Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.

Viral entry and egress are important determinants of virus infectivity and pathogenicity. β-Coronaviruses, including the COVID-19 virus SARS-CoV-2 and MHV, exploit the lysosomal exocytosis pathway for egress. Here we show that SARS-CoV-2 ORF3a, but not SARS-CoV ORF3a, promotes lysosomal exocytosis. SARS-CoV-2 ORF3a facilitates lysosomal targeting of the BORC-ARL8b complex, which mediates trafficking of lysosomes to the vicinity of the plasma membrane, and exocytosis-related SNARE proteins. The Ca 2+ channel TRPML3 is required for SARS-CoV-2 ORF3a-mediatd lysosomal exocytosis. Expression of SARS-CoV-2 ORF3a greatly elevates extracellular viral release in cells infected with the coronavirus MHV-A59 which itself lacks ORF3a. In SARS-CoV-2 ORF3a, Ser171 and Trp193 are critical for promoting lysosomal exocytosis and blocking autophagy. When these residues are introduced into SARS-CoV ORF3a, it acquires the ability to promote lysosomal exocytosis and inhibit autophagy. Our results reveal a mechanism by which SARS-CoV-2 interacts with host factors to promote its extracellular egress.