An open-label investigation of the pharmacokinetic profiles of lisdexamfetamine dimesylate and venlafaxine extended-release, administered alone and in combination, in healthy adults

James Ermer, Mary B Haffey, Cynthia Richards, Kenneth Lasseter, Benno Roesch, Jaideep Purkayastha, Mary Corcoran, Bree Harlin, Patrick Martin, James Ermer, Mary B Haffey, Cynthia Richards, Kenneth Lasseter, Benno Roesch, Jaideep Purkayastha, Mary Corcoran, Bree Harlin, Patrick Martin

Abstract

Background: Lisdexamfetamine 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.

Objective: This study aimed to describe the pharmacokinetics and safety of LDX and venlafaxine extended-release (VXR), alone or combined.

Study design: The study was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence.

Setting and participants: The study was conducted at two clinical study centres and included healthy adult males and females (18-45 years of age).

Intervention: The 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 measures: On 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).

Results: Among 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.

Conclusion: In 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.

Figures

Fig. 1
Fig. 1
Timing of study visits, and procedures. LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-release
Fig. 2
Fig. 2
Participant disposition. Treatment Arm A initial LDX alone, followed by combination LDX + VXR; Treatment Arm B initial VXR alone, followed by combination LDX + VXR. AE adverse event, LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-release
Fig. 3
Fig. 3
Mean (SD) plasma concentration versus time plots for a LDX and bd-amphetamine, following administration of LDX 30 mg/day (day 1, beginning of titration), LDX 70 mg/day (day 15, end of titration), and LDX 70 mg/day + VXR 225 mg/day (day 30, end of coadministration). LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-release
Fig. 4
Fig. 4
Mean (SD) plasma concentration versus time plots for a VEN, b ODV and c composite VEN + ODV following administration of VXR 75 mg/day (day 1, beginning of titration), VXR 225 mg/day (day 15, end of titration), and LDX 70 mg/day + VXR 225 mg/day (day 30, end of coadministration). LDX lisdexamfetamine dimesylate, ODVO-desmethylvenlafaxine, VEN venlafaxine
Fig. 5
Fig. 5
Mean (SD) changea from baseline in a pulse rate, b systolic blood pressure and c diastolic blood pressure on day 1 (beginning of titration), day 15 (end of titration) and day 30 (end of coadministration). LDX lisdexamfetamine dimesylate, VXR venlafaxine extended-release

References

    1. Vyvanse® (lisdexamfetamine dimesylate) capsules [package insert]. Wayne: Shire US Inc.; 2012.
    1. Pennick M. Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat. 2010;6(1):317–327. doi: 10.2147/NDT.S9749.
    1. Trivedi MH, Cutler A, Richards C, et al. Efficacy and safety of lisdexamfetamine dimesylate as augmentation therapy in adults with major depressive disorder treated with an antidepressant. Poster presented at: the 164th Annual Meeting of the American Psychiatric Association; May 14–18, 2011; Honolulu, HI.
    1. Madhoo M, Keefe RSE, Roth RM, et al. Efficacy and safety of lisdexamfetamine dimesylate in adults with executive dysfunction and partial or full remission of major depressive disorder. Abstract presented at: College of Psychiatric and Neurologic Pharmacists’ Annual Meeting; April 29–May 2, 2012; Tampa, FL.
    1. Krishnan S, Moncrief S. An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes. Drug Metab Dispos. 2007;35(1):180–184. doi: 10.1124/dmd.106.011973.
    1. Bach MV, Coutts RT, Baker GB. Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999;29(7):719–732. doi: 10.1080/004982599238344.
    1. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13–37. doi: 10.2174/1389200023338017.
    1. Sheehan JJ, Sliwa JK, Amatniek JC, et al. Atypical antipsychotic metabolism and excretion. Curr Drug Metab. 2010;11(6):516–525. doi: 10.2174/138920010791636202.
    1. Effexor XR® (venlafaxine hydrochloride) extended-release capsules [package insert]. Philadelphia: Wyeth Pharmaceuticals Inc.; 2011.
    1. Ball SE, Ahern D, Scatina J, et al. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2. Br J Clin Pharmacol. 1997;43(6):619–626. doi: 10.1046/j.1365-2125.1997.00591.x.
    1. Perahia DG, Pritchett YL, Kajdasz DK, et al. A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder. J Psychiatr Res. 2008;42(1):22–34. doi: 10.1016/j.jpsychires.2007.01.008.
    1. Adler LA, Goodman DW, Kollins SH, et al. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2008;69(9):1364–1373. doi: 10.4088/JCP.v69n0903.
    1. Adler LA, Weisler RH, Goodman DW, et al. Short-term effects of lisdexamfetamine dimesylate on cardiovascular parameters in a 4-week clinical trial in adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2009;70(12):1652–1661. doi: 10.4088/JCP.09m05335pur.
    1. Adler LA, Lynch LR, Shaw DM, et al. Medication adherence and symptom reduction in adults treated with mixed amphetamine salts in a randomized crossover study. Postgrad Med. 2011;123(5):71–79. doi: 10.3810/pgm.2011.09.2461.
    1. US Department of Health and Human Services. Guidance for Industry: Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. . Accessed 24 May 2012.
    1. US Food and Drug Administration. Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations. . Accessed 24 May 2012.
    1. Sir A, D’Souza RF, Uguz S, et al. Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. J Clin Psychiatry. 2005;66(10):1312–1320. doi: 10.4088/JCP.v66n1015.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する