Physiologically-based pharmacokinetic modeling of remdesivir and its metabolites in pregnant women with COVID-19.

Pregnant individuals are at high risk for severe illness from COVID-19, and there is an urgent need to identify safe and effective therapeutics for this population. Remdesivir (RDV) is a SARS-CoV-2 nucleotide analog RNA polymerase inhibitor. Limited RDV pharmacokinetic (PK) and safety data are available for pregnant women receiving RDV. The aims of this study were to translate a previously published nonpregnant adult physiologically based PK (PBPK) model for RDV to pregnancy and evaluate model performance with emerging clinical PK data in pregnant women with COVID-19. The pregnancy model was built in the Open Systems Pharmacology software suite (Version 10) including PK-Sim® and MoBi® with pregnancy-related changes of relevant enzymes applied. PK were predicted in a virtual population of 1000 pregnant subjects, and prediction results were compared with in vivo PK data from the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network  2032 study. The developed PBPK model successfully captured RDV and its metabolites' plasma concentrations during pregnancy. The ratios of prediction versus observation for RDV area under the curve from time 0 to infinity (AUC0-∞ ) and maximum concentration (Cmax ) were 1.61 and 1.17, respectively. For GS-704277, the ratios of predicted versus observed were 0.94 for AUC0-∞ and 1.20 for Cmax . For GS-441524, the ratios of predicted versus observed were 1.03 for AUC0-24 , 1.05 for Cmax , and 1.07 for concentrations at 24 h. All predictions of AUC and Cmax for RDV and its metabolites were within a twofold error range, and about 60% of predictions were within a 10% error range. These findings demonstrate the feasibility of translating PBPK models to pregnant women to potentially guide trial design, clinical decision making, and drug development.

Learning Outcomes in a Live Virtual versus In-Person Curriculum for Medical and Pharmacy Students.

Background: The coronavirus disease (COVID-19) pandemic has been a source of disruption, changing the face of medical education. In response to infection control measures at the University of California, San Diego, the hybrid in-person and recorded preclerkship curriculum was converted to a completely virtual format. The impact of this exclusive virtual teaching platform on the quality of trainee education is unknown. Objective: To determine the efficacy of a virtual course, relative to traditional hybrid in-person and recorded teaching, and to assess the impact of supplementary educational material on knowledge acquisition. Methods: A retrospective observational cohort study was performed to assess an introductory course, held mostly in person in 2019 versus completely virtual in 2020, for first-year medical students and second-year pharmacy students at the University of California, San Diego, School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences. Results: The midterm and final examination scores were similar for the hybrid and virtual courses. There was no association between the hours of recorded lectures watched and final examination scores for either course. In the 2019 in-person and recorded course, students who demonstrated consistent on-time use of practice quizzes scored statistically higher on the final examination (P = 0.0066). In the 2020 virtual course, students who downloaded quizzes regularly had statistically higher scores on the midterm examination (P < 0.0001). Conclusion: The similar examination scores for the hybrid in-person and recorded and exclusively virtual courses suggest that the short-term knowledge acquired was equivalent, independent of the modality with which the content was delivered. Consistent on-time use of practice quizzes was associated with higher examination scores. Future studies are needed to assess the difference between a completely in-person versus virtual curriculum.