ritonavir and Leukemia--Lymphocytic--Chronic--B-Cell

Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on venetoclax disposition and P-gp inhibition by venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic venetoclax doses and to explore various clinical dosing strategies that maintain venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that venetoclax dose reductions of at least 75% are needed when venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Female; Healthy Volunteers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Biological; Ritonavir; Sulfonamides

Patients with chronic lymphoid leukemia (CLL), even in the Omicron era and after vaccination, suffer from persistent COVID-19 infection, higher complications, and mortality compared with the general population. In this study, we evaluated retrospectively the effectiveness of nirmatrelvir + ritonavir among 1080 patients with CLL who were infected with severe acute respiratory syndrome coronavirus 2. Nirmatrelvir administration was associated with a reduction in COVID-19-related hospitalization or death by day 35. Specifically, the rate of COVID-19-related hospitalization or death in the treated group compared with the untreated group was 4.8% (14 out of 292) vs 10.2% (75 out of 733), respectively. Moreover, we report a 69% relative risk reduction in COVID-19-related hospitalization or death in patients with CLL at the age of ≥65 years. Multivariate analysis indicates that patients aged >65 years, patients who received heavy treatment (>2 previous treatments), patients with recent hospitalizations, intravenous immunoglobulin (IVIG) treatment, and comorbidity had significant improvement outcomes after treatment with nirmatrelvir.

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retrospective Studies; Ritonavir

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Ritonavir; SARS-CoV-2

Topics: COVID-19; COVID-19 Drug Treatment; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Ritonavir

Chronic lymphocytic leukemia (CLL) remains fatal due to the development of resistance to existing therapies. Targeting abnormal glucose metabolism sensitizes various cancer cells to chemotherapy and/or elicits toxicity. Examination of glucose dependency in CLL demonstrated variable sensitivity to glucose deprivation. Further evaluation of metabolic dependencies of CLL cells resistant to glucose deprivation revealed increased engagement of fatty acid oxidation upon glucose withdrawal. Investigation of glucose transporter expression in CLL reveals up-regulation of glucose transporter GLUT4. Treatment of CLL cells with human immunodeficiency (HIV) protease inhibitor ritonavir, which inhibits GLUT4, elicits toxicity similar to that elicited upon glucose deprivation. CLL cells resistant to ritonavir are sensitized by co-treatment with metformin, potentially targeting compensatory mitochondrial complex 1 activity. Ritonavir and metformin have been administered in humans for the treatment of diabetes in patients with HIV, demonstrating the tolerance to this combination in humans. Our studies strongly substantiate further investigation of Food and Drug Administration approved ritonavir and metformin for CLL.

Topics: Aged; Cell Survival; Cells, Cultured; Drug Synergism; Energy Metabolism; Female; Glucose; Glucose Transporter Type 4; HIV Protease Inhibitors; Humans; Hypoglycemic Agents; Immunoblotting; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Metformin; Microscopy, Fluorescence; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Oxidative Phosphorylation; Ritonavir; Tumor Cells, Cultured