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.

BackgroundsRecent experiments suggest that Citrus bergamia extracts could benefit people with dyslipidemia and obesity but this needs to be further validated.MethodsA total of 98 people age-matched older adults (65 years) with elevated blood lipids were enrolled to receive 12-week supplementation of a Citrus bergamia extracts-based formulation (CitriCholess)(n = 48) and placebo (n = 50).ResultsNo group differences were found in baseline bodyweight, body mass index (BMI), blood cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and glucose levels. CitriCholess supplementation resulted in lower levels than placebo in TG (1.83 ± 0.92 vs. 1.95 ± 1.34 mmol/L, P = 0.612), TC (5.14 ± 0.98 vs. 5.44 ± 0.77 mmol/L, P = 0.097), and LDL-C (3.13 ± 0.74 vs. 3.43 ± 0.62 mmol/L, P = 0.032). Compared to placebo, CitriCholess also resulted in greater reductions in body weight (−0.604 ± 0.939 vs. 0.06 ± 0.74 kg, P < 0.01), waist circumferences (−0.60 ± 1.349 cm vs. -0.16 ± 1.503 cm, P < 0.01) and BMI (−0.207 ± 0.357 vs. 0.025 ± 0.274, P < 0.01). Additionally, females had a significantly higher level of HDL-C than males. TC was significantly correlated with LDL-C, and to a less degree, with TG. TG was inversely correlated with HDL-C. Body weight and waist circumference were negatively correlated with HDL-C and positively correlated with glucose.Conclusion12-week supplementation of CitriCholess could benefit lipid metabolism and weight management in old adults with dyslipidemia.

We report pharmacokinetics, pharmacodynamics, and safety of a novel anti‐CD28 domain antibody antagonist (lulizumab pegol) in healthy subjects following single‐ or multiple‐dose administration. A minimal anticipated biological effect level approach was used to select a 0.01 mg starting dose for a single‐ascending‐dose (SAD), double‐blind, first‐in‐human study. Part 1 included 9 intravenous (IV; 0.01‐100 mg) and 3 subcutaneous (SC; 9‐50 mg) doses or placebo. In part 2, a keyhole limpet hemocyanin (KLH) immunization was performed in 16 subjects/panel, who received 1 of 3 IV doses (9‐100 mg) or placebo. In a double‐blind, multiple‐ascending‐dose (MAD) study, subjects received SC lulizumab 6.25 mg every 2 weeks, 12.5 mg weekly, 37.5 mg weekly, or placebo. Among 180 treated subjects, 169 completed the studies. Peak concentrations and areas under the curve from time 0 to infinity increased dose proportionally. Estimated SC bioavailability was 68.2%. Receptor occupancy of approximately ≥80% was maintained for ≥2 weeks at ≥9‐mg doses (SAD) and throughout the dosing interval (MAD). IV doses ≥9 mg inhibited antibody production against KLH for 2 weeks. No significant cytokine or immune cell changes were observed. No immunogenicity responses persisted, and there was no correlation to adverse events. Headache occurred in 21 SAD and 4 MAD subjects receiving lulizumab; in the MAD study 5 lulizumab subjects experienced infections. Lulizumab IV or SC was safe at all doses studied, without evidence of cytokine release.

Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.