SSAT067 PK of Atazanavir/Cobicistat and Darunavir/Cobicistat

Protocol Number: SSAT067

EudraCT Number: 2015-002956-28

Name of Investigational Product: Evotaz®, Rezolsta®

Name of active ingredients: Atazanavir, darunavir and cobicistat

Study title: Steady-state Pharmacokinetics of Atazanavir/Cobicistat and Darunavir/Cobicistat Once Daily Over 72 Hours in Healthy Volunteers

Phase of study: Phase I

Objectives:

Primary:

-To assess the steady-state pharmacokinetics of atazanavir/cobicistat and darunavir/cobicistat over 72 hours, in HIV negative healthy volunteers.

Secondary:

• To assess the inter subject variability in atazanavir, darunavir and cobicistat plasma concentrations over 72 hours
• To assess the safety and tolerability of atazanavir/cobicistat and darunavir/cobicistat over 10 days of administration to healthy volunteers
• To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure

Study design: 33 days (excluding screening and follow up), open label, pharmacokinetic study.

Indication: Not applicable

Methodology: Measurements of steady state pharmacokinetic profiles of plasma atazanavir/cobicistat and darunavir/cobicistat in male and female healthy volunteers.

Planned sample size: Up to 30 male and female healthy volunteers will be enrolled at baseline in order to achieve 16 completing the study

Summary of eligibility criteria: Healthy participants as determined by medical history, physical examination, 12-lead electrocardiogram, and clinical laboratory evaluations will be eligible to participate in the study. Women of childbearing potential must not be nursing or pregnant. Women of childbearing potential must have a negative pregnancy test at screening.

Number of study centres: One

Duration of treatment: 33 days (excluding screening and follow up visits)

Dose and route of administration: All participants will be administered Evotaz®) (atazanavir 300mg + cobicistat 150mg) once daily for 10 days, undergo a ten-day wash out period and then take Rezolsta® (darunavir 800mg + cobicistat 150mg) once daily for 10 days.

Criteria for evaluation:

• Pharmacokinetic parameters of atazanavir/cobicistat will be evaluated on blood drawn on day 10 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours post dose and days 11 to 13 (up to 72 hours post dose).
• Pharmacokinetic parameters of darunavir/cobicistat will be evaluated on blood drawn on day 30 at 0 (pre-dose), 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours post dose and days 31 to 33 (up to 72 hours post dose).
• Safety and tolerability of medications will also be assessed by questions, physical examination and laboratory parameters. These will be performed at regular intervals during the drug study.

Primary Endpoint:

-Steady state plasma concentrations of atazanavir/cobicistat and darunavir/cobicistat up to 72 hours post-dose.

Secondary End point:

• Safety and tolerability of the studied drugs over 10 days of administration.
• Relationship between genetic polymorphisms and exposure to the studied drugs.

Inclusion criteria

• The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements
• Male or non-pregnant, non-lactating females
• Between 18 to 65 years, inclusive
• Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive
• ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat is allowed for eligibility determination.
• Women of childbearing potential (WOCBP - definition in Appendix 5) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 4 weeks after the study

A female may be eligible to enter and participate in the study if she:

• is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
• is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:

• Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 4 weeks after discontinuation of all study medications;
• Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
• Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see protocol appendix 5 for an example listing of approved IUDs);
• Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject;
• Approved hormonal contraception (see protocol appendix 5 for a listing of examples of approved hormonal contraception) plus male condom;
• Any other method with published data showing that the expected failure rate is <1% per year.
• Any contraception method must be used consistently, in accordance with the approved product label and for at least 4 weeks after discontinuation of IP.
• Men who have partners who are women of childbearing potential (WOCBP - definition in Appendix 5) must be using an adequate method of contraception to avoid pregnancy in their partner throughout the study and for a period of at least 4 weeks after the study (see inclusion criteria 6)
• Willing to consent to their personal details being entered onto the TOPS database
• Willing to provide proof of identity by photographic ID at screen and any subsequent visit
• Registered with a GP in the UK

Exclusion criteria

• Any clinically significant acute or chronic medical illness
• Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations
• Positive blood screen for hepatitis B surface antigen or C antibody
• Positive blood screen for HIV-1 or 2 by antibody/antigen assay
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
• History or presence of allergy to darunavir, atazanavir cobicistat or excipients (sodium methyl parahydroxybenzoate, lactulose, Hypromellose Colloidal silicon dioxide, Silicified microcrystalline cellulose Crospovidone, Magnesium stearate, Polyvinyl alcohol- partially hydrolysed, Macrogol 3350,Titanium dioxide, Talc, Iron oxide red, Iron oxide black, Lactose monohydrate, Magnesium stearate, Gelatine Yellow iron oxide, Indigocarmin (E132), White ink, Shellac,Titanium dioxide (E171), Ammonium hydroxide, Propylene glycol , Simethicone, Hypromellose, Polyvinyl alcohol- partially hydrolysed, Macrogol 3350)
• Current or recent (within 3 months) gastrointestinal disease
• Known intolerance of lactose monohydrate, sunset yellow aluminium lake (E110), and patients with galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption
• Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study
• Exposure to any investigational drug (or placebo) or participation in a clinical study involving the donation of blood samples within 3 months of first dose of study drug
• Use of any other drugs (unless approved by the Investigator), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.
• Females of childbearing potential without the use of effective non-hormonal birth control methods, or not willing to continue practising these birth control methods for at least 4 weeks after the end of the treatment period