Safety, Virology, Pharmacokinetics, and Clinical Experience of High-Dose Intravenous Sotrovimab for the Treatment of Mild to Moderate COVID-19: An Open-Label Clinical Trial.

Background: Five hundred milligrams of intravenous (IV) sotrovimab has been shown to be well tolerated and efficacious against pre-Omicron strains in treating patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk for disease progression. Methods: This was an open-label, single-arm substudy of phase 3 COMET-TAIL (NCT04913675) assessing the safety and tolerability of a 2000 mg IV dose of sotrovimab. Symptomatic patients (aged ≥18 years) with COVID-19 at high risk for progression were enrolled from June 30 through July 11, 2022, when Omicron BA.5, BA.2.12.1, and BA.4 were the predominant circulating variants in the United States. The primary end point was the occurrence of adverse events (AEs), serious AEs (SAEs), AEs of special interest, and COVID-19 disease-related events (DREs) through day 8. Safety, pharmacokinetics, viral load, and hospitalization >24 hours for acute management of illness or death through day 29 were assessed. Results: All participants (n = 81) were Hispanic, 58% were female, and 51% were aged ≥55 years. Through day 8, no AEs, including infusion-related reactions or hypersensitivity, were reported; 2 participants reported DREs (mild cough, n = 2). One SAE (acute myocardial infarction), which was considered unrelated to sotrovimab or COVID-19 by the investigator, occurred on day 27 and was the only hospitalization reported. Maximum serum concentration (geometric mean) was 745.9 µg/mL. Viral load decreased from baseline through day 29; only 2 (3%) participants had a persistently high viral load (≥4.1 log10 copies/mL) at day 8. Conclusions: Two thousand milligrams of IV sotrovimab was well tolerated, with no safety signals observed. Trial registration: ClinicalTrials.gov Identifier: NCT04913675.

Population pharmacokinetics and exposure-response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID-19.

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two-compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across severe acute respiratory syndrome-coronavirus 2 variants.

Correction to: Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.

In the original article the authors failed to include the following footnote.

Longitudinal Impacts of Gastric Bypass Surgery on Pharmacodynamics and Pharmacokinetics of Statins.

PURPOSE: Undergoing Roux-en-Y gastric bypass (RYGB) is expected to affect orally administered drug absorption. Statins are commonly prescribed to patients with obesity for the prevention of atherosclerotic cardiovascular diseases by lowering cholesterol. This is the first longitudinal prospective study on impacts of RYGB on weight loss, pharmacodynamics, and pharmacokinetics of atorvastatin, rosuvastatin, and simvastatin, and their active metabolites, up to 1-year post-surgery. METHODS: Forty-six patients were recruited, five patients on atorvastatin, twelve on rosuvastatin, nine on simvastatin, and twenty on no statin. The concentrations of atorvastatin, rosuvastatin, and simvastatin with their active metabolites were monitored. RESULTS: Mean plasma concentrations of atorvastatin and metabolites and rosuvastatin normalized by the unit dose [(nM)/(mg/kg)] decreased by 3- to 6-month post-surgery. Conversely, simvastatin and its metabolite concentrations increased up to 6-month post-surgery, then declined to preoperative levels by 1-year post-surgery. The metabolisms of atorvastatin to hydroxyl-metabolites and simvastatin to simvastatin acid were decreased after RYGB. The weight loss and PD outcomes were comparable between statin and non-statin groups suggesting the key impacts were from RYGB. The discontinuation or reduction of dose of atorvastatin or rosuvastatin post-RYGB exhibited rebounds of LDL levels in some subjects, but the rebound was not apparent with patients on simvastatin pre-surgery. CONCLUSION: Discontinuations of statin dosing post-RYGB require LDL monitoring and reducing the dose to half seems to have better results. Patients on statin treatment post-RYGB should be followed-up closely based on our pharmacokinetic findings, to ensure therapeutic effects of the treatment with minimal adverse effects.

Simultaneous LC-MS/MS analysis of simvastatin, atorvastatin, rosuvastatin and their active metabolites for plasma samples of obese patients underwent gastric bypass surgery.

Statins, HMG-CoA reductase inhibitors, are considered the first line treatment of hyperlipidemia to reduce the risk of atherosclerotic cardiovascular diseases. The prevalence of hyperlipidemia and the risk of atherosclerotic cardiovascular diseases are higher in obese patients. Published methods for the quantification of statins and their active metabolites did not test for matrix effect of or validate the method in hyperlipidemic plasma. A sensitive, specific, accurate, and reliable LC-MS/MS method for the simultaneous quantification of simvastatin (SMV), active metabolite of simvastatin acid (SMV-A), atorvastatin (ATV), active metabolites of 2-hydroxy atorvastatin (2-OH-ATV), 4-hydroxy atorvastatin (4-OH-ATV), and rosuvastatin (RSV) was developed and validated in plasma with low (52-103 mg/dl, <300 mg/dl) and high (352-403 mg/dl, >300 mg/dl) levels of triglyceride. The column used in this method was ACQUITY UPLC BEH C18 column (2.1 × 100 mm I.D., 1.7 µm). A gradient elution of mobile phase A (10 mM ammonium formate and 0.04% formic acid in water) and mobile phase B (acetonitrile) was used with a flow rate of 0.4 ml/min and run time of 5 min. The transitions of m/z 436.3 → 285.2 for SMV, m/z 437.2 → 303.2 for SMV-A, m/z 559.2 → 440.3 for ATV, m/z 575.4 → 440.3 for 2-OH-ATV and 4-OH-ATV, m/z 482.3 → 258.1 for RSV, and m/z 412.3 → 224.2 for fluvastatin (internal standard, IS) were determined by Selected Reaction Monitoring (SRM) method to detect transitions ions in the positive ion mode. The assay has a linear range of 0.25 (LLOQ) -100 ng/ml for all six analytes. Accuracy (87-114%), precision (3-13%), matrix effect (92-110%), and extraction recovery (88-100%) of the assay were within the 15% acceptable limit of FDA Guidelines in variations for plasma with both low and high triglyceride levels. The method was used successfully for the quantification of SMV, ATV, RSV, and their active metabolites in human plasma samples collected for an ongoing clinical pharmacokinetic and pharmacodynamic study on patients prior to and post gastric bypass surgery (GBS).