An Open-Label Investigation of the Pharmacokinetic Profiles of Lisdexamfetamine Dimesylate and Venlafaxine Extended-Release, Administered Alone and in Combination, in Healthy Adults

Abstract

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 p...

A phase 1, randomized, double‐blind, placebo‐controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adult subjects

“…A minimum of 12 Japanese and 12 Caucasian subjects were required to complete the study. No formal calculations were performed to determine sample size, which was based on feasibility and similar to that of comparable studies …”

“…Lisdexamfetamine 70 mg once daily generally is associated with increased pulse rate versus baseline over the course of the day. 24 This has not previously been associated with a safety risk when used according to label instructions in Western populations, but experience in a Japanese population is more limited, which may have some clinical significance. One subject discontinued lisdexamfetamine treatment due to ECG changes.…”

Method validation and determination of lisdexamfetamine and amphetamine in oral fluid, plasma and urine by LC–MS/MS

“…To the best of our knowledge there are no articles related to detection of LDX in oral fluid and the existing articles related to plasma and urine methods for LDX lack information (Biederman et al, 2007;Boellner, Stark, Krishnan, & Zhang, 2010;Ermer, Corcoran, & Martin, 2015;Ermer, Haffey, Richards, Lasseter, Adeyi et al, 2013a;Ermer, Haffey, Richards, Lasseter, Roesch et al, 2013b;Ermer et al, 2011Ermer et al, , 2012Jasinski & Krishnan, 2009;Krishnan, Pennick, & Stark, 2008;Krishnan & Zhang, 2008;Pennick, 2010, 2 | MATERIALS AND METHODS…”

Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label, Randomized, Crossover Study

“…In an in vitro study in human liver microsomes, LDX did not produce concentration-dependent or mechanism-based inhibition of several CYP isozymes, including CYP1A2, CYP2C19, CYP2D6, and CYP3A4 [ 9 ]. Potential interactions of LDX with medications metabolized by CYP enzymes have also been examined in two clinical trials in healthy volunteers [ 10 , 11 ]. In one open-label study, LDX administered in combination with venlafaxine extended release (VXR), which is metabolized by CYP2D6 and CYP3A4 [ 4 ], was associated with small increases in VXR exposure, small decreases in exposure to the primary VXR metabolite ( O -desmethylvenlafaxine [ODV]), and no change in composite VXR + ODV exposure when compared with VXR alone in healthy volunteers [ 10 ].…”

“…Potential interactions of LDX with medications metabolized by CYP enzymes have also been examined in two clinical trials in healthy volunteers [ 10 , 11 ]. In one open-label study, LDX administered in combination with venlafaxine extended release (VXR), which is metabolized by CYP2D6 and CYP3A4 [ 4 ], was associated with small increases in VXR exposure, small decreases in exposure to the primary VXR metabolite ( O -desmethylvenlafaxine [ODV]), and no change in composite VXR + ODV exposure when compared with VXR alone in healthy volunteers [ 10 ]. When LDX was administered to healthy volunteers in combination with guanfacine extended release (GXR), which is metabolized by CYP3A4 [ 12 ], there were no changes in LDX or d -amphetamine exposure when compared with LDX alone.…”