Effect of Rifampin (RIF) on the Pharmacokinetics (PK) of Oral Cabotegravir (CAB) in Healthy Subjects

NCT02411435 | Completed Phase 1

• 1 other identifier: 117010
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

CAB is an integrase inhibitor that is currently in Phase 2 clinical trials for the treatment and prevention of human immunodeficiency virus-1 (HIV-1) infection. RIF, a rifamycin used for treatment of tuberculosis (common co-infection in HIV-infected subjects), is a known inducer of uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) and Cytochrome P450 3A4 (CYP3A4). CAB is primarily metabolized via UGT1A1 and UGT1A9, thus a drug interaction between CAB and RIF is possible. This study will be a phase I, single-center, open label, fixed-sequence cross-over study to compare the single dose PK of CAB oral 30 milligrams (mg) when co-administered with RIF 600 mg once daily at steady-state to those of CAB oral 30 mg administered alone. Fifteen subjects are planned to be enrolled to obtain 12 evaluable subjects for this study.

Conditions

Infection, Human Immunodeficiency Virus

Keywords

rifampin; drug interaction; pharmacokinetics; cabotegravir

Outcome Measures

Primary Outcomes (2)

• Plasma CAB maximum observed concentration after single dose administration (Cmax)

  Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose.

  Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28

• Plasma CAB area under the concentration versus time from time zero to infinity after single dose administration (AUC(0-∞))

  Plasma PK samples collected at the following time points: Period 1 pre-dose (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours post dose. Period 3 pre-dose Day 21 (within 15 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 (Day 3), 72 (Day 4), 120 (Day 6), 168 hours (Day 8) post dose.

  Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28

Secondary Outcomes (9)

• Plasma CAB concentration at 24 hours post dose (C24)

  Days 2 and 22

• Plasma CAB AUC from time zero to last time point with measurable concentration after single dose administration (AUC (0-t))

  Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28

• Plasma CAB time of occurrence of Cmax (tmax) and terminal phase half-life (t1/2)

  Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28

• Plasma CAB apparent clearance following oral dosing (CL/F)

  Days 1, 2, 3, 4, 6, 8, 21, 22, 23, 24, 26, and 28

• Number of subjects with adverse events (AEs) as a measure of safety and tolerability

  Up to 42 days

Study Arms (1)

Treatment A(CAB 30mg)+B (RIF 600mg)+C (CAB 30mg and RIF 600mg)

EXPERIMENTAL

Subjects will receive a single dose of CAB 30 mg on day 1. Subjects will then receive RIF 600 mg once daily on days 8-28 with co-administration of a single dose of CAB 30 mg on day 21.

Drug: CAB; Drug: RIF

Interventions

CAB DRUG

CAB 30 mg as 1 tablet will be administered orally with 240 mL of water in the fasted state.

Treatment A(CAB 30mg)+B (RIF 600mg)+C (CAB 30mg and RIF 600mg)

RIF DRUG

RIF 600 mg as 2 capsules of 300 mg will be administered orally with 240 mL of water in the fasted state.

Treatment A(CAB 30mg)+B (RIF 600mg)+C (CAB 30mg and RIF 600mg)

Eligibility Criteria

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

You may qualify if:

• Males and females between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• Body weight \>=50 kilogram (kg) and body mass index (BMI) within the range 18.5 - 31.0 kg/meter square (m\^2) (inclusive).
• Male or female - A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies: a) Non-reproductive potential defined as: Pre-menopausal females with one of the following \[for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy; b) Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause \>40 milli-international units per mililiter (MIU/mL) and estradiol \<40 picogram/milliliter (pg/mL) (\<147 picomoles/liter \[pmol/L\]) is confirmatory\]; c) Reproductive potential and agrees to follow one of the options listed in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until after the last dose of study medication and completion of the follow-up visit.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in the protocol.
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).

You may not qualify if:

• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study.
• 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 grams 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.
• A history of regular use of tobacco, or nicotine-containing products within 30 days prior to screening.
• 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 Medical Monitor, contraindicates their participation.
• Presence of Hepatitis B surface antigen (HBsAg), positive Hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Hepatitis B core antibody (HBcAb) with negative hepatitis B surface antibody should also be excluded.
• A positive pre-study drug/alcohol screen.
• A positive test for HIV antibody.
• 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).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Sponsors & Collaborators

• ViiV Healthcare: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

GSK Investigational Site

Overland Park, Kansas, 66211, United States

Location

Related Publications (1)

• Ford SL, Sutton K, Lou Y, Zhang Z, Tenorio A, Trezza C, Patel P, Spreen W. Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects. Antimicrob Agents Chemother. 2017 Sep 22;61(10):e00487-17. doi: 10.1128/AAC.00487-17. Print 2017 Oct.

  PMID: 28739783 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: April 2, 2015
• First Posted: April 8, 2015
• Study Start: July 1, 2015
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: January 6, 2016

Record last verified: 2016-01

Locations

US (1)