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

This study of LDX was an open-label, two-arm, single-sequence crossover investigation with randomization to treatment sequence investigation in healthy adults, consisting of a screening period, a 38-day treatment period, and safety telephone follow-up. There were two treatment arms: A (initial titration with LDX over 15 days followed by the addition of VXR, titrated over an additional 15 days) and B (initial titration with VXR over 15 days followed by the addition of LDX, titrated over an additional 15 days). During pre-dose baseline assessments, participant blood samples were obtained for CYP2D6 genotyping. To minimize the potential for adverse effects during initiation of treatment with either LDX (e.g., dizziness, palpitations) or VXR (e.g., nausea, vomiting), doses were gradually titrated upward at 5-day intervals to maximal doses of LDX 70 mg/day and VXR 225 mg/day; at the end of the study, VXR doses were also gradually decreased over a 1-week period. Figure 1 illustrates the dosing/titration schedule for each of the treatment arms and scheduled study assessments. On day −2 through day 2 and day 14 through day 31, participants remained at one of two clinical study centres (CSCs); on other days, participants made daily visits to the same CSC.

The study was approved by the Independent Investigational Review Board, Inc (Plantation, FL, USA) and was conducted in accordance with the principles of the Declaration of Helsinki and its amendments, all local ethical and legal requirements, as well as US Food and Drug Administration (FDA) guidance on appropriate conduct of in vivo drug-drug interaction studies [15]. All participants were required to provide signed informed consent prior to performance of any study-related procedures and a separate consent for genotyping sampling.

This study enrolled healthy adult male and non-pregnant, non-lactating females (aged 18–45 years). Participants were excluded if they had any current or recurrent disease that could affect the absorption, disposition or effect of the investigational products, or clinical or laboratory assessments; medical or psychiatric illness that might require treatment, affect ability to comply with investigational protocol, or present undue risk; history of significant anxiety or agitation; current diagnosis or history of glaucoma; current diagnosis or history of a tic disorder, or personal/family history of Tourette’s disorder; structural cardiac abnormality, transient ischaemic attack or stroke, or any other serious cardiac condition; history of hypertension, or high blood pressure at screening (systolic blood pressure [SBP] >139 mmHg and/or diastolic blood pressure [DBP] >89 mmHg, taken at rest while sitting); family history of sudden cardiac death or ventricular arrhythmia; history of alcohol or other substance abuse within the past year; a positive screen for drugs of abuse or alcohol during the screening visit or check-in; and consumption of alcohol within 7 days, or caffeine/xanthine-containing products within 24 h of the first study medication dose or during the study. Also excluded were individuals who had smoked or used nicotine-containing products within 30 days prior to the first dose of study medication or during the study, as well as those who had donated blood or blood products (e.g., plasma, platelets) within 60 days or had received another investigational product within 30 days prior to the first dose of study medication.

Study medication was administered with 240 mL room temperature water; dosing occurred on the scheduled days at the study clinic throughout the investigation period. Capsules were swallowed whole, not cut, chewed or crushed. On days of serial blood sampling (days 1, 15 and 30), study medication was administered following a fast of approximately 10 h, and food was not given until 4 h post-dosing. Water intake was restricted for 4 h prior to dosing and 2 h following dosing.

During baseline assessments, participant blood samples were obtained for CYP2D6 genotyping. For pharmacokinetic analysis, serial blood samples were collected up to 24 h after dose administration on days 1, 15 and 30; on these study days, samples were obtained pre-dose (at −0.5 h) and at the following times post-dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 9, 12 and at 0/24 h on days 2, 16, and 31. On days 14 and 29, a single blood sample was obtained at 0.5 h pre-dose. Plasma concentrations of LDX, d-amphetamine, VEN and ODV were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) methods. Samples from days on which participants were dosed with LDX alone were analysed for LDX and d-amphetamine only; samples from days on which participants were dosed with VXR alone were analysed for VEN and ODV only; and samples from days on which participants were dosed with both LDX and VXR were analysed for LDX, d-amphetamine, VEN and ODV. Briefly, LDX, d-amphetamine, VEN and ODV concentrations in human plasma were determined using a LC-MS/MS method validated over the range of 1–100 ng/mL for LDX and 2–200 ng/mL for d-amphetamine; over the range of 0.5–250 ng/mL for VEN and 1–500 ng/mL for ODV all based on 200 μL of human plasma. Human plasma containing LDX, d-amphetamine, VEN and ODV, and internal standards, D8-LDX, D5-amphetamine or D6-VEN and D6-ODV, was extracted with ethyl acetate/toluene (1:1) in the presence of saturated sodium chloride/sodium hydroxide for LDX/d-amphetamine and with ethyl acetate in sodium phosphate buffer for VEN/ODV. Following centrifugation, the organic layer was transferred and evaporated. After the addition of formic acid for LDX/d-amphetamine and ethyl acetate for VEN/ODV and reconstitution in mobile phase, an aliquot was injected onto a AB SCIEX API™ 4000 LC-MS/MS (Framingham, MA, USA) equipped with a high-performance liquid chromatography column. The peak area of the m/z 264 → 84 LDX product ion was measured against the peak area of the m/z 272 → 92 D8-LDX internal standard product ion. The peak area of the m/z 136 → 91 amphetamine product ion was measured against the peak area of the m/z 141 → 96 D5-amphetamine internal standard product ion. The peak area of the m/z 278 → 58 VEN product ion was measured against the peak area of the m/z 284 → 58 D6-VEN internal standard product ion. The peak area of the m/z 264 → 58 ODV product ion was measured against the peak area of the m/z 270 → 58 D6-ODV internal standard product ion. Peak area integrations were performed using Analyst software (version 1.4.2) from Applied Biosystems (Carlsbad, CA, USA). Concentrations were calculated using 8-point curves ranging from 1 to 100 ng/mL for LDX and 2 to 200 ng/mL for d-amphetamine with separate weighted linear regression; ranging from 0.5 to 250 ng/mL for VEN and 1 to 500 ng/mL for ODV with separate weighted linear regression. Based on a sample volume of 200 μL, the method had a lower limit of quantification of 1 ng/mL for LDX and 2 ng/mL for d-amphetamine; 0.5 ng/mL for VEN and 1 ng/mL for ODV. Values below this limit were reported as not quantifiable.

Pharmacokinetic parameters were determined from the plasma concentration-time data for LDX, d-amphetamine, VEN, ODV and composite (VEN + ODV) by non-compartmental analysis. The following pharmacokinetic parameters were calculated from plasma concentrations of d-amphetamine, LDX, VEN and ODV: maximum plasma concentration (C_max), time to reach C_max (t_max), area under the plasma concentration-time curve (AUC) from time zero to time of last measurable concentration (AUC_τ), elimination half-life (t_½) and relative bioavailability. Variability was assessed with percent coefficient of variation (% CV).

To demonstrate bioequivalence (in each arm), 24 subjects were needed in each treatment arm to achieve 90 % power based on allowing for a 5 % difference in true means and the true within-subject SD (based on the higher of the AUC SDs between LDX and VXR) being ≥0.20.

The safety analysis set was defined as all participants who received at least one dose of study medication and had at least one post-dose safety assessment. Pharmacokinetic parameters were analysed based on the pharmacokinetics analysis set, defined as all participants who received at least one dose of study medication, had at least one post-dose safety assessment, had no major protocol deviations related to intake of study medication (e.g., vomiting), and for whom the primary pharmacokinetic data were considered sufficient and interpretable. For each treatment arm, summary descriptive statistics were determined for all pharmacokinetic parameters as well as plasma concentrations of LDX, d-amphetamine, VEN and ODV at each scheduled sampling time. For each treatment arm, the means of log-transformed pharmacokinetic parameters were compared using mixed effects analysis of variance. To estimate the magnitude of difference in C_max and AUC_τ for LDX and d-amphetamine between LDX alone and LDX + VXR (Treatment Arm A) and for VEN, ODV and total VEN + ODV between VXR alone and LDX + VXR (Treatment Arm B)_, geometric mean ratios (GMRs) and their 90 % confidence intervals (CIs) were calculated. Combination LDX + VXR was considered not to have an interaction if the 90 % CIs for GMRs of analytes fell within the interval 0.80–1.25 based on C_max and AUC_τ.