James Ermer

Lisdexamfetamine Dimesylate: Linear Dose‐Proportionality, Low Intersubject and Intrasubject Variability, and Safety in an Open‐Label Single‐Dose Pharmacokinetic Study in Healthy Adult Volunteers

The pharmacokinetics of lisdexamfetamine dimesylate, a long‐acting prodrug stimulant, and its active moiety, d‐amphetamine, including dose‐proportionality and variability, were assessed in 20 healthy adults. Subjects received a single dose, sequentially, of 50, 100, 150, 200, and 250 mg of lisdexamfetamine dimesylate. Plasma lisdexamfetamine dimesylate and d‐amphetamine were measured before dosing and 0.25 to 96 hours postdose. Dose‐proportionality and intersubject and intrasubject variability of pharmacokinetic parameters were examined. Safety assessments included adverse events. All 20 subjects received 50 and 100 mg while 18, 12, and 9 subjects received 150, 200, and 250 mg of lisdexamfetamine dimesylate, respectively. Ten subjects were discontinued during the study for prespecified stopping rules (2 consecutive hourly readings of blood pressure: systolic >160 mm Hg or diastolic >100 mm Hg). Mean maximum observed plasma concentration (Cmax) and area under the concentration—time curve from time 0 to infinity (AUC0‐∞) increased linearly and dose‐dependently for d‐amphetamine. Median time to Cmax ranged from 4 to 6 hours for d‐amphetamine and 1.0 to 1.5 hours for lisdexamfetamine dimesylate. Intersubject and intrasubject variability over doses from 50 to 150 mg was low (<20%) for both Cmax and AUC0‐∞. Adverse events included nausea, dizziness, headache, psychomotor hyperactivity, and dysuria. These findings indicate that the pharmacokinetic parameters of d‐amphetamine were dose‐proportional and predictable over a wide range of lisdexamfetamine dimesylate doses.

Effects of Omeprazole on the Pharmacokinetic Profiles of Lisdexamfetamine Dimesylate and Extended-Release Mixed Amphetamine Salts in Adults

Abstract Objective: To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant, and mixed amphetamine salts extended-release (MAS XR), alone or with omeprazole, a proton pump inhibitor (PPI). Methods: This open-label, randomized, 4-period crossover study enrolled healthy adults (18–45 years). Subjects alternately received single doses of LDX 50 mg and MAS XR 20 mg at 4-day intervals. Following washout, subjects received omeprazole (40 mg/day x 14 days), with alternate single doses of LDX 50 mg or MAS XR 20 mg added on days 7 and 11. Blood samples were collected predose and 0 to 96 hours postdose for pharmacokinetic analysis. Safety assessments included adverse events (AEs). Results: Overall, 24 subjects were randomized; 21 completed the study. For LDX monotherapy, d-amphetamine mean (SD) exposure was 45.0 (13.97) ng/mL and 713.0 (134.75) ng · h/mL; when coadministered with omeprazole it was 46.3 (9.71) ng/mL and 761.6 (191.13) ng · h/mL, for Cmax and AUCinf, respectively. The median Tmax was 3 hours with and without omeprazole. For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng · h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng · h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (≥ 1 hour) Tmax with omeprazole. Both medications had AEs consistent with amphetamine use. Conclusions: Total exposure was unaffected by omeprazole for both compounds. However, ∼50% of subjects receiving MAS XR showed an earlier Tmax while on omeprazole, indicating unpredictable release of active drug by the second bead of MAS XR, most likely related to reduced stomach acid while on a PPI compromising the pulsed delivery of MAS XR. No clear trend was observed for LDX.

Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate

AbstractBackground and Objective: Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d-amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared. Methods: In this randomized, two-period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with ≤100 µCi 99mTc-diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg ≥7 days apart. Serial blood samples were drawn to measure d-amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed. Results: Eighteen subjects were enrolled and completed the study. The mean ± SD maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) of d-amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 ± 4.54 ng/mL and 719.1 ± 157.05 ng · h/mL, respectively; after IN administration, these parameters were 35.9 ± 6.49 ng/mL and 690.5 ± 157.05 ng · h/mL, respectively. PO and IN administration demonstrated similar median time to reach Cmax (tmax) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t1/2) values were also similar for PO (11.6 ± 2.8 hours) and IN (11.3 ± 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects. Conclusion: IN administration of lisdexamfetamine dimesylate resulted in d-amphetamine plasma concentrations and systemic exposure to d-amphetamine comparable to those seen with PO administration. Subject variability for d-amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants.

Pharmacokinetic Variability of Long-Acting Stimulants in the Treatment of Children and Adults with Attention-Deficit Hyperactivity Disorder

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology.Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmoticrelease formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile.The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.

Bioavailability of triple-bead mixed amphetamine salts compared with a dose-augmentation strategy of mixed amphetamine salts extended release plus mixed amphetamine salts immediate release.

ABSTRACT Objective: To compare the single-dose pharmacokinetics of triple-bead mixed amphetamine salts (MAS), an oral, once-daily, enhanced extended-release amphetamine formulation, with MAS extended release (MAS XR) (Adderall XR†) + MAS immediate release (MAS IR) administered 8 h later. Methods: This was a phase I, randomized, open-label, single-dose, single-center, two-period, crossover study in healthy adult volunteers designed to evaluate the bioavailability of triple-bead MAS over the course of a full day. Subjects were randomized to triple-bead MAS 37.5 mg or MAS XR 25 mg + MAS IR 12.5 mg administered 8 h later (MAS XR + MAS IR). The reference treatment was designed to mimic the clinical practice of providing extended coverage by supplementing a morning dose of MAS XR with a dose of MAS IR 8 h later in order to increase the duration of action. Plasma was assayed for d‑amphetamine and l‑amphetamine. Treatment-emergent adverse events (TEAEs), vital signs, electrocardiograms (ECGs), and laboratory data were also collected for safety evaluation. Results: Exposure to d‑ and l‑amphetamine was equivalent between triple-bead MAS and MAS XR + MAS IR based on maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞). For Cmax, least-squares mean ratios comparing triple-bead MAS with MAS XR + MAS IR were 101.0% and 90.9% for d‑amphetamine and l‑amphetamine, respectively, and for AUC0–∞ were 104.4% and 95.3% for d‑amphetamine and l‑amphetamine, respectively. Median time to maximum observed plasma concentration (Tmax) values for d‑amphetamine and l‑amphetamine were 8.0 h for triple-bead MAS and 10.0 h for MAS XR + MAS IR. There were no clinically meaningful differences between the study formulations for TEAEs or laboratory values. One subject experienced an ECG abnormality (asymptomatic premature ventricular contractions) leading to early termination from the study. Conclusions: In healthy adults, the exposure observed with triple-bead MAS 37.5 mg was bioequivalent to MAS XR 25 mg supplemented by MAS IR 12.5 mg administered 8 h later. These data demonstrate that a single morning dose of triple-bead MAS provides equivalent plasma concentrations to those observed with a dose-augmentation strategy of MAS XR in the morning followed by MAS IR in the afternoon, while minimizing peak-to-trough fluctuations. Triple-bead MAS was also generally well-tolerated in this study.

Pharmacokinetics of Lisdexamfetamine Dimesylate after Targeted Gastrointestinal Release or Oral Administration in Healthy Adults

The purpose of this work was to assess the pharmacokinetics and safety of lisdexamfetamine dimesylate (LDX) delivered and released regionally in the gastrointestinal (GI) tract. In this open-label, randomized, crossover study, oral capsules and InteliSite delivery capsules containing LDX (50 mg) with radioactive marker were delivered to the proximal small bowel (PSB), distal SB (DSB), and ascending colon (AC) during separate periods. Gamma scintigraphy evaluated regional delivery and GI transit. LDX and d-amphetamine in blood were measured postdose (≤72 h). Treatment-emergent adverse events (TEAEs) were assessed. Healthy males (n = 18; 18–48 years) were enrolled. Mean (S.D.) maximal plasma concentration (Cmax) was 37.6 (4.54), 40.5 (4.95), 38.7 (6.46), and 25.7 (9.07) ng/ml; area under the concentration-time curve to the last measurable time point was 719.1 (157.05), 771.2 (152.88), 752.4 (163.38), and 574.3 (220.65) ng · h · ml−1, respectively, for d-amphetamine after oral, PSB, DSB, and AC delivery of LDX. Median time to Cmax was 5, 4, 5, and 8 h, respectively. Most TEAEs were mild to moderate. No clinically meaningful changes were observed (laboratory, physical examination, or electrocardiogram). LDX oral administration or targeted delivery to small intestine had similar d-amphetamine systemic exposure, indicating good absorption, and had reduced absorption after colonic delivery. The safety profile was consistent with other LDX studies.

Double-blind, placebo-controlled, two-period, crossover trial to examine the pharmacokinetics of lisdexamfetamine dimesylate in healthy older adults.

Background Pharmacokinetic and safety data on stimulants in older adults are limited. The objective of this study was to characterize the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, in older adults. Methods In this two-period crossover trial, healthy adults (n = 47) stratified by age (55–64, 65–74, and ≥ 75 years) and gender received randomized, double-blind, single doses of LDX 50 mg or placebo. Baseline creatinine clearance, d-amphetamine and intact LDX pharmacokinetics, and safety were assessed. Results Mean (±standard deviation) baseline creatinine clearance in participants aged 55–64, 65–74, and ≥ 75 years was 102.5 ± 26.1, 105.3 ± 23.1, and 94.9 ± 27.3 mL per minute, respectively. In the groups aged 55–64, 65–74, and ≥ 75 years, the mean maximum plasma d-amphetamine concentration in men was 44.2 ± 11.1, 47.7 ± 7.0, and 53.4 ± 19.4 ng/mL, respectively; area under the concentration time curve from time 0 extrapolated to infinity (AUC0–inf) was 915.0 ± 164.9, 1123.0 ± 227.0, and 1325.0 ± 464.4 nghour/mL; median time to reach peak plasma concentration was 4.5, 3.5, and 5.5 hours; in women, mean maximum plasma d-amphetamine concentration was 51.0 ± 6.7, 50.2 ± 6.8, and 64.3 ± 12.1 ng/mL, AUC0–inf was 1034.5 ± 154.6, 988.4 ± 80.5, and 1347.8 ± 198.9 ng hour/mL, and median time to reach peak plasma concentration was 3.5, 4.1, and 5.5 hours, respectively. d-Amphetamine clearance was unrelated to baseline creatinine clearance. Five participants aged 55–64 years reported treatment-emergent adverse events (versus one each aged 65–74 and ≥ 75 years), and as did six women (versus one man). No trends in blood pressure or pulse changes were seen with LDX according to age. In participants aged 55–64, 65–74, and ≥ 75 years, the mean change from time-matched baseline pulse ranged from –5.0 to 14.7, –4.3 to 9.5, and –3.0 to 14.7 beats per minute; for systolic blood pressure, from –3.9 to 18.5 mmHg, –2.1 to 14.5 mmHg, and –5.9 to 16.0 mmHg; for diastolic blood pressure from –2.5 to 8.3 mmHg, from –0.8 to 9.4 mmHg, and –0.6 to 9.5 mmHg. Vital sign changes were similar between men and women. Conclusion Clearance of d-amphetamine decreased with age and was unrelated to creatinine clearance. No trends in pulse or blood pressure changes with LDX were seen according to age. The safety profile of LDX was consistent with prior observations in younger adult study participants.

Safety and pharmacokinetics of lisdexamfetamine dimesylate in adults with clinically stable schizophrenia: a randomized, double-blind, placebo-controlled trial of ascending multiple doses.

Abstract To assess the safety and pharmacokinetics of lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, this double-blind study enrolled adults with clinically stable schizophrenia who were adherent (≥12 weeks) to antipsychotic pharmacotherapy. The participants received placebo or ascending LDX doses (50, 70, 100, 150, 200, and 250 mg) daily for 5 days at each dose (dose periods, 1–6; days, 1–5). Of the 31 enrolled participants, 27 completed the study (placebo, n = 6; LDX, n = 21). Treatment-emergent adverse events (AEs) were reported by 4 participants receiving placebo and by 23 participants receiving LDX (all doses) with no serious AEs while on active treatment. For all periods, the mean postdose change on day 5 (up to 12 hours postdose) in systolic and diastolic blood pressure and pulse, respectively, ranged from −4.62 to 8.05 mm Hg, −3.67 to 4.43 mm Hg, and −3.57 to 14.43 beats per minute for placebo and −3.83 to 11.25 mm Hg, −1.55 to 5.80 mm Hg, and −0.36 to 21.26 beats per minute for LDX. With ascending LDX dose, the mean (SD) maximum plasma concentration for LDX-derived d-amphetamine ranged from 51.68 (10.28) to 266.27 (56.55) ng/mL. The area under the plasma concentration-time curve for 24 hours ranged from 801.8 (170.2) to 4397.9 (1085.9) ng[BULLET OPERATOR]h/mL. The d-amphetamine maximum plasma concentration and area under the plasma concentration-time curve increased linearly with ascending LDX dose. Antipsychotic agents did not markedly affect d-amphetamine pharmacokinetics. Over a wide range of ascending doses, LDX safety profile in adults with schizophrenia was consistent with previous findings with no unexpected treatment-emergent AEs. Pulse tended to increase with LDX dose; overall, blood pressure did not increase with LDX dose. Consistent with previous studies, pharmacokinetic parameters increased linearly with increasing LDX dose.

A Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Lisdexamfetamine Dimesylate in Individuals With Normal and Impaired Renal Function

Background: 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. Methods: 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). Results: 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. Conclusions: 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−1·1.73 m−2), the maximum LDX dose is 50 mg/d; in patients with ESRD (GFR: <15 mL·min−1·1.73 m−2), the maximum LDX dose is 30 mg/d. Neither LDX nor D-amphetamine is dialyzable.

A thorough QT study of guanfacine.

OBJECTIVES Guanfacine extended- release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials. gov identifier: NCT00672984). METHODS In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediaterelease guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. RESULTS In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours postdose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only 1-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. CONCLUSIONS Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours postdose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.