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Physiologically Based Pharmacokinetic Modeling of Oral Absorption, pH, and Food Effect in Healthy Volunteers to Drive Al...

Published in The AAPS Journal

A physiologically based pharmacokinetic (PBPK) human model for alpelisib, an oral α-specific class I phosphatidylinositol-3-kinase (PI3K) inhibitor, was established to simulate oral absorption and plasma pharmacokinetics of healthy subjects to allow model-informed drug development. The GastroPlus™ model consisted of an advanced absorption gut model...

Cell-to-Medium Concentration Ratio Overshoot in the Uptake of Statins by Human Hepatocytes in Suspension, but Not in Mon...

Published in The AAPS Journal

Suspended human hepatocytes (SHH) have long been used in assessing hepatic drug uptake, while plated human hepatocytes in short-term monolayer culture (PHH) have gained use in recent years. This study aimed to cross-evaluate SHH and PHH in measuring the hepatic uptake mediated by organic anion transporting polypeptide 1Bs (OATP1Bs). We compared the...

Identification and Utilization of Biomarkers to Predict Response to Immune Checkpoint Inhibitors

Published in The AAPS Journal

Immune checkpoint inhibitors (ICPI) have revolutionized cancer therapy and provided clinical benefit to thousands of patients. Despite durable responses in many tumor types, the majority of patients either fail to respond at all or develop resistance to the ICPI. Furthermore, ICPI treatment can be accompanied by serious adverse effects. There is an...

In Vitro to In Vivo Extrapolation of Metabolic Clearance for UGT Substrates Using Short-Term Suspension and Long-Term Co...

Published in The AAPS Journal

The use of micro-patterned co-cultured hepatocytes for human hepatic clearance predictions has previously been demonstrated using drugs metabolized by cytochrome P450 enzymes. The present study evaluates the in vitro to in vivo extrapolation (IVIVE) performance for UDP-glucuronosyltransferase (UGT) substrates. In vitro intrinsic clearances for 13 d...

Bioanalytical Challenges in Support of Complex Modalities of Antibody-Based Therapeutics

Published in The AAPS Journal

Antibody-based therapeutic classes are evolving from monoclonal antibodies to antibody derivatives with complex structures to achieve advanced therapeutic effect. These antibody derivatives may contain multiple functional domains and are often vulnerable to in vivo biotransformation. Understanding the pharmacokinetics of these antibody derivatives ...

Simultaneous Ivabradine Parent-Metabolite PBPK/PD Modelling Using a Bayesian Estimation Method

Published in The AAPS Journal

Ivabradine and its metabolite both demonstrate heart rate–reducing effect (If current inhibitors) and undergo CYP3A4 metabolism. The purpose of this study was to develop a joint parent-metabolite physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model to predict the PK and PD of ivabradine and its metabolite following intravenous (i...

Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuron...

Published in The AAPS Journal

Physiologically based pharmacokinetic (PBPK) modeling is less well established for substrates of UDP-glucuronosyltransferases (UGT) than for cytochrome P450 (CYP) metabolized drugs and more verification of simulations is necessary to increase confidence. To address specific challenges of UGT substrates, we developed PBPK models for four drugs clear...

Are Lessons Learned in Setting Cut Points for Detection of Anti-Drug Antibodies Also Useful in Serology Assays for Robus...

Published in The AAPS Journal

Successful Extrapolation of Paracetamol Exposure from Adults to Infants After Oral Administration of a Pediatric Aqueous...

Published in The AAPS Journal

Extending licensed drug use to the pediatric population has become an essential part of the drug development process. Nonetheless, ethical concerns limit clinical testing in pediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the target pediatric (sub)populations. However, b...

Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokine...

Published in The AAPS Journal

Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This ...