Pharmacokinetics of plasma lopinavir and ritonavir in tuberculosis–HIV co-infected African adult patients also receiving rifabutin 150 or 300 mg three times per week

Abstract

Background: 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. Methods: This 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. Results: The medians LPV C max and T max 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 AUC 0-12 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 C 0 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 AUC 0-12 of RTV in arm A was 12.7 μg h/mL versus 6.6 μg h/ml in arm B (p = 0.313). Conclusion: In 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.

Risk Assessment of Drug‐Induced Long QT Syndrome for Some COVID‐19 Repurposed Drugs

“…Under such conditions, lopinavir reaches about 10 µg/mL (15.9 µM) after an 800 mg dose. For its part, ritonavir has a bioavailability of 85%, and C max of about 11 µg/mL (15.5 µM) are observed after administration of a 600 mg oral dose 29 . Importantly, because of strong CYP3A4 inhibition, major drug‐drug interactions are observed with other CYP3A4 substrates 30–32 …”

Risk assessment of drug-induced Long QT Syndrome for some COVID-19 repurposed drugs

“…For its part, ritonavir has a bioavailability of 85%, and C max of about 11 μg/mL (15.5 μM) are observed after administration of a 600 mg oral dose. 29 Importantly, because of strong CYP3A4 inhibition, major drug-drug interactions are observed with other CYP3A4 substrates. 30-32…”

Potential small‐molecule drugs as available weapons to fight novel coronavirus (2019‐nCoV): A review

“…However, co‐administration with ritonavir (RTV; an inhibitor of the cytochromeP450 3A isoenzyme) inhibits LPV metabolism, significantly increasing plasma concentrations of the drug and affording high and consistent levels of LPV. Thus, a co‐formulation of LPV and RTV (LPV/RTV) has been developed for clinical use 15,16 . For instance, Cao et al conducted a randomized, controlled, open‐label trial involving hospitalized adult patients with confirmed SARS‐CoV‐2 infection.…”