Kim has received travel accommodations from and/or had expenses paid by Daiichi Sankyo and Amgen; and D.-W.K.'s institution has received research funding from Alpha Biopharma,

A two‐analyte integrated population pharmacokinetic (PK) model that simultaneously describes concentrations of antibody‐conjugated monomethyl auristatin E (acMMAE) and unconjugated MMAE following repeated administrations of polatuzumab vedotin (pola) was developed based on data from four clinical studies of pola in patients with non‐Hodgkin lymphoma. A two‐compartment model with a nonspecific, time‐dependent linear clearance, a linear time‐dependent exponentially declining clearance, and a Michaelis–Menten clearance provided a good fit of the acMMAE plasma PK profiles. All three acMMAE elimination pathways contributed to the input to the central compartment of unconjugated MMAE, which was also described by a two‐compartment model. Population PK parameters, covariate effects, and interindividual variability of model parameters were estimated. The impact of clinically relevant covariates on PK exposures of each analyte were quantified and reported to support key label claims.

Integrin-beta 1 (ITGB1) is aberrantly overexpressed or downregulated in solid cancers; however, its prognostic value remains controversial. Therefore, we conducted a meta-analysis to explore whether ITGB1 expression is correlated with overall survival (OS) and the clinicopathological characteristics of patients with solid cancers. We systematically searched the PubMed, Embase, and Web of Science databases for eligible studies published up to June 1, 2017. In total, 22 studies involving 3,666 patients were included. A sensitivity analysis was performed to assess the validity and reliability of the pooled OS. Among the 22 studies, 7 focused on lung cancer, 3 focused on colorectal cancer, 6 focused on breast cancer, 3 involved melanoma, and 3 involved pancreatic cancer. The pooled results showed that high ITGB1 expression was significantly associated with worse OS in lung cancer (pooled hazard ratio [HR]=1.78, 95% CI: 1.19–2.65, p<0.05) and breast cancer (pooled HR=1.88, 95% CI: 1.46–2.42, p<0.01). In addition, a significant association was observed between high ITGB1 expression and disease-free survival in breast cancer (pooled HR=1.63, 95% CI: 1.17–2.25, p<0.001) and pancreatic cancer (pooled HR=2.49, 95% CI: 1.35–4.61, p<0.001). However, high ITGB1 expression was not related to OS in colorectal cancer, pancreatic cancer, or melanoma. The pooled HRs used to evaluate the prognostic value of increased ITGB1 expression in lung cancer, breast cancer, and pancreatic cancer were not significantly altered, which indicates that the pooled results were robust. The results of this study indicate that the prognostic value of decreased ITGB1 expression varies among solid cancers.

Therapeutic biologics are often administered based on body size. A previous study has found that fixed dosing performs similarly to body size-based dosing in reducing intersubject variability in drug exposure across the mAbs studied. This study extended this evaluation to other therapeutic proteins and peptides. Eighteen therapeutic proteins and peptides with published population pharmacokinetic (PK) and/or pharmacodynamic (PD) models were selected for dosing approach evaluation. The relationships between body size and drug exposure (and PD end point when available) were evaluated, and simulation studies were conducted to compare the performance of the 2 dosing approaches. The results showed that fixed dosing performed better for 12 of 18 selected biologics in terms of reducing intersubject variability in exposure at both population and individual levels, whereas body size-based dosing performed better for the other 6 molecules. This result is consistent with the findings for mAbs. Therefore, fixed dosing is recommended for first-in-human studies of proteins and peptides along with mAbs. The final dosing approach for phase 3 studies should be determined based on a full assessment of body size effect on PK/PD when data are available and the therapeutic window of the drug.

Although pediatric doses for biotherapeutics are often based on patients' body weight (mg/kg) or body surface area (mg/m2), linear body size dose adjustment is highly empirical. Growth and maturity are also important factors that affect the absorption, distribution, metabolism and excretion (ADME) of biologics in pediatrics. The complexity of the factors involved in pediatric pharmacokinetics lends to the reconsideration of body size based dose adjustment. A proper dosing adjustment for pediatrics should also provide less intersubject variability in the pharmacokinetics and/or pharmacodynamics of the product compared with no dose adjustment. Biological proteins and peptides generally share the same pharmacokinetic principle with small molecules, but the underlying mechanism can be very different. Here, pediatric and adult pharmacokinetic parameters are compared and summarized for selected biotherapeutics. The effect of body size on the pediatric pharmacokinetics for these biological products is discussed in the current review.