ABSTRACT
Background. Classification of MIS-C, COVID-19, and other pediatric inflammatory conditions is challenged by phenotypic overlap and absence of diagnostic laboratory evidence. Due to public health need and based on limited data from early cases, CDC developed a necessarily broad MIS-C surveillance case definition in May 2020. Studies have since shown that some criteria do not distinguish between MIS-C and other conditions and may contribute to misclassification. To inform planned revision to the CDC definition, we evaluated the impact of narrowing these criteria on case inclusion in national MIS-C surveillance. Methods. Of state and local health-department reported cases meeting the current MIS-C case definition as of 04/14/2022, we describe the proportion that met revised criteria under consideration including fever duration, C-reactive protein (CRP) elevation using a defined cutoff, and organ involvement represented by specific criteria. We also evaluated cases identified using potential combinations of revised criteria. Results. Of 8,096 MIS-C cases fulfilling the original case definition, 6,332 (78%) had sufficient data for evaluation of criteria. Of these, 96% had fever for >=2 days and 94% had a CRP >= 3.0 mg/dL (Table 1). Cardiac involvement defined by key features of MIS-C was present in 84% of cases (62% if BNP/proBNP elevation was excluded);43% had shock. Dermatologic, gastrointestinal (GI) and hematologic involvement were present in 75%, 89% and 37% of cases, respectively. Neurologic (excluding headache), renal, and respiratory involvement were present in 16%, 20%, and 63% of cases, respectively. The number of cases with >= 2 of cardiac (without BNP/proBNP elevation), shock, dermatologic, GI, or hematologic involvement was 5,733 (91%). SARS-CoV-2 testing results are shown in Table 2. Conclusion. The CDC MIS-C case definition is intentionally broad. Using national surveillance data, we evaluated case inclusion under narrower criteria, prioritizing features of MIS-C that distinguish it from similar pediatric inflammatory conditions. A surveillance case definition may not capture all cases and is not intended to replace clinical judgment. We plan to assess additional criteria combinations, describe potentially excluded cases, and incorporate findings into a revised definition.
ABSTRACT
Background. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 diseases. Ensitrelvir exhibited an inhibition potency for organic cation transporter 1 (OCT1) and multidrug and toxin extrusion protein 1 (MATE1) in in vitro study and clinical drug-drug interaction (DDI) study is required judging fromDDI guidance.Metformin is widely used for treatment of diabetes, and is a sensitive substrate for OCT1 and MATE1. We evaluated the effect of ensitrelvir on the pharmacokinetics (PK) ofmetformin with physiologically-based pharmacokinetic (PBPK) modeling and simulation and clinical DDI study. Methods. The PBPK model of ensitrelvir was developed based on the physicochemical parameters, in vitro transporter inhibition parameters, and estimated PK parameters for human. DDI simulations between ensitrelvir and metformin were performed. Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK) was used to develop PBPK model and simulate the DDIs. The in vitro 50% inhibitory concentration (IC50) values of each transporter were used as inhibition constant (Ki) for DDI simulations. Based on the PBPK analysis, the clinical DDI study planed. Results. PBPK analysis: As the result of DDI simulation, ensitrelvir increased the area under the curve (AUC) of metformin by 12%. The result suggests that in vivo DDI potency of ensitrelvir via inhibition of OCT1 or MATE1 would be low at a single dose of ensitrelvir 1000 mg. Clinical DDI study: The plasma concentration-time profile of metformin and ensitrelvir were monitored after 96 hours from a single dose of metformin with or without ensitrelvir. Ensitrelvir does not have effect on the PK of metformin (a geometric mean of AUC ratio was 1.02, Japanese healthy subjects, N=14), suggesting no MATE1 and OCT1 inhibition by ensitrelvir at a clinical dose. The PBPK analysis could well predict the clinical DDI study result. Conclusion. The results of PBPK analysis and the clinical DDI study suggest that no OCT1 and MATE1 inhibition by ensitrelvir is in the clinical dose. Therefore, ensitrelvir does not have a clinically meaningful effect on the pharmacokinetic profile of OCT1 and/or MATE1 substrates including metformin.