg 1×1 | DEX-IR 10 mg b.i.d. | |||||
53.98 | 57.82 | 93.35 | 90.71 – 96.08 | 6.24 | 10.25 | |
871.8 | 884.4 | 98.57 | 95.91 – 101.31 | 5.94 | 16.16 | |
882.0 | 895.6 | 98.48 | 95.77 – 101.27 | 6.06 | 16.66 | |
DEX-MR 10 mg 1×2 | DEX-MR 20 mg 1×1 | |||||
53.94 | 53.97 | 99.95 | 97.15 – 102.82 | 6.18 | 11.26 | |
914.3 | 872.2 | 104.82 | 101.94 – 107.79 | 6.09 | 15.22 | |
925.7 | 882.5 | 104.90 | 101.91 – 107.98 | 6.31 | 15.51 | |
Fed conditions | ||||||
DEX-MR 10 mg 1×2 | DEX-IR 10 mg b.i.d. | |||||
48.67 | 57.00 | 85.38 | 81.25 – 89.72 | 10.80 | 9.39 | |
816.6 | 821.2 | 99.44 | 96.20 – 102.80 | 7.21 | 13.89 | |
825.5 | 831.5 | 99.28 | 95.98 – 102.70 | 7.35 | 14.02 | |
DEX-MR 20 mg 1×1 | DEX-IR 10 mg b.i.d. | |||||
47.53 | 57.00 | 83.37 | 79.06 – 87.92 | 11.55 | 10.88 | |
817.8 | 821.2 | 99.59 | 96.44 – 102.84 | 6.97 | 11.04 | |
828.7 | 831.5 | 99.66 | 96.44 – 103.00 | 7.14 | 11.01 | |
DEX-MR 10 mg 1×2 | DEX-MR 20 mg 1×1 | |||||
48.59 | 47.61 | 102.06 | 95.66 – 108.51 | 13.42 | 12.19 | |
816.0 | 818.4 | 99.71 | 95.84 – 103.73 | 8.63 | 12.11 | |
824.9 | 829.3 | 99.47 | 95.48 – 103.62 | 8.93 | 12.07 |
Under both fasted and fed conditions, the PK profile of the reference treatment DEX-IR had an early peak (at 1.75 h and 1.5 h, respectively) and a second, higher peak at around six hours, which is consistent with the b.i.d. dosing regimen. In contrast, the administration of DEX-MR resulted in a PK profile with a ~4–6 hour plateau phase during which concentrations do not drop below 75% of the peak plasma concentration. Similar profiles were observed in the other studies (Figures 2 and 3). The mean
Geometric mean dexamphetamine plasma concentration-time profiles following administration of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. after intake of a normocaloric (a) and a high-fat, high-calorie breakfast (b)
Geometric mean dexamphetamine plasma concentration-time profiles at steady-state following administration of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. after intake of (a) a normocaloric breakfast on day 6 and (b) a high-fat, high-calorie breakfast on day 7.
Under fasted conditions, a single 20 mg dose of DEX-MR 20 mg or DEX-MR 10 mg was bioequivalent to DEX-IR 10 mg given twice daily (τ 4 hours) with respect to rate (
Under fed conditions, DEX-MR 10 mg (20 mg dose) was bioequivalent to DEX-IR 10 mg given twice daily (τ 4 hours), both for rate and extent of bioavailability. DEX-MR 20 mg met the bioequivalence criteria for
Under fasted conditions intra-subject variability of all PK metrics was low (4.78–8.03%) and inter-subject variability moderate (10.25–16.66%). Under fed conditions intra-subject variability was slightly higher (6.97–11.55%) and inter-subject variability slightly lower (9.39–14.02%).
DEX-MR 10 mg and DEX-MR 20 mg, when administered as a single 20 mg dose, showed comparable bioavailability under both fasted and fed conditions. The 90% CIs of the geometric least squares ratios for
Both DEX-MR 10 mg and DEX-MR 20 mg showed comparable bioavailability when administered under fasted compared to fed conditions (Table 2). Under fasted conditions a relevant dose dumping was not observed. Administration under fasted conditions increased
PK metrics and food effect assessment – DEX-MR 10 mg (20 mg dose) and DEX-MR 20 mg (single-dose study), 28 subjects.
PK metric (unit) | Geometric Least Squares Mean | PE (%) | 90% CI | CVintra (%) | CVinter (%) | |
---|---|---|---|---|---|---|
DEX-MR 10 mg (1×2) | ||||||
fasting | fed | |||||
53.94 | 48.67 | 110.83 | 105.56 – 116.26 | 10.39 | 11.35 | |
914.8 | 816.6 | 112.02 | 107.91 – 116.29 | 8.12 | 14.56 | |
926.2 | 825.5 | 112.20 | 107.93 – 116.63 | 8.41 | 14.56 | |
DEX-MR 20 mg (1×1) | ||||||
fasting | fed | |||||
53.98 | 47.53 | 113.58 | 107.45 – 120.05 | 12.06 | 10.23 | |
871.8 | 817.8 | 106.61 | 102.43 – 110.96 | 8.68 | 11.59 | |
882.0 | 828.7 | 106.44 | 102.16 – 110.89 | 8.91 | 11.78 |
Sampling was sufficiently long to obtain reliable estimates of
Comparative bioavailabilities of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. after intake of a normocaloric vs. a high-fat, high-calorie breakfast (breakfast study), 20 subjects.
PK metric (unit) | Geometric Least Squares Mean | PE (%) | 90% CI | CVintra (%) | CVinter (%) | |
---|---|---|---|---|---|---|
Normocaloric breakfast | ||||||
DEX-MR 20 mg | DEX-IR 10 mg b.i.d. | |||||
48.16 | 55.48 | 86.79 | 83.89 – 89.79 | 6.16 | 13.42 | |
955.8 | 989.5 | 96.60 | 92.98 – 100.36 | 6.93 | 18.12 | |
982.5 | 1012.9 | 97.00 | 93.24 – 100.91 | 7.16 | 18.97 | |
High-fat, high-calorie breakfast | ||||||
DEX-MR 20 mg | DEX-IR 10 mg b.i.d. | |||||
45.82 | 53.98 | 84.88 | 80.07 – 89.99 | 10.31 | 13.37 | |
908.3 | 914.7 | 99.31 | 95.47 – 103.31 | 6.93 | 17.09 | |
932.4 | 942.5 | 98.93 | 95.31 – 102.68 | 6.54 | 17.08 |
A slightly lower rate and extent of absorption (i.e.,
Plasma concentration-time profiles for dexamphetamine following DEX-MR 20 mg and DEX-IR 10 mg b.i.d. at steady-state are shown in Figure 3. PK metrics are summarized in Supplementary Table S7 and comparative bioavailability analyses are shown in Table 4.
Comparative bioavailabilities of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. after intake of a normocaloric breakfast and a high-fat, high-calorie breakfast (multiple-dose study), 46 subjects.
PK metric (unit) | Geometric Least Squares Mean | PE (%) | 90% CI | CVintra (%) | CVinter (%) | |
---|---|---|---|---|---|---|
Normocaloric breakfast (day 6) | ||||||
DEX-MR 20 mg | DEX-IR 10 mg b.i.d. | |||||
64.08 | 67.31 | 95.20 | 93.18 – 97.26 | 6.13 | 14.16 | |
17.45 | 17.19 | 101.49 | 97.92 – 105.18 | 10.23 | 22.05 | |
904.3 | 897.9 | 100.71 | 98.99 – 102.45 | 4.91 | 16.19 | |
High-fat, high-calorie breakfast (day 7) | ||||||
DEX-MR 20 mg | DEX-IR 10 mg b.i.d. | |||||
59.60 | 68.00 | 87.64 | 85.50 – 89.85 | 7.09 | 13.73 | |
19.58 | 18.38 | 106.51 | 102.63– 110.53 | 10.62 | 21.36 | |
895.4 | 903.5 | 99.11 | 97.35 – 100.90 | 5.12 | 15.55 |
The PK profile of DEX-MR showed a plateau phase of ~7–8 hours with mean plasma concentrations ≥75% of the mean
Drug-related AEs reported by at least two participants across all treatment groups in each study are summarized in Supplementary Table S8. No serious adverse events or AEs of severe intensity were reported in any of the studies. In the single-dose study, 98 AEs were reported by 25 of 30 participants; 53 AEs were judged as drug-related. All AEs were of mild intensity, except for two that were of moderate intensity (headache and syncope). In the breakfast study, 24 AEs were reported by 11 of 20 participants; 22 AEs were judged as drug-related. All AEs were of mild intensity. One participant was withdrawn from the study before treatment period 4 due to numerous AEs. In the multiple-dose study, 122 AEs were reported by 36 of 50 participants; 93 AEs were judged as drug-related. All drug-related AEs were of mild intensity, except for two events of insomnia and one event of urinary tract obstruction, which were of moderate intensity. Two participants were withdrawn from the study due to AEs, one for drug-related insomnia and one for non-drug-related cellulitis right knee.
No clinically significant findings were noted in physical examinations, laboratory evaluations and ECGs, except for one drug-related AE of mild QT prolongation. Small increases in blood pressure and pulse rate after drug administration were observed, which can be attributed to the pharmacological action of the drugs. Mild drug-related AEs related to blood pressure and pulse rate (blood pressure increased and tachycardia) were reported for three subjects.
Overall, the results of the studies demonstrate bioequivalence of a single 20 mg dose of DEX-MR and two doses of DEX-IR 10 mg administered four hours apart in healthy adults. In the single-dose study, the lower limit of the 90% CIs (79.06%) for
The study results show that DEX-MR provides an initial release of dexamphetamine shortly after administration followed by a phase of delayed release, with a plateau phase of several hours with mean plasma concentrations ≥75 % of the peak plasma concentration. This release pattern resembles that of a typical sustained-release formulation, which might be due to the fact that the enteric-coated pellets continuously ‘trickle’ from the stomach into the duodenum, resulting in a more sustained pattern of release (16). This release profile is expected to provide a rapid onset of action combined with a prolonged duration of action lasting up to the late afternoon and evening. A long-acting DEX formulation may be beneficial for a significant number of pediatric ADHD patients. An observational study found that approx. 40% of children and adolescents with ADHD currently administer DEX-IR twice daily, highlighting the need for sustained efficacy throughout the day in managing ADHD symptoms (9).
In the single-dose study, bioequivalence between DEX-MR 20 mg and DEX-MR 10 mg at a dose of 20 mg in terms of
Food intake causes physiological changes in the gastrointestinal tract, such as delayed gastric emptying, increased release of bile salts, and increased gastrointestinal motility, which can influence the bioavailability of a drug (18). In the single-dose study, DEX-MR showed comparable bioavailability when administered under fasted compared to fed conditions, and no dose dumping effect was observed in the fasted state. As expected for this type of MR formulation, the envisioned delayed release of dexamphetamine was observed only under fed conditions, i.e.,
These findings support the administration of DEX-MR with or shortly after a meal to achieve the desired PK profile. The observed effect on
The results of the breakfast study and the multiple-dose study show that the meal composition (i.e. fat and caloric content) does not affect the bioavailability of DEX-MR or the bioequivalence of DEX-MR and DEX-IR under fed conditions. These findings indicate that DEX-MR provides a consistent dexamphetamine exposure regardless of meal conditions and supports administration of DEX-MR without restrictions in regards to the content of meals, which provides dosing flexibility and may contribute to enhanced compliance.
Low intra-subject variability was observed for
In all three studies, DEX-MR was generally well tolerated and no serious AEs were reported. The observed AEs were in line with the known safety profile of stimulant medications, and no new safety concerns were identified.
The studies have some limitations. A limitation is that the single-dose study was slightly underpowered to demonstrate bioequivalence between DEX-MR and DEX-IR under fed conditions. The studies were conducted in South Africa in mostly black participants, which limits generalizability to other populations. Insufficient data are available on the effects of race and ethnicity on the PK of amphetamines. The available data indicate that the PK profiles of amphetamines are similar between black and Caucasian populations (17). Furthermore, all participants were male, which also limits generalizability. Generally, women show a higher exposure to amphetamine compared to men; however, exposure is similar after normalization by dose and weight (17). The study was conducted in healthy volunteers, thus generalizability to the clinical target population may be limited. Further studies should evaluate the PK of DEX-MR in pediatric populations.
DEX-MR provides a rapid initial release of dexamphetamine followed by a subsequent prolonged phase of drug delivery. Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food intake delayed
The novel DEX-MR formulation is a potential alternative treatment option for individuals treated with twice-daily DEX-IR. The once-daily administration may offer benefits such as improved treatment adherence and reduced risk of misuse and diversion.