Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations.

Marzolini, Catia; Stader, Felix; Stoeckle, Marcel; Franzeck, Fabian; Egli, Adrian; Bassetti, Stefano; Hollinger, Alexa; Osthoff, Michael; Weisser, Maja; Gebhard, Caroline E; Baettig, Veronika; Geenen, Julia; Khanna, Nina; Tschudin-Sutter, Sarah; Mueller, Daniel; Hirsch, Hans H; Battegay, Manuel; Sendi, Parham (2020). Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations. Antimicrobial agents and chemotherapy, 64(9) American Society for Microbiology 10.1128/AAC.01177-20

[img]
Preview
Text
Antimicrobial Agents and Chemotherapy-2020-Marzolini-AAC.01177-20.full.pdf - Accepted Version
Available under License Publisher holds Copyright.

Download (1MB) | Preview

Background: Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP).Methods: LPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination.Results: The median age of study participants was 59 (range 24-85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4-10) and 8 days (IQR 5-10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9-31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p<0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values.Conclusions: High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases

UniBE Contributor:

Sendi, Parham

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0066-4804

Publisher:

American Society for Microbiology

Language:

English

Submitter:

Parham Sendi

Date Deposited:

17 Aug 2020 12:49

Last Modified:

09 Apr 2021 08:06

Publisher DOI:

10.1128/AAC.01177-20

PubMed ID:

32641296

BORIS DOI:

10.7892/boris.145939

URI:

https://boris.unibe.ch/id/eprint/145939

Actions (login required)

Edit item Edit item
Provide Feedback