Graphs displaying plasma PK profile of the long term and short term experiments for erlotinib and... more Graphs displaying plasma PK profile of the long term and short term experiments for erlotinib and gefitinib.
Graph describing the impact of tumor volume on the derivation of the concentration to achieve tum... more Graph describing the impact of tumor volume on the derivation of the concentration to achieve tumor stasis when considering a non-linear tumor growth behavior.
Displays the goodness of fit plots when fitting the PKPD model to tumor growth inhibition data in... more Displays the goodness of fit plots when fitting the PKPD model to tumor growth inhibition data in the cell line derived A431 xenografts.
Shows the goodness of fit plots when fitting a 1-compartmental model to the long term plasma PK d... more Shows the goodness of fit plots when fitting a 1-compartmental model to the long term plasma PK data.
Shows the total-Erk time course in patient derived A677 tumors after single dose application of e... more Shows the total-Erk time course in patient derived A677 tumors after single dose application of erlotinib or gefitinib respectively.
We have assessed two commercial software tools employing physiologically based models for predict... more We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery. 2002 Elsevier Science B.V. All rights reserved. a molecules in a large percentage of pharmaceutical discov- stability, lipophilicity, and salt forms. The physiological ery projects. It has been observed that drug development factors include gastrointestinal pH, gastric emptying, small often failed for reasons of poor pharmacokinetics (Prentis and large bowel transit times, active transport and efflux, et al., 1988). To avoid the high costs associated with such and gut wall metabolism. The formulation factors are failures the current practice is to consider metabolism and related to drug particle size, crystal form and dosage forms pharmacokinetic properties in parallel with pharmacologi- such as solution, tablet, capsule or suspension. cal tests during the discovery phase. High throughput in Considering the complexity of absorption and the num- vitro technology now allows properties of importance for ber of processes involved, an integrated approach taking oral absorption like solubility, permeability, lipophilicity most of the data into account is highly desirable. Physio- and pK to be measured early and for many compounds. logically based models provide a rational basis for integra- a
Population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) models are fr... more Population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir in children <4 months. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared to older children are minor. The PopPK model was used to simulate ganciclovir exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by FDA. PBPK and PopPK confirmed that the proposed valganciclovir dosing algorithm achieves similar ganciclovir exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the valganciclovir dosing algorithm for children <4 months and supported the regulatory approval. This article is protected by copyright. All rights reserved.
The objective of this study was to evaluate the performance of various allometric and in vitro-in... more The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUCp.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.
The aim of the present work is to learn if intravenous administration of L-carnitine accelerates ... more The aim of the present work is to learn if intravenous administration of L-carnitine accelerates the clearance of a lipid emulsion. Intravenous fat tolerance tests have been done on rats (0.4 g triacylglycerols•kg-1 B.W.). Measurement of the light scattering index of the plasma permitted determination of the exogenous lipid concentration and thus allowed to represent the clearance curve of the infused emulsion. It was found that prior administration of L-carnitine (110, 160 or 560 mg kg-1 B.W.) does not modify the clearance rate either of a long chain triglyceride emulsion or of a medium chain triglyceride based emulsion. The observed clearance in L-carnitine deficient animals, resulting either from intraperitoneal injections of D-carnitine (3 g•kg-1 B.W. for four days) or from a 6-months long diet of suboptimal amounts of precursor amino acids and vitamins for carnitine biosynthesis, was not reduced relative to the clearance in corresponding control animals. Also, the in vitro activities of the two enzymes involved in the clearance of the infused lipids, lipoprotein lipase (diaphragm and adipose tissue) and hepatic endothelial lipase, were unmodified by the L-carnitine.
1. Plasma concentrations of the two enantiomers of tertatolol were determined by gc/ms. Deuterium... more 1. Plasma concentrations of the two enantiomers of tertatolol were determined by gc/ms. Deuterium labelling of one of the tertatolol enantiomers was used for chiral discrimination. 2. No isotope effects were observed following simultaneous oral administration of tertatolol and [2H9]tertatolol. 3. After intravenous administration of the pseudoracemate or of each enantiomer separately, (+)-tertatolol showed a lower total clearance and volume of distribution, compared to the (-) enantiomer. 4. After oral administration of the pseudoracemate or of each enantiomer separately, no substantial difference in bioavailability were observed between the enantiomers.
Highlights d In vitro data and computational models can assist with calculating pro-arrhythmic ri... more Highlights d In vitro data and computational models can assist with calculating pro-arrhythmic risk d We use patient health records and FDA Adverse Event Reporting System reports d Use of such datasets helps assess relative drug risk and cardiac safety models d We quantify how patient characteristics can affect arrhythmia incidence
The availability of multidimensional data together with the development of modern techniques for ... more The availability of multidimensional data together with the development of modern techniques for data analysis represent an exceptional opportunity for clinical pharmacology. Data science—defined in this special issue as the novel approaches to the collection, aggregation, and analysis of data—can significantly contribute to characterize drug‐response variability at the individual level, thus enabling clinical pharmacology to become a critical contributor to personalized healthcare through precision dosing. We propose a minireview of methodologies for achieving precision dosing with a focus on an artificial intelligence technique called reinforcement learning, which is currently used for individualizing dosing regimen in patients with life‐threatening diseases. We highlight the interplay of such techniques with conventional pharmacokinetic/pharmacodynamic approaches and discuss applicability in drug research and early development.
Journal of veterinary pharmacology and therapeutics, 2016
This review provides a tutorial for individuals interested in quantitative veterinary pharmacolog... more This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing an...
In this review we present ways in which translational PK/PD modeling can address opportunities to... more In this review we present ways in which translational PK/PD modeling can address opportunities to enhance probability of success in drug discovery and early development. This is achieved by impacting efficacy and safety-driven attrition rates, through increased focus on the quantitative understanding and modeling of translational PK/PD. Application of the proposed principles early in the discovery and development phases is anticipated to bolster confidence of successfully evaluating proof of mechanism in humans and ultimately improve Phase II success. The present review is centered on the application of predictive modeling and simulation approaches during drug discovery and early development, and more specifically of mechanismbased PK/PD modeling. Case studies are presented, focused on the relevance of M&S contributions to realworld questions and the impact on decision making.
Graphs displaying plasma PK profile of the long term and short term experiments for erlotinib and... more Graphs displaying plasma PK profile of the long term and short term experiments for erlotinib and gefitinib.
Graph describing the impact of tumor volume on the derivation of the concentration to achieve tum... more Graph describing the impact of tumor volume on the derivation of the concentration to achieve tumor stasis when considering a non-linear tumor growth behavior.
Displays the goodness of fit plots when fitting the PKPD model to tumor growth inhibition data in... more Displays the goodness of fit plots when fitting the PKPD model to tumor growth inhibition data in the cell line derived A431 xenografts.
Shows the goodness of fit plots when fitting a 1-compartmental model to the long term plasma PK d... more Shows the goodness of fit plots when fitting a 1-compartmental model to the long term plasma PK data.
Shows the total-Erk time course in patient derived A677 tumors after single dose application of e... more Shows the total-Erk time course in patient derived A677 tumors after single dose application of erlotinib or gefitinib respectively.
We have assessed two commercial software tools employing physiologically based models for predict... more We have assessed two commercial software tools employing physiologically based models for prediction of intestinal absorption in human. IDEA 2.0 and GASTROPLUS 3.1.0 were compared both in their ability to predict fraction absorbed for a set of 28 drugs and in terms of the functionality offered. The emphasis was placed on the practical usefulness to pharmaceutical drug discovery. Predictions were assessed for three levels of input data (i) pure in silico input, (ii) thermodynamic solubility and in silico permeability, (iii) thermodynamic solubility and human colon carcinoma cell line (CACO-2) permeability. We found the pure in silico prediction ability of the tools to be comparable with 70% correct classification rate. With measured input data the IDEA prediction rate improved to 79% while GASTROPLUS stayed at 70%. In terms of functionality GASTROPLUS is a powerful system for the trained user. Open access to model parameters, diagnostic tools and the ability to integrate data make it particularly suitable for the later stages of discovery and development. IDEA is web based and presents a simple interface suitable for widespread use with minimal training. However the limited functionality and inconvenient handling of multiple compound batches currently restrict the usefulness of version 2.0 for drug discovery. 2002 Elsevier Science B.V. All rights reserved. a molecules in a large percentage of pharmaceutical discov- stability, lipophilicity, and salt forms. The physiological ery projects. It has been observed that drug development factors include gastrointestinal pH, gastric emptying, small often failed for reasons of poor pharmacokinetics (Prentis and large bowel transit times, active transport and efflux, et al., 1988). To avoid the high costs associated with such and gut wall metabolism. The formulation factors are failures the current practice is to consider metabolism and related to drug particle size, crystal form and dosage forms pharmacokinetic properties in parallel with pharmacologi- such as solution, tablet, capsule or suspension. cal tests during the discovery phase. High throughput in Considering the complexity of absorption and the num- vitro technology now allows properties of importance for ber of processes involved, an integrated approach taking oral absorption like solubility, permeability, lipophilicity most of the data into account is highly desirable. Physio- and pK to be measured early and for many compounds. logically based models provide a rational basis for integra- a
Population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) models are fr... more Population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir in children <4 months. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared to older children are minor. The PopPK model was used to simulate ganciclovir exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by FDA. PBPK and PopPK confirmed that the proposed valganciclovir dosing algorithm achieves similar ganciclovir exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the valganciclovir dosing algorithm for children <4 months and supported the regulatory approval. This article is protected by copyright. All rights reserved.
The objective of this study was to evaluate the performance of various allometric and in vitro-in... more The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUCp.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.
The aim of the present work is to learn if intravenous administration of L-carnitine accelerates ... more The aim of the present work is to learn if intravenous administration of L-carnitine accelerates the clearance of a lipid emulsion. Intravenous fat tolerance tests have been done on rats (0.4 g triacylglycerols•kg-1 B.W.). Measurement of the light scattering index of the plasma permitted determination of the exogenous lipid concentration and thus allowed to represent the clearance curve of the infused emulsion. It was found that prior administration of L-carnitine (110, 160 or 560 mg kg-1 B.W.) does not modify the clearance rate either of a long chain triglyceride emulsion or of a medium chain triglyceride based emulsion. The observed clearance in L-carnitine deficient animals, resulting either from intraperitoneal injections of D-carnitine (3 g•kg-1 B.W. for four days) or from a 6-months long diet of suboptimal amounts of precursor amino acids and vitamins for carnitine biosynthesis, was not reduced relative to the clearance in corresponding control animals. Also, the in vitro activities of the two enzymes involved in the clearance of the infused lipids, lipoprotein lipase (diaphragm and adipose tissue) and hepatic endothelial lipase, were unmodified by the L-carnitine.
1. Plasma concentrations of the two enantiomers of tertatolol were determined by gc/ms. Deuterium... more 1. Plasma concentrations of the two enantiomers of tertatolol were determined by gc/ms. Deuterium labelling of one of the tertatolol enantiomers was used for chiral discrimination. 2. No isotope effects were observed following simultaneous oral administration of tertatolol and [2H9]tertatolol. 3. After intravenous administration of the pseudoracemate or of each enantiomer separately, (+)-tertatolol showed a lower total clearance and volume of distribution, compared to the (-) enantiomer. 4. After oral administration of the pseudoracemate or of each enantiomer separately, no substantial difference in bioavailability were observed between the enantiomers.
Highlights d In vitro data and computational models can assist with calculating pro-arrhythmic ri... more Highlights d In vitro data and computational models can assist with calculating pro-arrhythmic risk d We use patient health records and FDA Adverse Event Reporting System reports d Use of such datasets helps assess relative drug risk and cardiac safety models d We quantify how patient characteristics can affect arrhythmia incidence
The availability of multidimensional data together with the development of modern techniques for ... more The availability of multidimensional data together with the development of modern techniques for data analysis represent an exceptional opportunity for clinical pharmacology. Data science—defined in this special issue as the novel approaches to the collection, aggregation, and analysis of data—can significantly contribute to characterize drug‐response variability at the individual level, thus enabling clinical pharmacology to become a critical contributor to personalized healthcare through precision dosing. We propose a minireview of methodologies for achieving precision dosing with a focus on an artificial intelligence technique called reinforcement learning, which is currently used for individualizing dosing regimen in patients with life‐threatening diseases. We highlight the interplay of such techniques with conventional pharmacokinetic/pharmacodynamic approaches and discuss applicability in drug research and early development.
Journal of veterinary pharmacology and therapeutics, 2016
This review provides a tutorial for individuals interested in quantitative veterinary pharmacolog... more This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing an...
In this review we present ways in which translational PK/PD modeling can address opportunities to... more In this review we present ways in which translational PK/PD modeling can address opportunities to enhance probability of success in drug discovery and early development. This is achieved by impacting efficacy and safety-driven attrition rates, through increased focus on the quantitative understanding and modeling of translational PK/PD. Application of the proposed principles early in the discovery and development phases is anticipated to bolster confidence of successfully evaluating proof of mechanism in humans and ultimately improve Phase II success. The present review is centered on the application of predictive modeling and simulation approaches during drug discovery and early development, and more specifically of mechanismbased PK/PD modeling. Case studies are presented, focused on the relevance of M&S contributions to realworld questions and the impact on decision making.
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Papers by Thierry Lave