Abstract
BackgroundTo evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients.MethodsThis is a pharmacokinetic study conducted in Ouagadougou among patients treated with a standard dosage of LPV/RTV 400/100 mg twice daily and RBT 150 mg TPW (arm A = 9 patients) or rifabutin 300 mg TPW (arm B = 7 patients) based regimens. Patients were recruited from the Bogodogo and Kossodo district hospitals in Ouagadougou from May 2013 to December 2015. Study inclusion criteria were that the patients were between 18 and 60 years of age, HIV-1 infected with pulmonary tuberculosis confirmed or suspected. Subsequent blood samples for pharmacokinetic monitoring were collected at 1, 2, 3, 4, 6, 8 and 12 h after combined drug ingestion for plasma drug monitoring using HPLC/MS assays.ResultsThe medians LPV Cmax and Tmax were respectively, 20 μg/mL and 4 h for the RBT 150 mg group (arm A) and 7.7 μg/mL and 3 h for the RBT 300 mg group (arm B). The AUC0–12 of LPV was 111.8 μg h/mL in patients belonging to arm A versus 69.9 μg/mL for those in arm B (p = 0.313). The C0 of LPV was lower than 4 μg/mL in three patients receiving RBT 300 mg. Of note, the RTV plasma concentrations were nearly halved among patients on RBT 300 mg compared to those on lower RBT doses. The AUC0–12 of RTV in arm A was 12.7 μg h/mL versus 6.6 μg h/ml in arm B (p = 0.313).ConclusionIn our study, the pharmacokinetic of LPV and RTV was found to be highly variable when coadministrated with RBT 150 mg or 300 mg three times per week. There is a need for specific large study to verify clinical and virological effects of this variation, especially when coadministrated with RBT of 300 mg TPW, and to prevent viral resistance in response to under-dosing of LPV.Trial registration PACTR201310000629390. Registered 28 October 2013, http://www.pactr.org/
Highlights
To evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and human immunodeficiency virus (HIV) co-infected adult patients
Rifamycins are potent inducers of the cytochrome P450 pathway, in particular the CYP3A4 isoform, which is involved in the hepatic metabolism of many drugs including proteases inhibitor (PI) leading to a reduction of their plasma concentrations, which may cause HIV treatment failure and favour the development of drug resistance [5,6,7,8,9]
The areas under the plasma concentration–time curve (AUC)0–12 of LPV was 111.8 (IQR: 67.4–150.4) μg h/mL in patients treated with RBT 150 mg versus 69.9 (IQR: 38.4–104.8) μg/mL in those treated with RBT 300 mg thrice weekly (p = 0.313)
Summary
To evaluate the pharmacokinetic of plasma lopinavir (LPV) and ritonavir (RTV) when co-administered with three times weekly (TPW) rifabutin (RBT) at a dose of either 150 or 300 mg in African tuberculosis (TB) and HIV co-infected adult patients. Important drug interactions between rifamycins and protease inhibitors (PIs), such as lopinavir/ritonavir (LPV/RTV), which is still widely used in most resource-constrained settings, represent one of the most critical issues for clinicians [3, 4]. Rifamycins are potent inducers of the cytochrome P450 pathway, in particular the CYP3A4 isoform, which is involved in the hepatic metabolism of many drugs including PIs leading to a reduction of their plasma concentrations, which may cause HIV treatment failure and favour the development of drug resistance [5,6,7,8,9]. PIs are inhibitors of CYP3A and determine the accumulation of rifamycins, causing an increased risk of toxicity [10]
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