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

• Status: Recruiting
• Trial end date: 2023-08-20
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Liverpool
• Collaborators: European and Developing Countries Clinical Trials Partnership (Funder); Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda; Joint Clinical Research Centre, Kampala, Uganda; University of Cape Town, Cape Town, South Africa; University of Turin, Turin, Italy
• Treatments: Atazanavir Sulfate; Rifampin

Criteria

Inclusion Criteria:

1. Willing and able to provide a signed and dated informed consent

2. HIV positive male or female ≥ 18 years of age

3. 50 - 75kg of weight

4. On ATV/rand 2 nucleos(t)ide reverse transcriptase inhibitor containing ART regimen for at least 6 months

5. Undetectable HIV viral load (<50 copies/ml) at screening PLUS an undetectable VL during the most recent test done between 6 and 12 months prior to screening.

6. A negative pregnancy test for females of child-bearing potential. Should also not be breast feeding.

7. On or willing to use effective contraception for at least 4 weeks prior to enrolment, throughout the study period and at least 4 weeks after end of the study(please see section 10.3 for a detailed definition of effective contraception for this study).

8. Clinically stable with no AIDS defining illness within the past 6 months.

9. A normal chest x-ray

10. Ability and willingness to understand and adhere to the study procedures for the entire study duration.

11. Able to attend for regular study follow-up visits

Exclusion Criteria:

1. Any clinical contraindications to the use of ATV/r, DTG or RIF.

2. Currently receiving treatment for tuberculosis

3. Hepatitis B surface antigen positive or Hepatitis C Antibody positive.

4. Requirement for concomitant medication with known major interactions with study drugs

5. Current participation in another clinical trial or research protocol

6. Symptoms of TB

• weight loss > 2.5% in 4 weeks;

• cough > 2 weeks;

• night sweats> 2 weeks;

• fever > 2 weeks;

7. Clinical or laboratory evidence of any of the following:

• AST/ALT > 1.5 x the upper limit of normal range (ULN)

• AST/ALT > 1.0 x ULN

• > 125 mg/dl fasting serum glucose;

• Serum creatinine ≥ 1.5 X ULN in the absence of dehydration. Or estimated glomerular filtration rate <60mL/min according to Cockcroft-Gault formula for creatinine clearance.

8. Moderate to severe anaemia (Haemoglobin level < 8 g/dL)

9. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history, clinical and/or laboratory results.

10. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.

11. Known chronic underlying disease such as sickle cell disease, diabetes and severe cardiac impairment.

12. Inability to tolerate oral medication, or to drink.

13. Patients taking drugs that are strong inducers of CYP3A4 such as carbamazepine and phenytoin.

14. Known hypersensitivity to any of the agents used in the study

15. Patients with prior herbal medication within one week of screening

16. Use of other investigational drugs within 30 days of enrolment

17. Patients taking medications prohibited by the protocol (see appendix 5)

18. History of substantial use of alcohol that interferes with expected normal activities as determined by the investigator. Additionally, alcohol should be avoided throughout the study period.