Effect of Carbamazepine on Dolutegravir Pharmacokinetics in Healthy Adult Subjects

NCT01967771 | Completed Phase 1

• 1 other identifier: 200901
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This study will be a phase I, open label, three period, fixed sequence crossover study to evaluate the effect of Carbamazepine (CBZ) on the steady-state pharmacokinetics of Dolutegravir (DTG) and on the safety and tolerability of DTG. Subjects will have a screening visit within 30 days prior to the first dose of study drug, three treatment periods, and a follow-up visit 7-14 days after the last dose of study drug. There is no washout between treatment periods.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

healthy volunteers; drug interaction; carbamazepine; Dolutegravir; pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• Steady state plasma DTG pharmacokinetics (PK) parameters

  PK parameters will include: Steady state plasma DTG concentration at the end of the dosing interval (Ctau), maximum concentration (Cmax), area under the time-concentration curve over the dosing interval \[AUC(0-tau)\], apparent clearance following oral dosing (CL/F), terminal phase half life (t1/2), concentration at time zero (C0) and minimum concentration (Cmin)

  Day 5 and Day 26

Secondary Outcomes (4)

• Change from baseline in 12-lead electrocardiogram (ECG)

  Up to 40 days

• Change from baseline in vital signs

  Up to 40 days

• Number of subjects with adverse events (AEs)

  Up to 40 days

• Toxicity grading of clinical laboratory tests

  Up to 40 days

Study Arms (1)

DTG/CBZ

EXPERIMENTAL

All subjects will be assigned to a single-sequence of three treatment periods without washout. Subjects will receive DTG 50 mg once daily (OD) for 5 days (Period 1), followed by CBZ 100 mg twice daily (BID) for 3 days (days 1-3 of Period 2), CBZ 200 mg BID for 3 days (days 4-6 of Period 2), CBZ 300mg BID for 10 days (days 7-16 of Period 2), followed by DTG 50 mg OD in combination with CBZ 300mg BID for 5 days (Period 3).

Drug: DTG; Drug: CBZ

Interventions

DTG DRUG

DTG will be supplied as 50 mg tablet to be administered orally

DTG/CBZ

CBZ DRUG

CBZ will be supplied as 100 mg and 200 mg extended release tablet to be administered orally

DTG/CBZ

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Male/females aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, bilateral oophorectomy or hysterectomy \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 milli international units per milliliter (MIU/mL) and estradiol \<40 picograms (pg)/mL (\<147 picomole per liter (pmol/L) is confirmatory\]; Child-bearing potential with negative pregnancy test as determined by \[serum or urine\] human chorionic gonadotropin (hCG) test at screening or prior to dosing AND Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 5 days post-last dose. OR has only same-sex partners, when this is her preferred and usual lifestyle.
• Body weight \>=50 kilograms (Kg) for males and \>=45 Kg for females and body mass index (BMI) within the range 18.5 - 31.0 Kg/m\^2 (square meters) (inclusive).
• Alanine aminotransferase, alkaline phosphatase and bilirubin \<= 1.5x Upper Limit of Normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). A single repeat is allowed for eligibility determination.
• Based on single corrected QT interval (QTc) value: QT duration corrected for heart rate by Bazett's formula (QTcB) \<450 millisecond (msec); or QTc \<480 msec in subjects with Bundle Branch Block.
• A negative HLA-B\*1502 allele screening assessment for subjects of Asian ethnicity only.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (HIV) antibody.
• Pregnant females as determined by positive \[serum or urine\] hCG test at screening or prior to dosing.
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation. Subjects will allergy to tricyclic antidepressants should not be enrolled.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Lactating females.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Song I, Weller S, Patel J, Borland J, Wynne B, Choukour M, Jerva F, Piscitelli S. Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation. Eur J Clin Pharmacol. 2016 Jun;72(6):665-70. doi: 10.1007/s00228-016-2020-6. Epub 2016 Feb 22.

  PMID: 26898568 DERIVED

MeSH Terms

Conditions

Infections; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• GSK Clinical Trials

  ViiV Healthcare

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 4, 2013
• First Posted: October 23, 2013
• Study Start: October 1, 2013
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: January 27, 2014

Record last verified: 2014-01

Locations

US (1)