Mary Corcoran

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.

Effect of MMX ® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials

Background MMX® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections. Aim To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies. Methods In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44). Results MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild. Conclusion MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics. ClinicalTrials.gov identifiers NCT01442688, NCT01402947, NCT01418365, and NCT01469637.

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 phase 1 randomized study evaluating the effect of omeprazole on the pharmacokinetics of a novel 5-hydroxytryptamine receptor 4 agonist, revexepride (SSP-002358), in healthy adults

Background About 30% of patients with gastroesophageal reflux disease continue to experience symptoms despite treatment with proton pump inhibitors. The 5-hydroxytryptamine 4 receptor agonist revexepride (SSP-002358) is a novel prokinetic that stimulates gastrointestinal motility, which has been suggested as a continued cause of symptoms in these patients. The aim of this study was to assess whether revexepride pharmacokinetics were affected by co-administration of omeprazole, in preparation for a proof-of-concept evaluation of revexepride added to proton pump inhibitor treatment. Methods In this phase 1, open-label, randomized, two-period crossover study, healthy adults aged 18–55 years were given a single dose of revexepride 1 mg or revexepride 1 mg + omeprazole 40 mg. Pharmacokinetic parameters were assessed for up to 48 hours after administration of the investigational product. Adverse events, clinical chemistry and hematology parameters, electrocardiograms, and vital signs were monitored. Results In total, 42 participants were enrolled and 40 completed the study. The median age was 24 years (18–54 years), 55% were women and 93% were white. The pharmacokinetic parameters of revexepride were similar without or with omeprazole co-administration. The mean area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞) was 23.3 ng · h/mL (standard deviation [SD]: 6.33 ng · h/mL) versus 24.6 ng · h/mL (SD: 6.31 ng · h/mL), and maximum plasma concentrations (Cmax) were 3.89 ng/mL (SD: 1.30 ng/mL) and 4.12 ng/mL (SD: 1.29 ng/mL) in participants without and with omeprazole, respectively. For AUC0–∞ and Cmax, the 90% confidence intervals for the ratios of geometric least-squares means (with:without omeprazole) were fully contained within the pre-defined equivalence limits of 0.80–1.25. Mean apparent terminal phase half-life was 9.95 hours (SD: 2.06 hours) without omeprazole, and 11.0 hours (SD: 3.25 hours) with omeprazole. Conclusion Co-administration of the 5-hydroxytryptamine receptor 4 agonist revexepride with omeprazole did not affect the pharmacokinetics of revexepride in healthy adults.

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.

Relative Bioavailabilities of Lisdexamfetamine Dimesylate and D-Amphetamine in Healthy Adults in an Open-Label, Randomized, Crossover Study After Mixing Lisdexamfetamine Dimesylate With Food or Drink.

Background: This 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. Methods: Healthy 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. Results: Geometric 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. Conclusions: Relative 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.

Pharmacokinetics and pharmacodynamics of guanfacine extended release in adolescents aged 13–17 years with attention-deficit/hyperactivity disorder

The safety and efficacy of guanfacine extended release (up to 4 mg/day) for attention‐deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6–17 years is well documented. Data suggest that weight‐adjusted doses of guanfacine extended release >0.08 mg/kg but ≤0.12 mg/kg, if tolerated, may provide additional clinical benefits. For many adolescents, such dosing would exceed 4 mg/day, the highest approved dose. This open‐label multicenter study evaluated the safety, tolerability, and steady‐state pharmacokinetics of guanfacine extended release at escalated forced doses ≤9 mg/day in adolescents (N = 31) aged 13–17 years with ADHD. Following doses of approximately 0.12 mg/kg, the highest weight group (>70–90 kg) exhibited lower mean clearance at steady‐state than the lowest weight group (≥30–50 kg). Consistent with its known antihypertensive effects, guanfacine extended release was associated with dose‐dependent decreases in blood pressure (BP) and heart rate (HR). The physiologic response of increased BP upon standing was blunted in a dose‐related manner while the physiologic response of increased HR upon standing was not substantively affected. The most common treatment‐emergent adverse events were somnolence, dizziness, and sinus bradycardia. These results, and those from prior studies, support further examination of the efficacy and safety of higher weight‐adjusted doses of guanfacine extended release for ADHD.