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Intracellular Penetration of Atazanavir, Ritonavir and Dolutegravir With Concomitant Rifampicin: A Dose Escalation
Amedeo De Nicolò1, Alice Palermiti1, Henry Mugerwa2
1Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, Italy.
Clinical Pharmacology and Therapeutics
|February 1, 2025
Summary
Increasing the dose of ritonavir-boosted atazanavir effectively compensates for reduced drug levels caused by rifampicin, even within cells. This strategy restores therapeutic drug concentrations, supporting its use in patients with HIV and tuberculosis.
Area of Science:
- Pharmacology
- Infectious Diseases
- Drug Interactions
Background:
- Ritonavir-boosted atazanavir (ATV/r) is used for HIV treatment.
- Rifampicin, a tuberculosis drug, significantly reduces ATV/r plasma concentrations.
- Intracellular drug penetration of ATV/r during rifampicin co-administration was previously unexplored.
Purpose of the Study:
- To investigate the intracellular penetration of atazanavir/ritonavir and dolutegravir into peripheral blood mononuclear cells (PBMCs).
- To evaluate the efficacy of ATV/r dose escalation in compensating for rifampicin-induced drug reduction at the intracellular level.
Main Methods:
- A sub-study involving 26 virologically suppressed people with HIV on ATV/r regimens.
- Four sequential periods involving different doses of ATV/r, rifampicin, and dolutegravir.
- Quantification of atazanavir, ritonavir, and dolutegravir in plasma and PBMCs using LC-MS/MS.
Main Results:
- Dose escalation of ATV/r successfully restored intracellular concentrations to levels comparable to those without rifampicin.
- Intracellular dolutegravir concentrations increased significantly with ATV/r dose escalation, mirroring plasma levels.
- Increasing the rifampicin dose further did not impact ATV/r concentrations in PBMCs.
Conclusions:
- Increased ATV/r dosage is an effective strategy to counteract rifampicin's effect on intracellular drug exposure.
- This approach supports the clinical use of ATV/r dose escalation in patients co-infected with HIV and tuberculosis.
- Maintaining adequate intracellular drug levels is crucial for treatment efficacy.
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