Comparative Population Pharmacokinetics of Darunavir in SARS CoV 2 Patients vs. HIV Patients: The Role of Interleukin 6
Darunavir is an anti HIV protease inhibitor repurposed for SARS CoV 2 treatment. The aim of this study was to assess the population pharmacokinetics of darunavir in SARS CoV 2 patients compared with HIV patients. Two separate models were created by means of a nonlinear mixed effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. A one compartment model well described darunavir concentrations in both groups. In SARS CoV 2 patients (n 30) interleukin (IL) 6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd) respectively; no covariates were identified in HIV patients (n 25) Darunavir CL/F was significantly lower in SARS CoV 2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p 0.001) CART analysis found that an IL 6 level of 18 pg/mL may split the SARS CoV 2 population in patients with low versus high darunavir CL/F (mean standard deviation 3.47 1.90 vs. 8.03 3.24 L/h; proportion of reduction in error 0.46) Median (interquartile range) darunavir CL/F was significantly lower in SARS CoV 2 patients with IL 6 levels 18 pg/mL than in SARS CoV 2 patients with IL 6 levels 18 pg/mL or HIV patients (2.78 [2.16 4.47] vs. 7.24 [5.88 10.38] vs. 9.75 [8.45 13.79] L/h, respectively; p 0.0001) Increasing IL 6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL 6 levels associated with severe SARS CoV 2 disease may downregulate the cytochrome P450 (CYP) 3A4 mediated metabolism of darunavir. This is a proof of concept of SARS CoV 2 disease drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS CoV 2 patients.
Clinical Pharmacokinetics