Physiologically based pharmacokinetic model for T84.66: A monoclonal anti-CEA antibody

Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a “target mediated” elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1582–1600, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64917/1/21918_ftp.pd

Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide

Abstract Tirzepatide is a first‐in‐class glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population‐based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well‐described by a two‐compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half‐life of tirzepatide was ~5 days and enabled sustained exposure with once‐weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations

971-P: Renal Impairment Has No Impact on the Clinical Pharmacokinetics of Tirzepatide

Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics (PK) and tolerability of TZP in subjects with renal impairment (with or without T2DM) vs. healthy subjects with normal renal function. Subjects in this single-dose study were categorized by renal impairment defined by baseline estimated glomerular filtration rate (eGFR, MDRD equation): 14 with normal renal function (≥90 mL/min/1.73m2), 8 with mild impairment (60-89 mL/min/1.73m2), 8 with moderate impairment (30-59 mL/min/1.73m2), 7 with severe impairment (&amp;lt;30 mL/min/1.73m2) and 8 with end stage renal disease (ESRD) requiring dialysis. All subjects received a single subcutaneous dose of 5 mg TZP. Blood samples were collected to determine TZP plasma concentrations to estimate PK parameters. Adverse events were monitored to assess safety and tolerability. Log-transformed AUC0-∞, AUC0-tlast, and Cmax were evaluated by analysis of variance and 90% CI of the ratio between groups was estimated. Additionally, relationship between TZP PK parameters and eGFR (MDRD and CKD-EPI) and creatinine clearance (Cockcroft-Gault) was assessed by regression analysis. PK parameters were similar between subjects with severe renal impairment and healthy subjects (geometric LSM ratios [90% CI] of 1.03 [0.836, 1.27], 1.04 [0.841, 1.28] and 1.23 [0.966, 1.56] for AUC∞, AUC0-tlast, and Cmax, respectively). Similar results were observed when comparing the PK parameters of mild, moderate and ESRD groups vs. healthy subjects. There was no statistically significant relationship at the two-sided 10% significance level between exposure and eGFR. No notable differences in safety profiles were observed. There were no clinically relevant effects of renal impairment on TZP PK. Thus, patients with renal impairment treated with tirzepatide may not require dose adjustments. Disclosure S. Urva: None. T. Quinlan: None. J. Landry: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Martin: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company </jats:sec

Meta-analysis on the relationship between everolimus exposure and safety and efficacy.

3099 Background: Data on everolimus exposure–safety and response relationships are available from individual studies. We performed a meta-analysis to assess these relationships using everolimus predose minimum blood concentration (Cmin). Methods: Individual patient data from 5 phase 2 or 3 oncology studies in which steady-state predose pharmacokinetic samples were taken from patients administered everolimus monotherapy 10 mg/day were pooled. In a Cox regression, the times to first grade ≥3 select adverse events (AEs) associated with everolimus and first progression-free survival (PFS) event were related to log-transformed instant or time-averaged Cmin as time-varying covariates stratified by study. Probability of tumor size reduction according to RECIST (yes vs no) was assessed using a generalized linear mixed model fitted with GEE method with log-transformed instant or time-averaged Cmin as covariates and treatment arm as fixed effect. Results: 945 patients were evaluable for efficacy, 938 for safety. Patient characteristics were relatively well balanced across studies. Regardless of whether instant or time-averaged Cmin was used, a 2-fold increase in everolimus exposure increased the risk of grade ≥3 pulmonary, metabolic, and stomatitis events (Table); no increased risk of other grade ≥3 AEs was observed. A 2-fold increase in everolimus exposure increased the likelihood of tumor size reduction; there was a trend of reduced risk of a PFS event (Table). Conclusions: A 2-fold increase in everolimus exposure is associated with a higher probability of tumor size reduction and increased risk of high-grade pulmonary, metabolic, and stomatitis AEs associated with everolimus. [Table: see text] </jats:p