Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

Abstract

Background Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. Objective The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. Methods 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. Results 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 (V d), 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.

Potential Effects of COVID-19 on Cytochrome P450-Mediated Drug Metabolism and Disposition in Infected Patients

“…The 13 patients of the study had median CRP levels of > 170 U/l [ 57 ]. Another study reported a major difference in the median oral clearance (CL/F) of darunavir between COVID-19 patients with IL-6 > 18 pg/ml, patients with an IL-6 < 18 pg/ml, and HIV patients not infected with SARS-CoV-2 (2.78, 7.24, 9.75 l/h) [ 54 ]. However, no significant difference was observed in CL/F between patients with IL-6 < 18 pg/ml and HIV patients.…”

“…IL-6 was the only factor that was significantly correlated with CL/F. Other factors that were tested included age, body weight, BSA, serum creatinine, ALT, and AST levels, and concomitant hydroxychloroquine administration [ 54 ]. Similarly, plasma lopinavir concentrations were six times higher in COVID-19 patients (median CRP 186 mg/l) compared to HIV patients [ 55 ].…”

“…Except one (darunavir), all the concentrations are indicative of lopinavir levels Patients Medication Concentration Biomarkers Observation Ref. 13 Lopinavir/ritonavir Cmax-Cmin 20–30 mg/l Median CRP > 170 U/l Inflammation was associated with lower CYP concentration [ 57 ] 30 Darunavir CL/F: IL-6 levels > 18 pg/ml: 2.78 l/h ; IL-6 levels < 18 pg/ml: 7.24 l/h (HIV: 9.75 l/h) Median IL-6 31.0 pg/ml (HIV 2.0 pg/ml) IL-6 was the only factor with significant association to oral clearance [ 54 ] 17 Lopinavir/ritonavir AUC: 668,788 ng·h/ml (HIV patients: 113,200 ng·h/ml) Median CRP 186 mg/l Mechanically ventilated patients; positive correlation between CRP vs. lopinavir trough concentration [ 55 ] 92 Lopinavir/ritonavir Cmin level: 26.5 µg/ml CRP > 75 mg/l: 30.7 µg/ml CRP < 75 mg/l: 20.9 µg/ml (HIV patients: 7.1 µg/ml) Median non-ICU CRP 53 mg/l; ICU CRP 89 mg/l Positive correlation between CRP vs. lopinavir trough concentration; tocilizumab lowered trough levels [ 58 ] 12 Lopinavir/ritonavir Cmax: 18,150 ng/ml; Cmin: 18,000 ng/ml (HIV: 5365 ng/ml) Median CRP: 48.9 mg/l Hospitalized patients [ 117 ] 8 Lopinavir/ritonavir Cmin: 13.6 µg/ml (HIV: 7.1 µg/ml) Mean 38.05 mg/l Association of lopinavir Cmin vs. CRP [ 59 ] 21 …”

“…The package insert of the drug indicates that only 10% of the metabolism is mediated by CYP enzymes [53], so it is unclear if the higher PK values are results of renal impairment, infection-related downregulation of the metabolizing enzymes, or perhaps a combination of both. Lopinavir/ritonavir and darunavir are the anti-retroviral medications that are approved to treat HIV and are now being repurposed for SARS-CoV-2 [54][55][56]. As a result, recent PK reports on these antiviral drugs compare their median peak-trough levels in COVID-19 patients with previous studies with HIV-infected individuals.…”

“…It is pertinent to recognize that COVID-19 patients might experience polypharmacy due to the drugs needed to treat the disease and symptoms as well as the agents for comorbidities prevalent in COVID-19 patients [4,7]. Plasma concentrations of COVID-19 drugs such as lopinavir and darunavir are increased in COVID-19 patients [54,57], and this scenario can be extended to other medications as well. It is imperative that additional perspectives be added in the treatment plans of severe COVID-19 patients.…”