Co-Administration of LDX (SPD489) and Venlafaxine XR (EFFEXOR XR) in Healthy Volunteers

A Phase 1, Open-label, Drug Interaction Study Evaluating the Pharmacokinetic Profiles of SPD489 and EFFEXOR XR, Administered Alone and in Combination in Healthy Adult Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01235338

Enrollment

Registered

2010-11-05

Start date

2010-10-28

Completion date

2011-01-17

Last updated

2021-06-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Brief summary

This study will examine the effects of co-administration of SPD489 and the antidepressant EFFEXOR XR on the pharmacokinetics of lisdexamfetamine, d-amphetamine, and EFFEXOR XR. In addition, serial blood pressure and pulse measures will be obtained and examined to ensure that there are no unexpected changes in vital signs following co administration of SPD489 and EFFEXOR XR that would impact the further study of this drug combination. The hypothesis is that a drug drug interaction could possibly exist.

Interventions

DRUGLDX + Venlafaxine XR

* Day 1-5 LDX 30mg * Day 6-10 LDX 50mg * Day 11-15 LDX 70mg * Day 16-20 LDX 70mg and Venlafaxine XR 75mg daily * Day 21-25 LDX 70mg and Venlafaxine XR 150mg daily * Day 26-30 LDX 70mg and Venlafaxine XR 225mg daily * Day 31-34 Venlafaxine XR 150mg daily * Day 35-38 Venlafaxine XR 75mg daily.

DRUGVenlafaxine XR + LDX

* Day 1-5 Venlafaxine XR 75mg * Day 6-10 Venlafaxine XR 150mg * Day 11-15 Venlafaxine XR 225mg * Day 16-20 Venlafaxine XR 225mg and LDX 30mg daily * Day 21-25 Venlafaxine XR and LDX 50mg daily * Day 26-30 Venlafaxine XR 225mg and LDX 70mg daily * Day 31-34 Venlafaxine XR 150mg * Day 35-38 Venlafaxine XR 75mg.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 45 Years

Healthy volunteers

Yes

Inclusion criteria

1. Age 18-45 years 2. Subject is willing to comply with any applicable contraceptive requirements of the protocol and is: * Male, or * Non-pregnant, non-lactating female * Females must be at least 90 days post partum or nulliparous. 3. Female subjects must have a negative serum beta Human Chorionic Gonadotropin (HCG) pregnancy test 4. Satisfactory medical assessment 5. Ability to provide information on family history of hypertension. 6. Body Mass Index (BMI) between 18.5 and 30.0kg/m² inclusive. 7. Ability to swallow all investigational products.

Exclusion criteria

1. Current or recurrent disease (e.g., cardiovascular, renal, liver, gastrointestinal, malignancy or other conditions) 2. Current or relevant previous history of physical or psychiatric illness. 3. Significant illness. 4. History of significant anxiety, tension, or agitation as assessed by the Investigator. 5. History of or current diagnosis of glaucoma. 6. History of a seizure disorder (other than infantile febrile seizures), any tic disorder or a current diagnosis and/or known family history of Tourette's Disorder. 7. History of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke, or other serious cardiac problems. 8. History of controlled or uncontrolled hypertension or a resting sitting systolic BP \>139mmHg or diastolic BP \>89mmHg. 9. Known family history of sudden cardiac death or ventricular arrhythmia. 10. Suicidal ideation or any lifetime history of suicidal behavior. 11. Consumption of alcohol, Seville oranges, grapefruit, or any grapefruit containing products within 7 days of first dose of investigational product. 12. Current use of any medication (including prescription, over the counter \[OTC\], herbal or homeopathic preparations or supplements) with the exception of the occasional dose of acetaminophen, or hormonal contraceptives. 13. History of alcohol or other substance abuse within the last year. 14. A positive screen for alcohol or drugs of abuse. 15. Male subjects who consume more than 21 units of alcohol per week or 3 units per day. Female subjects who consume more than 14 units of alcohol per week or 2 units per day. \[1 alcohol unit =1 beer = 1 wine (5oz) = 1 liquor (1.5oz) = 0.75oz alcohol\] 16. A positive human immunodeficiency virus (HIV) antibody screen, Hepatitis B surface antigen (HBsAg), or Hepatitis C virus (HCV) antibody screen. 17. Use of tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products in any form (e.g. gum, patch). Ex-users must report that they have stopped using tobacco for at least 30 days prior to receiving the first dose of investigational product. 18. Routine consumption of more than 2 units of caffeine per day or subjects who experience caffeine withdrawal headaches. (One caffeine unit is contained in the following items: one 6oz. cup of coffee, two 12oz. cans of cola, one 12oz. cup of tea, three 1oz. chocolate bars, or one 8oz. serving of an energy drink. Decaffeinated coffee, tea, or cola are not considered to contain caffeine). 19. Donation of blood or blood products (e.g., plasma or platelets) within 60 days prior to receiving the first dose of investigational product.

Design outcomes

Primary

Measure	Time frame	Description
Tmax of Composite (Venlafaxine + o-Desmethylvenlafaxine)	Day 15 and Day 30 (24 hour sampling)	—
Tmax of d-Amphetamine	Day 15 and Day 30 (24 hour sampling)	—
Tmax of Venlafaxine Hydrochloride	Day 15 and Day 30 (24 hour sampling)	—
Tmax of o-Desmethylvenlafaxine	Day 15 and Day 30 (24 hour sampling)	—
Maximum Plasma Concentration (Cmax) of Lisdexamfetamine Dimesylate	Day 15 and Day 30 (24 hour sampling)	Lisdexamfetamine dimesylate (SPD489) itself is inactive, but following oral administration is converted to the active isomer, d-amphetamine, that is responsible for the drug's therapeutic activity.
Cmax of d-Amphetamine	Day 15 and Day 30 (24 hour sampling)	d-Amphetamine is the active isomer of Lisdexamfetamine dimesylate (SPD489) and is responsible for the drug's therapeutic activity.
Cmax of Venlafaxine Hydrochloride	Day 15 and Day 30 (24 hour sampling)	Venlafaxine Hydrochloride is the active ingredient of Effexor XR
Cmax of o-Desmethylvenlafaxine	Day 15 and Day 30 (24 hour sampling)	Venlafaxine, after oral administration, is metabolized in the liver to an active metabolite, o-Desmethylvenlafaxine.
Cmax of Composite (Venlafaxine + o-Desmethylvenlafaxine)	Day 15 and Day 30 (24 hour sampling)	—
Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Lisdexamfetamine Dimesylate	Day 15 and Day 30 (24 hour sampling)	—
AUC of d-Amphetamine	Day 15 and Day 30 (24 hour sampling)	—
AUC of Venlafaxine Hydrochloride	Day 15 and Day 30 (24 hour sampling)	—
AUC of o-Desmethylvenlafaxine	Day 15 and Day 30 (24 hour sampling)	—
AUC of Composite (Venlafaxine + o-Desmethylvenlafaxine)	Day 15 and Day 30 (24 hour sampling)	—
Time of Maximum Plasma Concentration (Tmax) of Lisdexamfetamine Dimesylate	Day 15 and Day 30 (24 hour sampling)	—

Secondary

Measure	Time frame
Diastolic Blood Pressure	Baseline and up to 39 days
Pulse Rate	Baseline and up to 39 days
Systolic Blood Pressure	Baseline and up to 39 days

Countries

United States

Participant flow

Pre-assignment details

Of the 80 randomized subjects, 3 did not receive any investigational product and therefore were not included in the Safety Analysis/Pharmacokinetic Analysis Sets (n = 77).

Participants by arm

Arm	Count
LDX + Venlafaxine XR LDX (Lisdexamfetamine Dimesylate, SPD489, Vyvanse®) 30 mg once daily (QD) Days 1-5, then LDX 50 mg QD Days 6-10, then LDX 70 mg QD Days 11-15, then LDX 70 mg + venlafaxine XR (Venlafaxine Hydrochloride extended-release, Effexor® XR) 75 mg QD Days 16-20, then LDX 70 mg + venlafaxine XR 150 mg QD Days 21-25, then LDX 70 mg + venlafaxine XR 225 mg QD Days 26-30, then venlafaxine XR 150 mg QD Days 31-34, then venlafaxine XR 75 mg QD Days 35-38.	40
Venlafaxine XR + LDX Venlafaxine XR (Venlafaxine Hydrochloride extended-release, Effexor® XR) 75 mg QD Days 1-5, then venlafaxine XR 150 mg QD Days 6-10, then venlafaxine XR 225 mg QD Days 11-15, then venlafaxine XR 225 mg + LDX (Lisdexamfetamine Dimesylate, SPD489, Vyvanse®) 30 mg QD Days 16-20, then venlafaxine XR 225 mg + LDX 50 mg QD Days 21-25, then venlafaxine XR 225 mg + LDX 70 mg QD Days 26-30, then venlafaxine XR 150 mg QD Days 31-34, then venlafaxine XR 75 mg QD Days 35-38.	37
Total	77

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	2
Overall Study	Exclusion criteria violations	1	1
Overall Study	Positive drug screen	0	1
Overall Study	Prohibited meds	1	0
Overall Study	Protocol Violation	1	1
Overall Study	Withdrawal by Subject	5	0

Baseline characteristics

Characteristic	LDX + Venlafaxine XR	Venlafaxine XR + LDX	Total
Age, Continuous	33.2 years STANDARD_DEVIATION 7.01	33.8 years STANDARD_DEVIATION 7.29	33.5 years STANDARD_DEVIATION 7.1
Age, Customized Between 18 and 45 years	40 Participants	37 Participants	77 Participants
Region of Enrollment United States	40 Participants	37 Participants	77 Participants
Sex: Female, Male Female	12 Participants	10 Participants	22 Participants
Sex: Female, Male Male	28 Participants	27 Participants	55 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	33 / 40	46 / 67	25 / 37	20 / 67
serious Total, serious adverse events	1 / 40	0 / 67	0 / 37	0 / 67

Population: PAS

Arm	Measure	Group	Value (MEAN)	Dispersion
LDX + Venlafaxine XR	Cmax of d-Amphetamine	Day 15	88.91 ng/ml	Standard Deviation 26.87
LDX + Venlafaxine XR	Cmax of d-Amphetamine	Day 30	88.91 ng/ml	Standard Deviation 22.72
Venlafaxine XR + LDX	Cmax of d-Amphetamine	Day 15	0 ng/ml	Standard Deviation 0
Venlafaxine XR + LDX	Cmax of d-Amphetamine	Day 30	85.27 ng/ml	Standard Deviation 20.55

Primary

Cmax of o-Desmethylvenlafaxine

Venlafaxine, after oral administration, is metabolized in the liver to an active metabolite, o-Desmethylvenlafaxine.