PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach.

The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration-time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0- t ). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first-pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro-input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods.

[1]  T Lavé,et al.  Challenges and opportunities with modelling and simulation in drug discovery and drug development , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[2]  Joerg Keldenich.  Measurement and Prediction of Oral Absorption , 2009, Chemistry & biodiversity.

[3]  Huadong Tang,et al.  A NOVEL MODEL FOR PREDICTION OF HUMAN DRUG CLEARANCE BY ALLOMETRIC SCALING , 2005, Drug Metabolism and Disposition.

[4]  A. S. Hedayat,et al.  A Unified Approach for Assessing Agreement for Continuous and Categorical Data , 2007, Journal of biopharmaceutical statistics.

[5]  Hugues Dolgos,et al.  Early integration of pharmacokinetic and dynamic reasoning is essential for optimal development of lead compounds: strategic considerations. , 2009, Drug discovery today.

[6]  Bill J Smith,et al.  Prediction of Human Pharmacokinetics From Preclinical Information: Comparative Accuracy of Quantitative Prediction Approaches , 2009, Journal of clinical pharmacology.

[7]  L. Berezhkovskiy,et al.  Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination. , 2004, Journal of pharmaceutical sciences.

[8]  Yuichi Sugiyama,et al.  Application of physiologically based pharmacokinetic modeling and clearance concept to drugs showing transporter-mediated distribution and clearance in humans , 2010, Journal of Pharmacokinetics and Pharmacodynamics.

[9]  Patrizia Crivori,et al.  Evaluation of a basic physiologically based pharmacokinetic model for simulating the first-time-in-animal study. , 2007, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[10]  L Zhang,et al.  Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation During Regulatory Review , 2011, Clinical pharmacology and therapeutics.

[11]  L. A. Fenu,et al.  Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs , 2007, Drug Metabolism and Disposition.

[12]  V. Lukacova,et al.  Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects , 2009, The AAPS Journal.

[13]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[14]  Hannah M. Jones,et al.  Modelling and PBPK Simulation in Drug Discovery , 2009, The AAPS Journal.

[15]  Harvey Wong,et al.  Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling , 2010, Drug Metabolism and Disposition.

[16]  Neil Parrott,et al.  Applications of physiologically based absorption models in drug discovery and development. , 2008, Molecular pharmaceutics.

[17]  Leslie Z Benet,et al.  Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. , 2008, Advanced drug delivery reviews.

[18]  Malcolm Rowland,et al.  Physiologically-based pharmacokinetics in drug development and regulatory science. , 2011, Annual review of pharmacology and toxicology.

[19]  A. D. Rodrigues,et al.  Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been? , 2008, Pharmaceutical Research.

[20]  Patrick Poulin,et al.  Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. , 2003, Toxicology letters.

[21]  K. Bischoff,et al.  Interspecies correlation of plasma concentration history of methotrexate (NSC-740). , 1970, Cancer chemotherapy reports.

[22]  Malcolm Rowland,et al.  Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes , 2007, Pharmaceutical Research.

[23]  Yoshitaka Yano,et al.  Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles. , 2004, Journal of pharmaceutical sciences.

[24]  Maurice Dickins,et al.  Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man , 2008 .

[25]  Fahima Nekka,et al.  Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substrates. , 2010, Journal of pharmaceutical sciences.

[26]  Malcolm Rowland,et al.  PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution. , 2011, Journal of pharmaceutical sciences.

[27]  S. Haddad,et al.  Extrapolating in vitro metabolic interactions to isolated perfused liver: predictions of metabolic interactions between R-bufuralol, bunitrolol, and debrisoquine. , 2010, Journal of pharmaceutical sciences.

[28]  Philip A. Arundel,et al.  A Multi-Compartmental Model Generally Applicable to Physiologically-Based Pharmacokinetics , 1997 .

[29]  A. Barve,et al.  Linear Correlation of the Fraction of Oral Dose Absorbed of 64 Drugs Between Humans and Rats , 1998, Pharmaceutical Research.

[30]  Sean Ekins,et al.  A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human. , 2011, Toxicology and applied pharmacology.

[31]  Patrick Poulin,et al.  Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution. , 2002, Journal of pharmaceutical sciences.

[32]  B Agoram,et al.  Predicting the impact of physiological and biochemical processes on oral drug bioavailability. , 2001, Advanced drug delivery reviews.

[33]  F Kesisoglou,et al.  Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling , 2009, Xenobiotica; the fate of foreign compounds in biological systems.

[34]  Sheila Annie Peters,et al.  Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Lineshape Analysis , 2008, Clinical pharmacokinetics.

[35]  R. Obach,et al.  Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[36]  U. Bredberg,et al.  Prediction of drug tissue to plasma concentration ratios using a measured volume of distribution in combination with lipophilicity. , 2008, Journal of pharmaceutical sciences.

[37]  Masoud Jamei,et al.  Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut - the effect of diltiazem on the time-course of exposure to triazolam. , 2010, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[38]  Rhys D O Jones,et al.  PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach. , 2011, Journal of pharmaceutical sciences.

[39]  Kannan Krishnan,et al.  Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures. , 2002, Environmental health perspectives.

[40]  Thierry Lavé,et al.  Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans. , 2003, Journal of pharmaceutical sciences.

[41]  Thomas Peyret,et al.  A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals. , 2010, Toxicology and applied pharmacology.

[42]  Kairui Feng,et al.  The Simcyp® Population-based ADME Simulator , 2009 .

[43]  R. Sarangapani,et al.  On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[44]  J. Dressman,et al.  Estimation of the Increase in Solubility of Drugs as a Function of Bile Salt Concentration , 2004, Pharmaceutical Research.

[45]  Malcolm Rowland,et al.  PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance. , 2011, Journal of pharmaceutical sciences.