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Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

ABSTRACT: BACKGROUND:The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100?mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000-8000?ng/mL. A trend towards a 28?day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir. OBJECTIVES:To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonavir. PATIENTS AND METHODS:Mechanically ventilated patients with COVID-19 infection included in the French COVID-19 cohort and treated with lopinavir/ritonavir were included. Lopinavir/ritonavir combination was administered using the usual adult HIV dose regimen (400/100?mg q12h, oral solution through a nasogastric tube). A half-dose reduction to 400/100?mg q24h was proposed if lopinavir Ctrough was >8000?ng/mL, the upper limit considered as toxic and reported in HIV-infected patients. Lopinavir and ritonavir pharmacokinetic parameters were determined after an intensive pharmacokinetic analysis. Biological markers of inflammation and liver/kidney function were monitored. RESULTS:Plasma concentrations of lopinavir and ritonavir were first assessed in eight patients treated with lopinavir/ritonavir. Median (IQR) lopinavir Ctrough reached 27?908?ng/mL (15?928-32?627). After the dose reduction to 400/100?mg q24h, lopinavir/ritonavir pharmacokinetic parameters were assessed in nine patients. Lopinavir Ctrough decreased to 22?974?ng/mL (21?394-32?735). CONCLUSIONS:In mechanically ventilated patients with severe COVID-19 infections, the oral administration of lopinavir/ritonavir elicited plasma exposure of lopinavir more than 6-fold the upper usual expected range. However, it remains difficult to safely recommend its dose reduction without compromising the benefit of the antiviral strategy, and careful pharmacokinetic and toxicity monitoring are needed.

SUBMITTER: Le MP

PROVIDER: S-EPMC7454557 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

Lê Minh Patrick MP Jaquet Pierre P Patrier Juliette J Wicky Paul-Henri PH Le Hingrat Quentin Q Veyrier Marc M Kauv Juliette J Sonneville Romain R Visseaux Benoit B Laouénan Cédric C Bouadma Lila L Descamps Diane D de Montmollin Etienne E Peytavin Gilles G Timsit Jean-François JF

The Journal of antimicrobial chemotherapy 20200901 9

<h4>Background</h4>The combination lopinavir/ritonavir is recommended to treat HIV-infected patients at the dose regimen of 400/100 mg q12h, oral route. The usual lopinavir trough plasma concentrations are 3000-8000 ng/mL. A trend towards a 28 day mortality reduction was observed in COVID-19-infected patients treated with lopinavir/ritonavir.<h4>Objectives</h4>To assess the plasma concentrations of lopinavir and ritonavir in patients with severe COVID-19 infection and receiving lopinavir/ritonav ...[more]

PMID: 32688374

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Project description:PurposeWhile fever may be a presenting symptom of COVID-19, fever at hospital admission has not been identified as a predictor of mortality. However, hyperthermia during critical illness among ventilated COVID-19 patients in the ICU has not yet been studied. We sought to determine mortality predictors among ventilated COVID-19 ICU patients and we hypothesized that fever in the ICU is predictive of mortality.Materials and methodsWe conducted a retrospective cohort study of 103 ventilated COVID-19 patients admitted to the ICU between March 14 and May 27, 2020. Final follow-up was June 5, 2020. Patients discharged from the ICU or who died were included. Patients still admitted to the ICU at final follow-up were excluded.Results103 patients were included, 40 survived and 63(61.1%) died. Deceased patients were older {66 years[IQR18] vs 62.5[IQR10], (p = 0.0237)}, more often male {48(68%) vs 22(55%), (p = 0.0247)}, had lower initial oxygen saturation {86.0%[IQR18] vs 91.5%[IQR11.5], (p = 0.0060)}, and had lower pH nadir than survivors {7.10[IQR0.2] vs 7.30[IQR0.2] (p < 0.0001)}. Patients had higher peak temperatures during ICU stay as compared to hospital presentation {103.3°F[IQR1.7] vs 100.0°F[IQR3.5], (p < 0.0001)}. Deceased patients had higher peak ICU temperatures than survivors {103.6°F[IQR2.0] vs 102.9°F[IQR1.4], (p = 0.0008)}. Increasing peak temperatures were linearly associated with mortality. Febrile patients who underwent targeted temperature management to achieve normothermia did not have different outcomes than those not actively cooled. Multivariable analysis revealed 60% and 75% higher risk of mortality with peak temperature greater than 103°F and 104°F respectively; it also confirmed hyperthermia, age, male sex, and acidosis to be predictors of mortality.ConclusionsThis is one of the first studies to identify ICU hyperthermia as predictive of mortality in ventilated COVID-19 patients. Additional predictors included male sex, age, and acidosis. With COVID-19 cases increasing, identification of ICU mortality predictors is crucial to improve risk stratification, resource management, and patient outcomes.

Project description:BackgroundBiomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS.MethodsThis prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS.ResultsIn COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001).ConclusionsCOVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

Project description:BackgroundIn most countries, patients receiving mechanical ventilation (MV) are treated in intensive care units (ICUs). However, in some countries, including Japan, many patients on MV are not treated in ICUs. There are insufficient epidemiological data on these patients. Here, we sought to describe the epidemiology of patients on MV in Japan by comparing and contrasting patients on MV treated in ICUs and in non-ICU settings. A preliminary comparison of patient outcomes between ICU and non-ICU patients was a secondary objective.MethodsData on adult patients receiving MV for at least 3 days in ICUs or non-ICU settings from April 2010 through March 2012 were obtained from the Quality Indicator/Improvement Project, a voluntary data-administration project covering more than 400 acute-care hospitals in Japan. We excluded patients with cancer-related diagnoses. Patient demographic data and the critical care provided were compared between groups.ResultsOver the study period, 17,775 patients on MV were treated only in non-ICU settings, whereas 20,516 patients were treated at least once in ICUs (46.4% vs. 53.6%). Average age was higher in non-ICU patients than in ICU patients (72.8 vs. 70.2, P?<?0.001). Mean number of ventilation days was greater in non-ICU patients (11.7 vs. 9.5, P?<?0.001). Hospital mortality was higher in non-ICU patients (41.4% vs. 38.8%, P?<?0.001). Standard critical care (e.g., arterial line placement, enteral nutrition, and stress-ulcer prevention) was provided significantly less often in non-ICU patients. Multivariate analysis showed that ICU admission significantly decreased hospital mortality (adjusted odds ratio 0.713, 95% CI 0.676 to 0.753).ConclusionsA large proportion of Japanese patients on MV were treated in non-ICU settings. Analysis of administrative data indicated preliminarily that hospital mortality rates in these patients were higher in non-ICU settings than in ICUs. Prospective analyses comparing non-ICU and ICU patients on MV by severity scoring are needed.

Dataset Information

Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

Publications

Pharmacokinetics of lopinavir/ritonavir oral solution to treat COVID-19 in mechanically ventilated ICU patients.

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