Water molecules mediating polar interactions in ligand-protein complexes can substantially contribute to binding affinity and specificity. To account for such water molecules in computer-aided drug design, we performed an extensive search in the Cambridge Structural Database (CSD) to identify the geometrical criteria defining interactions of water molecules with ligand and protein. In addition, with ab initio calculations the propensity of ligand hydration was evaluated. Based on this information, we developed an algorithm (AcquaAlta) to reproduce water molecules bridging polar interactions between ligand and protein moieties. This approach was validated with 20 crystal structures and yielded a match of 76% between experimental and calculated water positions. When water molecules establishing only weak interactions with the protein were neglected, the match could be improved to 88%. Supported by a pharmacophore-based alignment tool, the solvation algorithm was then applied to the docking of oligopeptides to the periplasmic oligopeptide binding protein A (OppA). Calculated waters based on the crystal poses matched an average of 66% of the experimental waters. With water molecules calculated based on the docked ligands, the average match with the experimental waters dropped to 53%.
BackgroundThe iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study.MethodsPatients aged < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data.ResultsA total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 μg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients.ConclusionsThese findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients.Trial registrationNCT02541604.
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