Dose Escalation Study to Determine the Pharmacokinetics of Atazanavir Administered With RIfampicin to HIV Positive Adults on sEcond-line ART Regimen With Suppressed HIV-1 Viral Load

Summary

The standard treatment for TB consists of rifampicin (RIF) as part of the regimen. However, due to drug-drug interactions (DDI), the bioavailability of PIs is greatly reduced when co-administered with RIF necessitating use of higher doses of the PI to overcome this effect. However, the potential effect of this increased dose on the DDI with bPIs is uncertain. Though some data has been collected that shows safe use of higher doses of LPV to overcome the DDI with standard doses of RIF in HIV-infected individuals, no substantive data has been collected on ATV to correctly adjust its dose when co-administered with RIF-based TB treatment.

Physiologically-based pharmacokinetic (PBPK) modelling was developed to understand ATV and RIF DDIs, and identified potential dosing strategies to overcome this challenge in adults and special populations under workpackage 1 of the VirTUAL consortium. From this work, it is anticipated that the dose of ATV/r should be increased from 300/100 once daily to 300/100mg twice daily in order to overcome the interaction with rifampicin and attain therapeutic plasma concentrations.

This dose escalation trial aims to:

1. Evaluate the steady state plasma and intracellular PK of ATV/r, when administered in adjusted (PBPK model-predicted) doses concurrently with RIF
2. Evaluate the safety and tolerability / acceptability of the adjusted dose of ATV/r that provides the therapeutic concentration when co-administered with RIF.
3. Evaluate the concentration of dolutegravir (DTG) and RIF when co-administered and explore the potential DDI with ATV/r

Conditions

• HIV/AIDS
• Tuberculosis

Interventions

DRUG

Dose escalation

The trial will enrol virologically suppressed HIV infected volunteers who are stable on ATV/r and 2 NRTI containing ART following stringent screening to rule out evidence of renal, hepatic or gastrointestinal dysfunction which may affect the PK evaluation. A steady-state PK (PK1) sample collection shall be done on day 7 (+/-3) after enrolment. RIF will be added at standard dose (600 mg once daily) with a further PK evaluation 14 days later (PK2); due to the potential risk of sub therapeutic PI concentrations and emergence of HIV drug resistant strains, these individuals will be given DTG 50 mg twice daily for the duration of the dose-escalation study. ATV/r dose will be increased in a single step to the total modelled dose (PK3), given as twice daily doses. Once at maximum ATV/r dose, RIF will be increased to 1200 mg once a day for a further seven days (PK4). RIF will then be stopped, ATV/r stepped down to 300/100mg once a day and DTG continued for a further one week.

Sponsors & Collaborators

• European and Developing Countries Clinical Trials Partnership (Funder)

  collaborator UNKNOWN

• Joint Clinical Research Centre, Kampala, Uganda

  collaborator UNKNOWN

• University of Cape Town, Cape Town, South Africa

  collaborator UNKNOWN

• Makerere University

  collaborator OTHER

• University of Turin, Turin, Italy

  collaborator UNKNOWN

• University of Liverpool

  lead OTHER

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-10-30

Primary Completion

2022-05-20

Completion

2023-05-20

Countries

• Uganda

Study Locations