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Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6.
Cojutti, Pier Giorgio; Londero, Angela; Della Siega, Paola; Givone, Filippo; Fabris, Martina; Biasizzo, Jessica; Tascini, Carlo; Pea, Federico.
  • Cojutti PG; Department of Medicine, University of Udine, Udine, Italy.
  • Londero A; Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, ASUFC, P.le S. Maria della Misericordia 3, 33100, Udine, Italy.
  • Della Siega P; Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
  • Givone F; Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
  • Fabris M; Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
  • Biasizzo J; Institute of Clinical Pathology, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
  • Tascini C; Institute of Clinical Pathology, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
  • Pea F; Clinic of Infectious Diseases, Santa Maria della Misericordia University Hospital of Udine, ASUFC, Udine, Italy.
Clin Pharmacokinet ; 59(10): 1251-1260, 2020 10.
Article in English | MEDLINE | ID: covidwho-734040
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 (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.

CONCLUSIONS:

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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / HIV Infections / Interleukin-6 / HIV Protease Inhibitors / Coronavirus Infections / Darunavir Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Journal: Clin Pharmacokinet Year: 2020 Document Type: Article Affiliation country: S40262-020-00933-8

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / HIV Infections / Interleukin-6 / HIV Protease Inhibitors / Coronavirus Infections / Darunavir Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Variants Limits: Adult / Aged / Female / Humans / Male / Middle aged Language: English Journal: Clin Pharmacokinet Year: 2020 Document Type: Article Affiliation country: S40262-020-00933-8