Avelumab Dose Selection for Clinical Studies in Pediatric Patients with Solid Tumors.

BACKGROUND AND OBJECTIVE: A phase I/II trial evaluated the safety, antitumor activity, and pharmacokinetics of avelumab (anti-PD-L1 antibody) in pediatric patients with refractory/relapsed solid tumors (NCT03451825). This study aimed to inform avelumab dose selection in pediatric populations using population pharmacokinetic modeling and simulations. METHODS: Patients aged < 18 years with refractory/relapsed solid tumors enrolled in phase I received avelumab 10 or 20 mg/kg intravenously every 2 weeks. A pediatric population pharmacokinetic model was developed via the frequentist prior approach. RESULTS: Pharmacokinetic parameters from 21 patients who received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15) were analyzed. Patients had a wide range of weights and ages (medians, 37.3 kg and 12 years). Exposures with 10-mg/kg dosing were lower vs adult dosing, particularly in patients weighing < 40 kg, whereas 20-mg/kg dosing achieved or exceeded adult exposures, irrespective of body weight. A two-compartment linear model with time-varying clearance using body weight as a covariate, with the frequentist prior approach, best described pediatric data. In this model, optimal overlap in exposure with adult data was achieved with 800 mg every 2 weeks for patients aged ≥ 12 years and weighing ≥ 40 kg, and 15 mg/kg every 2 weeks for patients aged < 12 years or weighing < 40 kg. CONCLUSIONS: Based on exposure matching, the recommended doses for further avelumab studies, including combination studies, are 15 mg/kg every 2 weeks for pediatric patients aged < 12 years or weighing < 40 kg and the adult flat dose of 800 mg every 2 weeks for pediatric patients aged ≥ 12 years and weighing ≥ 40 kg. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03451825.

Recovery of rat type II cell surfactant components during primary cell culture.

A culture system designed to maintain the differentiated characteristics of rat type II cells based on protocols used for human fetal lung pneumocytes was investigated. Type II cells were isolated either from adult rats with elastase (adult type II cells) or from young rats (4-11 days postnatal) with collagenase and trypsin (young type II cells) and were incubated with dexamethasone (Dex, 10 nM) and cAMP (0.1 mM). By day 4 of culture with hormone treatment, the mRNA levels in adult type II cells were less than 3% of day 0 values, whereas surfactant protein (SP)-A protein content was 26%. However, young type II cells maintained lamellar bodies and microvilli and secreted phospholipid in response to ATP. SP-A, -B, and -C mRNA levels were elevated to 159, 350, and 39%, respectively, of day 0 values with a synergistic response to Dex and cAMP, whereas SP-A protein content rose to 119%. Surfactant mRNA and protein did not recover in cells cultured without hormones. This cell culture system restored surfactant components in rat type II cells.