Postoperative nausea and vomiting (PONV) remains a significant clinical issue that can detract from patients' quality of life in hospital/treatment facility, as well as in the days immediately postdischarge. In addition, PONV may increase perioperative costs, increase perioperative morbidity, increase postanesthesia care unit stay, prolong hospital stays, length of stay/delay discharge, delay the time that the patient can go back to work, and lead to readmissions. Despite the existence of multiple tools to stratify patients according to their risk of developing PONV and multiple PONV treatment guidelines, clinicians do not appear to systematically address the treatment and/or prophylaxis of PONV in a uniform fashion with both pharmacologic and nonpharmacologic strategies in attempts to minimize PONV occurrences.
While unicompartmental knee arthroplasty (UKA) and osteotomy procedures are commonly used to treat knee osteoarthritis, the differences in complication profiles between procedures are still poorly understood.
Odronextamab is a fully-human IgG4-based CD20xCD3 bispecific antibody that binds to CD3 on T cells and CD20 on B cells, triggering T-cell-mediated cytotoxicity independent of T-cell-receptor recognition. Adequate safety, tolerability, and encouraging durable complete responses have been observed in an ongoing first-in-human (FIH) study of odronextamab in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT02290951). We retrospectively evaluated the pharmacokinetic, pharmacodynamic, and antitumor characteristics of odronextamab in a series of in vitro/in vivo preclinical experiments, to assess their translational value to inform dose escalation for the FIH study. Half-maximal effective concentration values from in vitro cytokine release assays (range: 0.05-0.08 mg/L) provided a reasonable estimate of odronextamab concentrations in patients associated with cytokine release at a 0.5 mg dose (maximum serum concentration: 0.081 mg/L) on week 1/day 1, which could therefore be used to determine the week 1 clinical dose. Odronextamab concentrations resulting in 100% inhibition of tumor growth in a Raji xenograft tumor mouse model (1-10 mg/L) were useful to predict efficacious concentrations in patients and inform dose-escalation strategy. Although predicted human pharmacokinetic parameters derived from monkey data overestimated projected odronextamab exposure, they provided a conservative estimate for FIH starting doses. With step-up dosing, the highest-tested weekly odronextamab dose in patients (320 mg) exceeded the 1 mg/kg single dose in monkeys without step-up dosing. In conclusion, combination of odronextamab in vitro cytokine data, efficacious concentration data from mouse tumor models, and pharmacokinetic evaluations in monkeys has translational value to inform odronextamab FIH study design in patients with R/R B-NHL.
