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Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N -acetyl-beta- d -glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n  = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n  = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n  = 121), and (iv) healthy volunteers (n  = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations. [ABSTRACT FROM AUTHOR]

PF‐06817024 is a high affinity, humanized antibody that binds interleukin‐33, a proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream type 2 inflammation. This Phase 1, randomized, placebo‐controlled study was conducted in 3 parts to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics of escalating single and limited repeat PF‐06817024 doses in healthy participants (Part 1), a single dose of PF‐06817024 in participants with chronic rhinosinusitis with nasal polyps (Part 2), and repeat doses of PF‐06817024 in participants with moderate to severe atopic dermatitis (atoptic dermatitis; Part 3). PF‐06817024 was generally well tolerated in all participant populations. Most participants experienced a treatment‐emergent adverse event (healthy participants, 78.4% and 100%; participants with chronic rhinosinusitis with nasal polyps, 90.9% and 88.9%; and participants with atoptic dermatitis, 60.0% and 62.5% in the PF‐06817024 and placebo groups, respectively). No substantial deviations from dose proportionality were observed for single intravenous doses of 10‐1000 mg, indicating linear PK in healthy participants. Mean terminal half‐life ranged from 83 to 94 days after single intravenous administration in healthy participants and was similar to that observed after administration in the studied patient populations. Incidences of antidrug antibodies in the studied populations were 10.8%, 9.1%, and 5.0% for healthy participants, participants with chronic rhinosinusitis with nasal polyps, and participants with atoptic dermatitis, respectively. In addition, dose‐dependent increases were observed in total serum interleukin‐33 levels of treated participants, indicating target engagement. Overall, the PK and safety profile of PF‐06817024 supports further investigation of the drug as a potential treatment for allergic diseases. [ABSTRACT FROM AUTHOR]

Zimlovisertib (PF‐06650833) is a selective, reversible inhibitor of interleukin‐1 receptor‐associated kinase 4 (IRAK4) with anti‐inflammatory effects. This phase 1, open‐label, fixed‐sequence, two‐period, single‐dose study aimed to evaluate the mass balance and excretion rate of zimlovisertib in healthy male participants using a 14C‐microtracer approach. All six participants received 300 mg 14C‐zimlovisertib with lower radioactivity per mass unit orally in Period A, then unlabeled zimlovisertib 300 mg orally and 14C‐zimlovisertib 135 μg intravenously (IV) in Period B. Study objectives included extent and rate of excretion of 14C‐zimlovisertib, pharmacokinetics, and safety and tolerability of oral and IV zimlovisertib. Total radioactivity recovered in urine and feces was 82.4% ± 6.8% (urine 23.1% ± 12.3%, feces 59.3% ± 9.7%) in Period A. Zimlovisertib was absorbed rapidly following oral administration, with the fraction absorbed estimated to be 44%. Absolute oral bioavailability of the 300‐mg dose was 17.4% (90% confidence interval 14.1%, 21.5%) using the dose‐normalized area under the concentration–time curve from time 0 to infinity. There were no deaths, serious adverse events (AEs), severe AEs, discontinuations or dose reductions due to AEs, and no clinically significant laboratory abnormalities. These results demonstrate that zimlovisertib had low absolute oral bioavailability and low absorption (<50%). [ABSTRACT FROM AUTHOR]

A study was conducted to examine the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on TI1-alpha expression. AT2 cells were determined from Sprague-Dawley rats by elastase disaggregation while total RNA was obtained using the acid phenol-guanidinium-chloroform method. Results indicated that soluble factors and changes in cell shape influence T1-alpha expression in association with AEC phenotypes.

A study was conducted to investigate the influence of epidermal growth factor (EGF) on active Na2+ absorption by alveolar epithelium. Disaggregation was carried out to obtain cells from male Sprague-Dawley rats while total RNA was determined from monolayers using the acid phenol-guanidinium-chloroform technique. Results indicated that EGF supports active Na+ resorption across alveolar epithelial cell monolayers.

Research was conducted to study the effects of keratinocyte growth factor on alveolar epithelial cell active ion transport and on rat epithelial Na channel subunit and Na+-K+-adenosinetriphosphatase subunit isoform expression. Alveolar type II cells were determined from adult male Sprague-Dawley rats. Results suggested that the upregulation of either Na pump and chanel activities may result in a net increase in transepithelial Na transport.

Primary cultures of rat alveolar epithelial cells (AEC) and lung membranes were analyzed by immunochemical techniques to determine the presence of glycosylated Na2+ -K+ -adenosine triphosphatase (ATPase) beta-subunits. Immunochemical analysis of rat AEC cultures and rat lung, brain and kidney membranes indicated the presence of Na2+ -K+ -ATPase beta subunits in brain and kidney membranes. However, the Na2+ -K+ -ATPase in rat lung and AEC was detectable only by deglycosylation instead of standard Western blotting.

Epidermal growth factor (EGF) is involved in the regulation of cell permeability to water and solutes in the alveolar epithelium. EGF receptors in the basolateral side of these epithelial cells respond to EGF treatment by reducing tight junctional permeability while stimulating active transport of sodium ions. Sodium enters the cell through apical sodium channels and leaves through basolateral sodium pumps. The EGF receptor inhibitor tyrphostin RG-50864 prevented these effects.

Integrin [[Alpha].sub.3]-subunit expression modulates alveolar epithelial cell monolayer formation. Am J Physiol Lung Cell Mol Physiol 279: L183-L193, 2000.--We investigated expression of the [[Alpha].sub.3]-integrin subunit by rat alveolar epithelial cells (AECs) grown in primary culture as well as the effects of monoclonal antibodies with blocking activity against the [[Alpha].sub.3]-integrin subunit on AEC monolayer formation, [[Alpha].sub.3]-Integrin subunit mRNA and protein were detectable in AECs on day I and increased with time in culture, [[Alpha].sub.3]- and [[Beta].sub.1]-integrin subunits coprecipitated in immunoprecipitation experiments with [[Alpha].sub.3]- and [[Beta].sub.1]-subunit-specific antibodies, consistent with their association as the [[Alpha].sub.3][[Beta].sub.1]-integrin receptor at the cell membrane. Treatment with blocking anti-[[Alpha].sub.3] monoclonal antibody from day 0 delayed development of transepithelial resistance, reduced transepithelial resistance through day 5 compared with that in untreated AECs, and resulted in large subconfluent patches in monolayers viewed by scanning electron microscopy on day 3. These data indicate that [[Alpha].sub.3]- and [[Beta].sub.1]-integrin subunits are expressed in AEC monolayers where they form the heterodimeric [[Alpha].sub.3] [[Beta].sub.1]-integrin receptor at the cell membrane. Blockade of the [[Alpha].sub.3]-integrin subunit inhibits formation of confluent AEC monolayers. We conclude that the [[Alpha].sub.3]-integrin subunit modulates formation of AEC monolayers by virtue of the key role of the [[Alpha].sub.3] [[Beta].sub.1]-integrin receptor in AEC adhesion. alveolar epithelium; [[Beta].sub.1]-integrin; cell adhesion; extracellular matrix; transepithelial resistance