The Pharmacokinetics of Dolutegravir, Darunavir/Cobocistat When Co-administered in Healthy Volunteers

NCT03094507 | Completed Phase 1

• 1 other identifier: SSAT073
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to look at the levels of three HIV medications: dolutegravir, darunavir and cobicistat in the blood after drug intake has been stopped, in order to understand how long these drugs persist in the blood. The study will specifically look at blood levels of these three drugs after taking them every day for 14 days. There will be two groups. Participants in Group 1 will take dolutegravir everyday for 14 days, then nothing for 7 days, then dolutegravir and darunavir/cobicistat together for 14 days, nothing for 7 days, and then darunavir/cobicistat alone for 14 days. If participants go into Group 2 they will begin with darunavir/cobicistat everyday for 14 days, then nothing for 7 days, then dolutegravir and darunavir/cobicistat together for 14 days, nothing for 7 days, and then dolutegravir alone for 14 days. Drug levels for both groups will be measured on days 14, 35 and 56. If the participants decide to take part, the duration of the study will be up to 57 days plus a screening visit which will take place up to 28 days prior to the start of the study, and a follow up visit, which takes place 15 to 22 days after the last dose of study medication. Eligible participants will be randomized (1:1 ratio) to group 1 or group 2. Participants and the study doctor will know which study medications the participant is taking at all times during the study.

Conditions

HIV

Outcome Measures

Primary Outcomes (5)

• Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Cthrough

  Trough concentration (Ctrough) is defined as the concentration at 24 hours after the observed drug dose

  8 weeks

• Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Cmax

  Cmax defined as the maximum observed plasma concentration.

  8 weeks

• Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by t1/2

  t1/2 = Elimination half-life

  8 weeks

• Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Tmax

  Tmax = time point at Cmax

  8 weeks

• Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by total drug exposure

  Total drug exposure is expressed as the area under the plasma concentration-time curve from 0-24 hours after dosing (AUC0-24h)

  8 weeks

Secondary Outcomes (5)

• Assess the safety and tolerability of the studied drugs when co-administered to HIV negative healthy volunteers, assessed by The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events

  10 weeks

• investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by Peak plasma concentration (Cmax)

  8 weeks

• investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by trough concentration (Ctrough)

  8 weeks

• investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by Area under the plasma concentration versus time curve (AUC)

  8 Weeks

• Exploratory: the impact of antiretroviral drugs on platelet function

  8 weeks

Study Arms (2)

Group One

EXPERIMENTAL

Tivicay (Dolutegravir 50 mg) for 14 days OD (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 43-56)

Drug: Tivicay; Drug: Rezolsta

Group Two

EXPERIMENTAL

Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Tivicay (Dolutegravir 50 mg) for 14 days OD (days 43-56)

Drug: Tivicay; Drug: Rezolsta

Interventions

Tivicay DRUG

50 mg once daily

Also known as: Dolutegravir

Group One; Group Two

Rezolsta DRUG

darunavir 800 mg/cobicistat 150 mg once daily

Also known as: darunavir/cobicistat

Group One; Group Two

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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 the study drugs and their components: darunavir, cobicistat, dolutegravir 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) Mannitol (E421) Microcrystalline cellulose Povidone K29/32, Sodium starch glycolate, Sodium stearyl fumarate, Polyvinyl alcohol-partially hydrolyzed, Titanium dioxide (E171), Macrogol Talc Iron oxide yellow (E172)
• Current or recent (within three 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 three 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 four weeks after the end of the treatment period

Sponsors & Collaborators

• St Stephens Aids Trust: lead
• ViiV Healthcare: collaborator

Study Sites (1)

St Stephen's Centre

London, SW10 9NH, United Kingdom

Location

MeSH Terms

Interventions

dolutegravir; cobicistat mixture with darunavir

Study Officials

• Marta Boffito

  St Stephen's AIDS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 3, 2017
• First Posted: March 29, 2017
• Study Start: April 19, 2017
• Primary Completion: January 17, 2018
• Study Completion: March 17, 2018
• Last Updated: May 22, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)