Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption

Willmann, Stefan; Edginton, Andrea N.; Kleine-Besten, Marcus; Jantratid, Ekarat; Thelen, Kirstin; Dressman, Jennifer B.

doi:10.1211/jpp/61.07.0008

Cited by 7 publications

(12 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, the majority of the aforementioned models can incorporate some of the physiological factors known to affect the drug's regional absorption. Remarkable progress has been made in the field of solubility and dissolution, where factors such as the pH-dependent solubility for ionisable compounds, variable GI fluid volumes, supersaturation and precipitation, presence of bile micelles and bile salt-mediated solubility enhancement, to name a few, have already been incorporated in these models (6,7,(26)(27)(28)(29)(30). Nevertheless, in terms of regional intestinal membrane permeability (once the intraluminal and intracellular processes have been accounted for), there is a need for improvements (6)(7)(8)26,28).…”

Section: Introductionmentioning

confidence: 99%

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

View full text Add to dashboard Cite

Abstract. Regional intestinal effective permeability (P eff ) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P eff values. These new intestinal P eff values or Bintrinsic^P eff (P eff,int ) were subsequently employed for the prediction of the ileal absorption clearance (CL abs,ileum ) for a set of structurally diverse compounds. Additionally, the method was combined with a semimechanistic absorption PBPK model for the prediction of the fraction absorbed (f abs ). The results showed that P eff,int can successfully be employed for the prediction of the ileal CL abs and the f abs . P eff,int also showed to be a robust predictor of the f abs when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f abs observed for lowly permeable compounds when using the historical P eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.KEY WORDS: intestinal permeability; oral drug absorption; physiologically based pharmacokinetic modelling.

show abstract

Section: Introductionmentioning

confidence: 99%

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

View full text Add to dashboard Cite

show abstract

“…For humans, the database for anatomical and physiological parameters allows the individualization of the virtual human depending on his ethnicity, gender, age, body weight, and height (Willmann et al, 2007b, 2009a). For pediatric applications metabolization and excretion processes are automatically scaled to children of a given age using prior knowledge about the age-dependence of organ volumes and blood flow rates (growth) as well as the age-dependence of enzyme activities and renal or hepatobiliary excretion capacities (maturation; Edginton et al, 2006a,c).…”

Section: Resultsmentioning

confidence: 99%

“…were varied independent of the metabolizers’ phenotype. The derivation of physiological parameter distributions in virtual populations is detailed in Willmann et al (2007b, 2009a) and implemented in the PK-Pop module of PK-Sim ® . For the population generation the settings were: European population (ICRP), age range between 18 and 40, gender male, and without further restrictions.…”

Section: Methodsmentioning

confidence: 99%

A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

Eißing¹

2011

Front. Physio.

180

144

View full text Add to dashboard Cite

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach.

show abstract

“…PK-Sim® is part of a larger SystemsBiology software platform. PK-Sim® has been able to predict and simulate the pharmacokinetic behaviour of a variety of structurally different drugs [23][24][25][26][27][28][29][30][31][32]. A description of the PBPK model structure implemented in PK-Sim® has been described elsewhere [33].…”

Section: Physiologically-based Pharmacokinetic (Pbpk) Modellingmentioning

confidence: 99%

“…It is well documented that PK-Sim® is able to predict and simulate the pharmacokinetic behaviour of a variety of structurally different drugs [28][29][30][31][32][33][34][35][36][37]. The PBPK model behind PK-Sim® describes 17 organs plus several other containers (arterial and venous blood pool, portal vein, bile, urine, etc), each organ consisting of three to four subcompartments, leading to a total number of >70 compartments that are pre-parameterized according to their physiology [38,39].…”

Section: Figurementioning

confidence: 99%

Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically‐based pharmacokinetic modelling

Weber

Willmann

Bischoff

et al. 2012

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower concentrations of HDL but raising the concentrations of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidaemia. WHAT THIS STUDY ADDS• The study provides information on preclinical pharmacokinetics (PK) and pharmacodynamics (PD) as well as information on physiologically-based pharmacokinetic modelling of a novel inhibitor of CETP, BAY 60-5521, as an approach to support the prediction of a potentially effective dose in humans. AIMSThe purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60-5521, in humans. METHODSA combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60-5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTSThe PBPK approach predicts a greater extent of distribution for BAY 60-5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60-5521 of 51 mg in humans. CONCLUSIONThe approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60-5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study.

show abstract

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption

Abstract: The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Cited by 7 publications

References 34 publications

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically‐based pharmacokinetic modelling

Contact Info

Product

Resources

About