Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label, Randomized, Crossover Study.
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ABSTRACT: Introduction
This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity.Methods
Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C max) and area under the plasma concentration versus time curve from 0 to infinity (AUC0-∞), were assessed using geometric mean ratios with 90 % CIs.Results
Geometric least squares (LS) means (without versus with LDX) for C max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC0-∞ (ng · h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C max. Parent/metabolite C max and AUC0-∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC0-∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported.Conclusions
LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.
SUBMITTER: Ermer J
PROVIDER: S-EPMC4488187 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThis open-label, crossover study examined lisdexamfetamine dimesylate (LDX) and D-amphetamine pharmacokinetics in healthy adults after administration of an intact LDX capsule or after the capsule was emptied into orange juice or yogurt and the contents consumed.MethodsHealthy adult volunteers (N = 30) were administered a 70-mg LDX capsule or the contents of a 70-mg capsule mixed with yogurt or orange juice using a 3-way crossover design. Blood samples were collected serially for up to 96 hours after dose. Pharmacokinetic endpoints included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from zero to infinity (AUC0-∞) or to last assessment (AUClast). Relative LDX and D-amphetamine bioavailabilities from the contents of a 70-mg LDX capsule mixed with orange juice or yogurt were compared with those from the intact LDX capsule using bioequivalence-testing procedures.ResultsGeometric least squares mean ratios (90% confidence intervals [CIs]) for D-amphetamine (active moiety) were within the prespecified bioequivalence range (0.80-1.25) when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.971 (0.945, 0.998); AUC0-∞: 0.986 (0.955, 1.019); AUClast: 0.970 (0.937, 1.004)] or yogurt [Cmax: 0.970 (0.944, 0.997); AUC0-∞: 0.945 (0.915, 0.976); AUClast: 0.944 (0.912, 0.977)]. Geometric least squares mean ratios (90% CIs) for LDX (inactive prodrug) were below the accepted range when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.641 (0.582, 0.707); AUC0-∞: 0.716 (0.647, 0.792); AUClast: 0.708 (0.655, 0.766)]; the lower 90% CI for Cmax [0.828 (0.752, 0.912)] was below the accepted range when the contents of a 70-mg LDX capsule were mixed with yogurt.ConclusionsRelative bioavailability of D-amphetamine (the active moiety) did not differ across administrations, which suggests that emptying an LDX capsule into orange juice or yogurt and consuming it is an alternative to intact capsules.
| S-EPMC5158093 | biostudies-literature
Project description:BackgroundIn clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.ObjectiveThe primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.Study designThis was an open-label, randomized, three-period crossover, DDI study.SettingThe study was conducted in a single clinical research center.ParticipantsForty-two healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.Main outcome measuresBlood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).ResultsForty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.ConclusionsIn healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.
| S-EPMC3689918 | biostudies-literature
Project description:Lisdexamfetamine (LDX) and D-amphetamine pharmacokinetics were assessed in individuals with normal and impaired renal function after a single LDX dose; LDX and D-amphetamine dialyzability was also examined.Adults (N = 40; 8/group) were enrolled in 1 of 5 renal function groups [normal function, mild impairment, moderate impairment, severe impairment/end-stage renal disease (ESRD) not requiring hemodialysis, and ESRD requiring hemodialysis] as estimated by glomerular filtration rate (GFR). Participants with normal and mild to severe renal impairment received 30 mg LDX; blood samples were collected predose and serially for 96 hours. Participants with ESRD requiring hemodialysis received 30 mg LDX predialysis and postdialysis separated by a washout period of 7-14 days. Predialysis blood samples were collected predose, serially for 72 hours, and from the dialyzer during hemodialysis; postdialysis blood samples were collected predose and serially for 48 hours. Pharmacokinetic end points included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from time 0 to infinity (AUC0-?) or to last assessment (AUClast).Mean LDX Cmax, AUClast, and AUC0-? in participants with mild to severe renal impairment did not differ from those with normal renal function; participants with ESRD had higher mean Cmax and AUClast than those with normal renal function. D-amphetamine exposure (AUClast and AUC0-?) increased and Cmax decreased as renal impairment increased. Almost no LDX and little D-amphetamine were recovered in the dialyzate.There seems to be prolonged D-amphetamine exposure after 30 mg LDX as renal impairment increases. In individuals with severe renal impairment (GFR: 15 ? 30 mL·min·1.73 m), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL·min·1.73 m), the maximum LDX dose is 30 mg/d. Neither LDX nor D-amphetamine is dialyzable.
| S-EPMC4949011 | biostudies-literature
Project description:BackgroundLisdexamfetamine dimesylate (LDX), a prodrug consisting of d-amphetamine and l-lysine, is being studied in clinical trials of major depressive disorder. Additional drug-drug interaction studies were warranted.ObjectiveThis study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined.Study designThe study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence.Setting and participantsThe study was conducted at two clinical study centres and included healthy adult males and females (18-45 years of age).InterventionThe study included two single-sequence crossover designs: LDX alone followed by LDX + VXR (Treatment Arm A); and VXR alone followed by VXR + LDX (Treatment Arm B). Drug treatment was initiated on day 1 with once-daily LDX or VXR alone with 15 days' titration to final dose (LDX 30, 50 and 70 mg for 5 days each; VXR 75, 150 and 225 mg for 5 days each). On days 16-30, VXR, titrated to a final dose of 225 mg, or LDX, titrated to a final dose of 70 mg, was coadministered for participants in Treatment Arm A or B, respectively. On days 31-38, VXR doses were tapered.Main outcome measuresOn days 1-2, 15-16 and 30-31, safety evaluations and blood samples were obtained pre-dose through 24 h post-dose for analysis of LDX, d-amphetamine, venlafaxine (VEN), and O-desmethylvenlafaxine (ODV). Combination treatment was considered bioequivalent to single treatment if 90 % confidence intervals (CIs) for geometric mean ratios (GMRs) of analytes fell within the interval 0.80-1.25 based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUCτ). Safety assessments included treatment-emergent adverse events (TEAEs), pulse rate and blood pressure (BP), clinical laboratory assessments, and 12-lead electrocardiograms (ECG).ResultsAmong 80 enrolled subjects, 77 were included in pharmacokinetic and safety analyses. Combination LDX + VXR was bioequivalent to LDX alone, based on exposure to d-amphetamine (GMR [95 % CI], Cmax (ng/mL): 0.97 [0.82, 1.14], AUCτ: 0.95 [0.81, 1.12]). Exposure to VEN with LDX + VXR (vs. VXR alone) was increased (Cmax: 1.10 [0.88, 1.38], AUCτ: 1.13 [0.88, 1.45]) and ODV decreased (Cmax: 0.91 [0.77, 1.06], AUCτ: 0.83 [0.71, 0.96]), whereas composite VEN + ODV was bioequivalent to VXR alone (Cmax: 0.96 [0.84, 1.09], AUCτ: 0.98 [0.85, 1.13]). TEAEs with LDX or LDX + VXR were similar. Maximum mean increases from baseline were: pulse rate, +8.73 to 12.76 beats/min with either treatment alone and +17.67 to 20.85 beats/min with LDX + VXR; systolic BP, +4.32 to 6.56 mmHg with either treatment alone and +12.96 to 13.78 mmHg with LDX + VXR; diastolic BP, +5.39 to 5.74 mmHg with either treatment alone and +12.09 to 12.46 mmHg with LDX + VXR. One participant was withdrawn due to a serious TEAE (presyncope). No unexpected, clinically meaningful trends or changes from baseline in mean laboratory or ECG parameters were observed during the trial.ConclusionIn healthy adults, combination LDX + VXR (vs. LDX alone) did not alter exposure to d-amphetamine. Although small changes in exposure to VEN (increased) and ODV (decreased) were seen with combination treatment, total VEN + ODV exposure showed no change (vs. VEN alone). LDX + VXR led to increases in BP and pulse rate, supporting existing recommendations for vital sign monitoring when using these medications.
| S-EPMC3608883 | biostudies-literature
Project description:Negative symptoms of schizophrenia (NSS), related to hypodopaminergic activity in the mesocortical pathway and prefrontal cortex, are predictive of poor outcomes and have no effective treatment. Use of dopamine-enhancing drugs (eg, psychostimulants) has been limited by potential adverse effects. This multicenter study examined lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, as adjunctive therapy to antipsychotics in adults with clinically stable schizophrenia and predominant NSS. Outpatients with stable schizophrenia, predominant NSS, limited positive symptoms, and maintained on stable atypical antipsychotic therapy underwent a 3-week screening, 10-week open-label adjunctive LDX (20-70 mg/day), and 4-week, double-blind, randomized, placebo-controlled withdrawal. Efficacy measures included a modified Scale for the Assessment of Negative Symptoms (SANS-18) and Positive and Negative Syndrome Scale (PANSS) total and subscale scores. Ninety-two participants received open-label LDX; 69 received double-blind therapy with placebo (n=35) or LDX (n=34). At week 10 (last observation carried forward; last open-label visit), mean (95% confidence interval) change in SANS-18 scores was -12.9 (-15.0, -10.8; P<0.0001). At week 10, 52.9% of participants demonstrated a minimum of 20% reduction from baseline in SANS-18 score. Open-label LDX was also associated with significant improvement in PANSS total and subscale scores. During the double-blind/randomized-withdrawal phase, no significant differences (change from randomization baseline) were found between placebo and LDX in SANS-18 or PANSS subscale scores. In adults with clinically stable schizophrenia, open-label LDX appeared to be associated with significant improvements in negative symptoms without positive symptom worsening. Abrupt LDX discontinuation was not associated with positive or negative symptom worsening. Confirmation with larger controlled trials is warranted.
| S-EPMC3773663 | biostudies-other
Project description:Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0-last), and area under the concentration-time curve from 0 h to infinity (AUC0-?) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.).
| S-EPMC4249579 | biostudies-literature
Project description:American Academy of Sleep Medicine practice parameters designate sodium oxybate (SXB) as a standard of care for cataplexy, excessive daytime sleepiness (EDS), and disrupted night-time sleep in narcolepsy. Recently, a lower-sodium oxybate (LXB) with 92% less sodium than SXB was approved in the United States for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. Two phase I, open-label, randomized, single-dose crossover pharmacokinetic studies in healthy adults were conducted. Single 4.5-g oral doses of LXB and SXB were administered in a fasted or fed state. In the fasted state at equivalent oxybate doses, LXB, compared with SXB, had a lower maximum plasma concentration (Cmax ; study 1 [total aqueous volume, 240 ml]: 101.8 vs. 135.7 µg/ml; study 2 [60 ml]: 94.6 vs. 123.0 μg/ml), delayed time to Cmax (Tmax ; study 1: 0.75 vs. 0.5 h; study 2: 1.0 vs. 0.5 h), but similar area under the curve (AUC; study 1: AUC0-t , 235.4 vs. 263.9 μg∙h/ml; AUC0-∞ , 236.5 vs. 265.2 μg∙h/ml; study 2: AUC0-t , 241.5 vs. 254.7 μg∙h/ml; AUC0-∞ , 243.1 vs. 256.3 μg∙h/ml). Bioequivalence criteria were met for AUC but not Cmax (both studies). Cmax and AUC were lower under fed than fasted conditions (LXB and SXB); differences between fed versus fasted were smaller for LXB than SXB. These pharmacokinetic differences between LXB and SXB are likely due to the lower sodium content in LXB. Pooled analyses demonstrated that a higher Cmax is associated with a higher incidence of nausea and vomiting.
| S-EPMC8604214 | biostudies-literature
Project description:PURPOSE/BACKGROUND:Psychostimulant augmentation is considered a potential treatment strategy for individuals with major depressive disorder who do not adequately respond to antidepressant monotherapy. The primary objective of this 12-month open-label extension study was to evaluate the safety and tolerability of lisdexamfetamine dimesylate (LDX) as augmentation therapy to an antidepressant in adults with major depressive disorder. METHODS/PROCEDURES:Eligible adults who completed 1 of 3 short-term antecedent LDX augmentation of antidepressant monotherapy studies were treated with dose-optimized LDX (20-70 mg) for up to 52 weeks while continuing on the index antidepressant (escitalopram, sertraline, venlafaxine extended-release, or duloxetine) assigned during the antecedent short-term studies. Safety and tolerability assessments included the occurrence of treatment-emergent adverse events and vital sign changes. FINDINGS/RESULTS:All 3 antecedent studies failed to meet the prespecified primary efficacy endpoint, so this open-label study was terminated early. Headache (15.5% [241/1559]), dry mouth (13.6% [212/1559]), insomnia (13.1% [204/1559]), and decreased appetite (12.1% [189/1559]) were the most frequently reported treatment-emergent adverse events. The greatest mean ± SD increases observed for systolic and diastolic blood pressure and for pulse were 2.6 ± 10.85 and 1.7 ± 7.94 mm Hg and 6.9 ± 10.27 bpm, respectively. Monitoring determined that less than 1% of participants experienced potentially clinically important changes in systolic blood pressure (10 [0.6%]), diastolic blood pressure (8 [0.5%]), or pulse (6 [0.4%]). IMPLICATIONS/CONCLUSIONS:The overall safety and tolerability of long-term LDX augmentation of antidepressant monotherapy was consistent with the profiles of the short-term antecedent studies, with no evidence of new safety signals.
| S-EPMC6039401 | biostudies-literature
Project description:BACKGROUND:SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE:The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS:Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS:All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS:Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required. CLINICALTRIALS. GOV IDENTIFIER:NCT01328756.
| S-EPMC5843702 | biostudies-literature
Project description:BackgroundA 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED).MethodsAdults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses.ResultsOf the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides.ConclusionsIn this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.
| S-EPMC5400413 | biostudies-literature