Pharmacokinetics of a Modified-Release Dexamphetamine Sulfate Formulation Following Single and Multiple Dosing in Healthy Adults: Comparative Bioavailability with Immediate-Release Dexamphetamine Sulfate, between Strengths, Assessment of Food and Meal Composition Effects

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.

Concentrations below the LLOQ prior to time to maximum observed plasma concentration (t_max) were set to zero. The area under the plasma concentration vs. time curve (AUC) was calculated using the linear-up/logarithmic-down trapezoidal method.

In the single-dose and breakfast study, PK metrics included the maximum observed plasma concentration (Cmax), AUC from time zero to the time of the last quantifiable concentration (AUC_0–t), AUC with extrapolation to infinity (AUC_0–∞), t_max, and the apparent elimination half life (t_½).

In the multiple-dose study, PK metrics included the maximum observed concentration at steady-state (C_max,ss), the concentration at the end of the dosing interval τ (C_τ,ss), AUC during the dosing interval (AUC_0–τ,ss), time to maximum plasma concentration (t_max,ss), the minimum plasma concentration (C_min,ss), the average plasma concentration (C_av,ss) calculated as AUC_0–τ,ss/τ, and fluctuation (C_max,ss – C_min,ss)/C_av,ss.

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 log_e-transformed values of C_max, AUC_0–t and AUC_0–∞ in the single-dose and breakfast studies, and of Cmax,ss, Cτ,ss and AUC_0–τ,ss in the multiple-dose study. Treatment, period, and sequence were included as fixed effects in the model and subject within sequence as a random effect. The estimated geometric least squares means ratios and their associated 90% confidence intervals (CIs) of the log_e-transformed data were back-transformed. In accordance with regulatory requirements (10), bioequivalence or lacking food effects were concluded if the 90% CI was entirely contained within the range 80.00% to 125.00% for AUC_0–t, AUC_0–∞ and Cm_ax (single-dose and breakfast studies) and for C_max,ss, C_τ,ss and AUC_0–τ,ss (multiple-dose study), respectively. In the single-dose studies evaluation was performed according to the ‘Two at a Time’ approach (11–14), i.e., treatments not relevant in the pairwise comparison were excluded from the data set whilst the codes for period and sequence were kept. No adjustments were made for multiple comparisons (15).

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 AUC_0–t: Extrapolated AUC was 1.06% (median; range 0.26–3.76%). Plasma concentration-time profiles for dexamphetamine following single-dose administration of DEX-MR and DEX-IR under fasted and fed conditions are shown in Figure. 1. PK metrics are summarized in Supplementary Table S5 and comparative bioavailability analyses are shown in Table 1.

FIGURE 1.

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 C_max for DEX-MR 10 mg and DEX-MR 20 mg was slightly lower than that of the reference treatment. DEX-MR 10 mg and DEX-MR 20 mg had similar PK profiles over time. The mean t_½ of DEX-MR ranged from 10.50 to 10.93 h and was comparable to DEX-IR with 10.68 to 10.92 h.

FIGURE 2

FIGURE 3.

Sampling was sufficiently long to obtain reliable estimates of AUC_0–t: Extrapolated AUC was 2.17% (median; range 0.82–11.24%). Mean plasma concentration-time profiles for dexamphetamine following administration of DEX-MR 20 mg and DEX-IR 10 mg b.i.d. under different breakfast conditions (normocaloric vs. high-fat, high-calorie) are shown in Figure 2. PK metrics are summarized in Supplementary Table S6 and comparative bioavailability analyses are shown in Table 3.

A slightly lower rate and extent of absorption (i.e., C_max and AUC) were observed for both DEX-MR and DEX-IR when consumed after a high-fat, high-calorie breakfast compared to a normocaloric breakfast. The bioavailability of DEX-MR was comparable to that of DEX-IR both when administered after consumption of a normocaloric and a high-fat, high-calorie breakfast. Like in the single-dose study, a slightly lower mean C_max was observed for DEX-MR compared to DEX-IR when given after a high-fat, high-calorie breakfast. A slightly reduced mean C_max was also observed under normocaloric breakfast conditions. The 90% CIs of the geometric means ratios for C_max, AUC_0–t and AUC_0–∞ were entirely within the pre-defined acceptance range of 80.00% to 125.00%, indicating lacking effects of the type of breakfast between the two formulations.

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.

The PK profile of DEX-MR showed a plateau phase of ~7–8 hours with mean plasma concentrations ≥75% of the mean C_max. Mean pre-dose plasma concentrations for day 4 to 7 showed that steady state was reached by day 6 both for DEX-MR and DEX-IR (data not shown). DEX-MR 20 mg and DEX-IR 10 mg b.i.d. showed comparable bioavailability under both breakfast conditions. When administered after a high-fat, high-calorie breakfast, the mean C_max,ss was slightly lower (reduction of ~12%) for DEX-MR compared to DEX-IR. However, the 90% CIs of the geometric least squares means ratios of C_{max, ss}, C_min,ss and AUC_0–τ,ss were within the pre-defined bioequivalence range for both breakfast conditions.

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.