Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development.

Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.-administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD-1/PD-L1 inhibitor development, (ii) through co-development with i.v. presentations for anti-severe acute respiratory syndrome-coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE-mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab.

Effect of epidural analgesia on cancer outcomes after gastric cancer resection: a single-centre cohort study in Taiwan.

OBJECTIVE: To investigate the influence of epidural anaesthesia and analgesia (EA) on cancer recurrence and overall survival after surgery for gastric cancer. STUDY DESIGN AND SETTING: A retrospective study which involved patients with stage I-III gastric cancer undergoing curative resection in a medical centre from January 2012 to December 2017 and followed up until December 2019 through electronic medical chart review. Patient demographics, anaesthetic and surgical characteristics and pathologic features were also gathered. PRIMARY AND SECONDARY OUTCOME MEASURES: The effects of EA on postoperative cancer recurrence and overall survival were evaluated using proportional hazards regression models with inverse probability of treatment weighting (IPTW). Multivariable Cox regression analyses were conducted for sensitivity analysis as well. RESULTS: Among the 413 patients with median follow-up of 38.5 months (IQR: 22.1-59.7), 66 (16.0%) received EA after gastric cancer surgery. EA was not associated with greater cancer recurrence (IPTW-adjusted HR: 0.55, 95% CI: 0.27 to 1.13, p=0.102) or cancer specific (IPTW- adjusted HR: 0.53, 95% CI: 0.27 to 1.04, p=0.07) and all-cause mortality (IPTW-adjusted HR: 0.65, 95% CI: 0.37 to 1.16, p=0.143) after gastric cancer resections. For sensitivity analysis, multivariable Cox regression analysis also generated non-significant EA effects on cancer recurrence and survival after surgery. CONCLUSIONS: There was no significant association between EA and cancer recurrence or overall survival in patients with stage I-III gastric cancer receiving surgical resection of primary tumour. Prospective study should be considered to elucidate the relationship between EA and cancer outcomes after gastric cancer surgery.

Effect of epidural analgesia on long-term outcomes after curative surgery for pancreatic cancer: A single-center cohort study in Taiwan.

BACKGROUND: Whether epidural anesthesia and analgesia (EA) improves long-term outcomes after pancreatic cancer surgery remains controversial. We conducted this retrospective cohort study to investigate the influence of EA on cancer recurrence and overall survival after surgery for pancreatic cancer. METHODS: We conducted an electronic medical chart review of patients with pancreatic cancer who underwent curative resection at our hospital from 2008 to 2017 and were followed up until December 2019. Patient demographics, anesthetic and surgical characteristics, and pathologic features were also collected. The effects of EA on postoperative cancer recurrence and overall survival were evaluated using proportional hazards regression models with inverse probability of treatment weighting (IPTW) based on propensity scores to balance unequal distributions of observed covariates. For sensitivity analysis, multivariable regression modeling and quintile-stratified propensity adjustments were also used. RESULTS: Among the 252 included patients, the median follow-up period was 15.9 months (interquartile range 6.8-28.2 months), and 88 (35%) received EA after pancreatic cancer surgery. EA was not associated with greater cancer recurrence (IPTW adjusted HR: 0.98; 95% CI, 0.78%-1.24%; p = 0.87) or all-cause mortality (IPTW adjusted HR: 1.02; 95% CI, 0.82%-1.27%; p = 0.85) after pancreatic cancer resection. In sensitivity analysis, both the multivariable and stratified Cox regression analyses failed to demonstrate significant effects of EA on cancer recurrence and survival after surgery. CONCLUSION: There were no significant associations between EA and cancer recurrence and overall survival after curative surgery for pancreatic cancer. Prospective studies should be considered to elucidate the relationship between EA and cancer outcomes after pancreatic cancer surgery.

Assay pH and critical reagent optimization in measuring concentrations of a monoclonal antibody and its target.

Aim: To mitigate assay interference in the drug and target assays to support the development of monoclonal antibody REGN-Z. Results: Mild acidic assay conditions and capture and detection antibodies with different affinities and t1/2 under different assay pHs were used to mitigate interference in the total drug and total target assays. A free target assay was also developed using a lower-affinity capture antibody with a much slower association and dissociation rate. The impact of sample incubation, dilution and storage on the accurate detection of the free target was also evaluated. Conclusion: The total drug, total and free target assays can accurately quantitate drug and target concentrations when tested with a subset of clinical study samples.

The Associations between Perioperative Blood Transfusion and Long-Term Outcomes after Stomach Cancer Surgery.

BACKGROUND: Whether perioperative packed red blood cell (pRBC) transfusion is associated with inferior long-term outcomes after stomach cancer surgery remains controversial. METHODS: This research used a retrospective cohort study. Patients with stage I~III stomach cancer undergoing tumor resection were collected at a tertiary medical center. Patient characteristics, surgical features and pathologic findings were gathered from an electronic medical chart review. The associations of perioperative pRBC transfusion with postoperative disease-free and overall survivals were evaluated using Cox regression analysis with an inverse probability of treatment weighting (IPTW). Restricted cubic spline functions were employed to characterize dose-response relationships between the amount of transfusion and cancer outcomes after surgery. RESULTS: Among the 569 patients, 160 (28.1%) received perioperative pRBC transfusion. Perioperative transfusion was associated with worse disease-free survival (IPTW adjusted HR: 1.42, 95% CI: 1.18-1.71, p < 0.001) and overall survival (IPTW adjusted HR: 1.27, 95% CI: 1.05-1.55, p = 0.014). A non-linear dose-response relationship was noted between the amount of transfusions and worse disease-free or overall survival. CONCLUSIONS: Perioperative pRBC transfusion was associated with worse disease-free and overall survival after stomach cancer surgery, and strategies aiming to minimize perioperative transfusion exposure should be further considered to reduce the potential risk.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

Xeno-free and feeder-free culture and differentiation of human embryonic stem cells on recombinant vitronectin-grafted hydrogels.

Recombinant vitronectin-grafted hydrogels were developed by adjusting surface charge of the hydrogels with grafting of poly-l-lysine for optimal culture of human embryonic stem cells (hESCs) under xeno- and feeder-free culture conditions, with elasticity regulated by crosslinking time (10-30 kPa), in contrast to conventional recombinant vitronectin coating dishes, which have a fixed stiff surface (3 GPa). hESCs proliferated on the hydrogels for over 10 passages and differentiated into the cells derived from three germ layers indicating the maintenance of pluripotency. hESCs on the hydrogels differentiated into cardiomyocytes under xeno-free culture conditions with much higher efficiency (80% of cTnT+ cells) than those on conventional recombinant vitronectin or Matrigel-coating dishes just only after 12 days of induction. It is important to have an optimal design of cell culture biomaterials where biological cues (recombinant vitronectin) and physical cues (optimal elasticity) are combined for high differentiation of hESCs into specific cell lineages, such as cardiomyocytes, under xeno-free and feeder-free culture conditions.

Effects of Rare Earth Metals on Steel Microstructures.

Rare earth metals are used in semiconductors, solar cells and catalysts. This review focuses on the background of oxide metallurgy technologies, the chemical and physical properties of rare earth (RE) metals, the background of oxide metallurgy, the functions of RE metals in steelmaking, and the influences of RE metals on steel microstructures. Future prospects for RE metal applications in steelmaking are also presented.