Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers

A Phase 1, Multicompartmental Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers

Cabotegravir (CAB) long-acting (LA) is a promising candidate for human immunodeficiency virus (HIV) pre exposure prophylaxis (PrEP) due to its potent antiretroviral activity and infrequent dosing requirements. Currently, the CAB concentrations achieved in the anatomical sites associated with sexual HIV transmission following the proposed 600 milligram (mg) intramuscular (IM) PrEP dose are unknown. These data will enhance our understanding of CAB distribution to the anatomical mucosal tissue believed to be relevant to sexual HIV-1 transmission and supplement the data to support future PrEP clinical trial development. The primary objective is to determine the PK concentrations of CAB following LA administration in plasma and in vaginal tissue (VT), cervical tissue (CT), and cervicovaginal fluid (CVF) in healthy women and in rectal tissue (RT) and rectal fluid (RF) in healthy men and women following a single 600 mg IM dose. This will be a Phase 1, open label study in healthy subjects to assess the pharmacokinetics of CAB LA in the plasma and mucosal locations associated with sexual HIV-1 transmission: VT, CT, CVF, RT and RF. The study will consist of a screening period, a 28-day oral lead-in phase at a dose of 30 mg per day followed by a 14-42 day washout period, and a single dose of CAB LA 600 mg as an IM (intragluteal) injection with compartmental pharmacokinetic (PK) sampling for up to 12 weeks. Subjects will return for safety assessments and plasma PK sampling at Week 24 and Week 36 post-injection and undergo a follow-up/withdrawal visit at Week 52 post-injection.

Inclusion Criteria:

• Between 18 and 55 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.
• A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the medical monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. A single repeat of a procedure or lab parameter is allowed to determine eligibility.
• Body weight >= 40 kilogram (kg) and body mass index (BMI) within the range 18.5 to 35 kg /meter square (inclusive).
• Male or female
• A female subject is eligible to participate if she is pre-menopausal, has an intact uterus and cervix, AND is not pregnant (as confirmed by a negative 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: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Documented Bilateral Oophorectomy. b)Reproductive potential and agrees to follow one of the options listed below 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 at least five terminal half-lives OR until any continuing pharmacologic effect has ended, whichever is longer (can be up to 66 weeks on study) after the last dose of study medication and completion of the follow-up visit. Female subjects desiring pregnancy or foresee that they might wish to become pregnant within 52 weeks of receiving a CAB LA injection must be excluded. All subjects participating in the study must be counseled on safe sexual practices including the use of effective barrier methods to minimize risk of HIV transmission.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

• Liver Function: ALT or AST > upper limit of normal (ULN)
• Total bilirubin >ULN (isolated total bilirubin >ULN is acceptable if total bilirubin is fractionated and direct bilirubin <35%)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Corrected QT (QTc) Interval: QTc > 450 milliseconds (msec):

NOTES: The QTc is the QT interval corrected for heart rate according to Bazette's formula (QTcB), machine-read or manually over-read. QTcB will be used to determine eligibility for an individual subject. Exclusion criteria for screening electrocardiogram (ECG) (a single repeat is allowed for eligibility determination): Heart rate (<45 and >100 beats per minute (bpm) for males and <50 and >100 bpm for females; QRS duration: >120 msec; QTc interval: >450 msec for males and females

• The subject's systolic blood pressure is outside the range of 90-140 millimeter (mm) mercury (Hg), or diastolic blood pressure is outside the range of 45-90 mmHg.
• History of clinically significant cardiovascular disease including:

Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except early repolarization); History/evidence of symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty (PCTA) or any clinically significant cardiac disease; Any conduction abnormality (including but not specific to left or right complete bundle branch block, AV block (2nd degree [type II] or higher), Wolf Parkinson White [WPW] syndrome); Sinus pauses > 3 seconds.

• Any significant arrhythmia which, in the opinion of the principal Investigator and GSK Medical Monitor, will interfere with the safety for the individual subject. Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular tachycardia.
• History of ongoing or clinically relevant seizure disorder within the previous 2 years, including subjects who have required treatment for seizures within this time period. A prior history of seizure, with a seizure free period of at least 2 years, off anti-epileptics, may be considered for enrolment if the investigator believes the risk of seizure recurrence is low. All cases of prior seizure history should be discussed with the medical monitor prior to enrolment
• Use of any concurrent prohibited medications as outlined in protocol
• 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 gram (g) of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• Inability or unwillingness to comply with lifestyle and/or dietary restrictions outlined in protocol.
• High-risk behavior for HIV infection which includes, but is not limited to, one of the following risk factors within six months before entering the study (Day 1 of the oral lead-in): Unprotected vaginal or anal sex with a known HIV infected person or a casual partner, engaged in sex work for money or drugs, acquired a sexually transmitted disease, high risk partner currently or in the previous six months or intravenous drug use.
• 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.
• For subjects participating in magnetic resonance imaging (MRI) imaging: Contraindication for MRI scanning (as assessed by local MRI safety questionnaire), which includes but is not limited to: a) Intracranial aneurysm clips (except Sugita) or other non-MRI compatible metallic objects; b) Intra- orbital metal fragments that have not been removed by a medical professional; c) Pacemakers or other implanted cardiac rhythm management devices and non-MRI compatible heart valves, d) Inner ear implants, e) History of claustrophobia
• Positive hepatitis B surface antigen or positive hepatitis B core antibody with negative hepatitis B surface antibody test result at screening or within 3 months prior to first dose of study treatment.
• Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment
• A positive pre-study drug/alcohol screen. A positive drug screen is permitted if due to a prescribed medication, provided that medication is not on the list of prohibited medications and approved by the investigator and medical monitor.
• A positive test for HIV antibody.
• A positive pre-study screen for sexually transmitted diseases including Neisseria gonorrhea or Chlamydia trachomatis, Trichomonas, syphilis, or an active Herpes simplex virus (HSV) genital lesion.
• Presence of a tattoo or other dermatological condition overlying the buttocks which in the opinion of the investigator may interfere with the interpretation of injection site reactions.
• 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.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated.

Additional Criteria for Female Subjects Only:

• Any current medical conditions that in the opinion of the investigator may compromise the conduct or analysis of the genital tract sampling (e.g., active genital tract infection or lesions).
• Inability to abstain from the use of intravaginal products (e.g. tampons, spermicides, lubricants, vaginal hygiene products, diaphragms) for 72 hours prior to the genital tract sample collection visits and for up to 72 hours after.
• Inability to abstain from any sexual activity (e.g., vaginal intercourse, masturbation, and penetration of the vagina by penises, fingers, tampons, sex toys) for 72 hours prior to the genital tract sample collection visits and for up to 72 hours after.

Additional Criteria for Male Subjects and Female Subjects who consent to rectal PK sampling:

• Any current medical conditions that in the opinion of the investigator may compromise the conduct or analysis of the rectal compartment sampling (e.g., active rectal compartment infection, lesions or disease).
• Inability to abstain from the use of intrarectal products (e.g., suppositories, lubricants) for 72 hours prior to the rectal compartment sample collection visits and for up to 72 hours after.
• Inability to abstain from any receptive anal sexual activity (e.g., anal receptive intercourse and penetration of the rectum by fingers, sex toys or other) for 72 hours prior to the rectal compartment sample collection visit and for up to 72 hours after.