Pharmacokinetic study of two different rifabutin doses co-administered with lopinavir/ritonavir in African HIV and tuberculosis co-infected adult patients

Henri Gautier Ouedraogo,Paola Villani,Giorgia Sulis,Grissoum Tarnagda,Mario Regazzi,Tegwinde Rebeca Compaoré,Alberto Matteelli,Lassana Sangare,Jacques Simporé,Seni Kouanda,Alberto Roggi,Kadari Cisse,Serge Diagbouga

doi:10.1186/s12879-020-05169-2

Abstract

BackgroundThis study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection.MethodsThis is a two-arm, open-label, pharmacokinetic, randomised study conducted in Burkina Faso between May 2013 and December 2015. Enrolled patients were randomised to receive either 150 mg RBT EOD (arm A, 9 subjects) or 300 mg RBT EOD (arm B, 7 subjects), both associated with LPV/r taken twice daily. RBT plasma concentrations were evaluated after 2 weeks of combined HIV and TB treatment. Samples were collected just before drug ingestion and at 1, 2, 3, 4, 6, 8, and 12 h after drug ingestion to measure plasma drug concentration using an HPLC-MS/MS assay.ResultsThe Cmax and AUC0–12h medians in arm A (Cmax = 296 ng/mL, IQR: 205–45; AUC0–12h = 2528 ng.h/mL, IQR: 1684–2735) were lower than those in arm B (Cmax = 600 ng/mL, IQR: 403–717; AUC0–12h = 4042.5 ng.h/mL, IQR: 3469–5761), with a statistically significant difference in AUC0–12h (p = 0.044) but not in Cmax (p = 0.313). No significant differences were observed in Tmax (3 h versus 4 h). Five patients had a Cmax below the plasma therapeutic limit (< 300 ng/mL) in the 150 mg RBT arm, while the Cmax was above this threshold for all patients in the 300 mg RBT arm. Additionally, at 48 h after drug ingestion, all patients had a mycobacterial minimum inhibitory concentration (MIC) above the limit (> 64 ng/mL) in the 300 mg RBT arm, while 4/9 patients had such values in the 150 mg RBT arm.ConclusionThis study confirmed that the 150 mg dose of rifabutin ingested EOD in combination with LPV/r is inadequate and could lead to selection of rifamycin-resistant mycobacteria.Trial registrationPACTR201310000629390, 28th October 2013.

Highlights

This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/ r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection
The analysis of the pharmacokinetic parameters of d-RBT showed that Maximum concentration (Cmax), AUC0–24 h and Time at which the Cmax is observed (Tmax) were higher for patients in the 300 mg RBT every other day (EOD) group compared to those receiving 150 mg RBT EOD
In our study serial blood samples were withdrawn to characterize accurately Cmax and the AUC0–12h of RBT, and to be able to compare the drug systemic exposure related to the two dosing regimens adopted

Summary

Introduction

This study aimed to assess the pharmacokinetic profile of 150 mg rifabutin (RBT) taken every other day (every 48 h) versus 300 mg RBT taken every other day (E.O.D), both in combination with lopinavir/ritonavir (LPV/ r), in adult patients with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection. Rifamycins (rifampicin, RIF or rifabutin, RBT) represent the core component of conventional anti-TB treatment regimens, even in combination with ART. RBT is a less potent inducer of CYP3A4 compared to RIF [7,8,9,10,11]. It is recommended for prophylaxis and treatment of Mycobacterium avium complex (MAC) as well as for treatment of drug-susceptible TB [11]. The 25-O-desacetyl-rifabutin metabolite contributes up to 10% of the total anti-bacterial activity [12, 13]

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