ABSTRACT
Hematopoietic cell transplant (HCT) recipients are at increased risk of morbidity and mortality from COVID-19. They may have lower SARS-CoV-2-directed antibody levels due to protein loss from the gastrointestinal (GI) tract as a result of preparative regimen-related toxicity and graft-vs.-host disease (GVHD). In fact, previous studies suggested that GI GVHD or diarrhea from other etiologies were associated with a reduction in the half-life of monoclonal antibodies (mAbs). Hence, understanding the pharmacokinetic (PK) profile of mAbs targeting SARS-CoV-2 in this vulnerable population is critical for dose-selection and predicting the duration of protection against COVID-19. This analysis aims to use a population pharmacokinetics (popPK) approach to evaluate the PK of sotrovimab and the effect of covariates in HCT recipients. In a Phase I trial (COVIDMAB), all participants received 500 mg sotrovimab IV prophylactically within one week prior to starting transplant conditioning. Sotrovimab serum concentrations were determined weekly for up to 12 weeks in autologous (n=5) and allogeneic (n=15) HCT recipients (129 observations). Sotrovimb PK and the effect of covariates were analyzed using popPK modeling in NONMEM (version 7.4). GVHD and diarrhea severity data were collected weekly via survey and included as time-dependent covariates during the covariate screening process. The final PK model with covariates was validated using simulation-based validation and goodness of fit plots. PK data were compared to non-transplant patients from 1891 patients with COVID-19 in COMET-ICE, COMET-PEAK, BLAZE-4, and COMET-TAIL and 38 healthy individuals enrolled in GlaxoSmithKline Pharma Study 217653. A two-compartment model best described sotrovimab PK in HCT recipients. In comparison to non-transplant patients, sotrovimab clearance (CL) was 14.0% higher in HCT recipients. Weight was a significant covariate on sotrovimab CL and (Figure Presented) volume of distribution in the central compartment (V2). With every 10 kg increase in body weight, sotrovimab CL and V2 were estimated to increase by 9.5% and 5.5%, respectively. Diarrhea severity was also a significant covariate on sotrovimab CL. HCT recipients with grade 3 diarrhea showed an increase in CL by 1.5-fold compared to those without diarrhea. Based on popPK analyses, sotrovimab CL was higher in HCT recipients compared to non-transplant patients. Higher bodyweight as well as diarrhea resulted in increased sotrovimab CL. There were only 3 patients with GI GVHD, and larger studies are needed to determine whether diarrhea due to GI GVHD or conditioning toxicity was responsible for the observed increase in sotrovimab CL. Further validation of these findings in a larger number of HCT recipients is also warranted to help optimize mAb dosing for COVID-19 prophylaxis and determine whether presence of large-volume diarrhea may require intensified dosing strategiesCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Severe coronavirus disease 2019 (COVID-19) pneumonia survivors often exhibit long-term pulmonary sequelae, but the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high-dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. We found that chronic lung impairment was accompanied by persistent respiratory immune alterations. We showed that functional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)specific memory T and B cells were enriched at the site of infection compared with those of blood. Detailed evaluation of the lung immune compartment revealed that dysregulated respiratory CD8+ T cell responses were associated with the impaired lung function after acute COVID-19. Single-cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells contributing to persistent tissue conditions after COVID-19. Our results have revealed pathophysiological and immune traits that may support the development of lung sequelae after SARS-CoV-2 pneumonia in older individuals, with implications for the treatment of chronic COVID-19 symptoms.