Application of Full Physiological Models for Pharmaceutical Drug Candidate Selection and Extrapolation of Pharmacokinetics to Man

Parrott, Neil; Jones, Hannah M.; Paquereau, Nicolas; Lavé, Thierry

doi:10.1111/j.1742-7843.2005.pto960308.x

Cited by 87 publications

(46 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the current study, the overall prediction accuracy using these equations was reduced to 42% and 32% within 2-fold of observed for rat and human, respectively. A decreased prediction accuracy of these equations was also observed by others (Parrott et al, 2005a;Jones et al, 2006a). This may be explained by distribution processes that are not covered in these equations, such as active transport or ionic interactions of charged bases with acidic phospholipids of cell membranes.…”

Section: Prediction Of Human Pharmacokineticsmentioning

confidence: 82%

Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs

Buck¹,

Sinha²,

Fenu³

et al. 2007

Drug Metab Dispos

239

177

View full text Add to dashboard Cite

ABSTRACT:The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P tp ) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V ss ). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P tp data (method Vd2). Best V ss predictions were obtained using method Vd2, providing that rat P tp input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V ss predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.In the drug discovery process considerable resources are required to assess the pharmacokinetic (PK) properties of potential drug candidates in vivo in animals. To optimize the use of such in vivo testing, there has been a growing interest in predicting the PK behavior of drug candidates (Theil et al., 2003;van de Waterbeemd and Gifford, 2003). If sufficiently reliable, such simulations could also help to select the most promising candidates for development and reject those with a low probability of success (van de Waterbeemd and Gifford, 2003).The majority of the approaches to predict human PK developed to date typically focus on the drug's behavior in individual processes of absorption, distribution, metabolism and excretion (ADME). The characterization of a drug's PK in a complex biological system is best described by assembling these processes in one global model. In this context, physiologically based pharmacokinetics (PBPK) models have been developed (Bischoff, 1986). PBPK models map the complex drug transport scheme onto a physiologically realistic compartmental structure (Fig. 1). The major structural elements of the PBPK disposition model are derived from the anato...

show abstract

Section: Prediction Of Human Pharmacokineticsmentioning

confidence: 82%

Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs

Buck¹,

Sinha²,

Fenu³

et al. 2007

Drug Metab Dispos

239

177

View full text Add to dashboard Cite

show abstract

“…Therefore, the incorporation of such processes into PBPK models currently still requires in vivo data which are typically generated in the rat [26] [27]. Equally or even more elusive to quantitative predictions are clearance mechanisms in extrahepatic tissues, e.g., the intestinal wall, where direct scaling is known to be very difficult [27] [28]. These elimination mechanisms are, therefore, not enclosed in the initial generic disposition model.…”

Section: Purpose and Principles Of Physiologically Based Pharmacokinementioning

confidence: 99%

Development and Application of Physiologically Based Pharmacokinetic-Modeling Tools to Support Drug Discovery

Lüpfert¹,

Reichel

2005

C&B

View full text Add to dashboard Cite

Physiologically based pharmacokinetic (PBPK) modeling integrates physicochemical (PC) and in vitro pharmacokinetic (PK) data using a mechanistic framework of principal ADME (absorption, distribution, metabolism, and excretion) processes into a physiologically based whole-body model. Absorption, distribution, and clearance are modeled by combining compound-specific PC and PK properties with physiological processes. Thereby, isolated in vitro data can be upgraded by means of predicting full concentration-time profiles prior to animal experiments. The integrative process of PBPK modeling leads to a better understanding of the specific ADME processes driving the PK behavior in vivo, and has the power to rationally select experiments for a more focussed PK project support. This article presents a generic disposition model based on tissue-composition-based distribution and directly scaled hepatic clearance. This model can be used in drug discovery to identify the critical PK issues of compound classes and to rationally guide the optimization path of the compounds toward a viable development candidate. Starting with a generic PBPK model, which is empirically based on the most common PK processes, the model will be gradually tailored to the specifics of drug candidates as more and more experimental data become available. This will lead to a growing understanding of the 'drug in the making', allowing a range of predictions to be made for various purposes and conditions. The stage is set for a wide penetration of PK modeling and simulations to form an intrinsic part of a project starting from lead discovery, to lead optimization and candidate selection, to preclinical profiling and clinical trials.

show abstract

“…Mathematically complex physiological scaling methods applied to laboratory animals are useful in predicting many pharmacokinetic parameters in humans for a given drug but require costly and time consuming measurements of multiple variables, such as organ size, blood flow rates, tissue to blood partitioning, plasma protein binding, enzymatic kinetic parameters, and other metabolic factors such as drug absorption and clearance (Mahmood and Balian 1999;Parrott et al 2005). The construction of such physiological models is thus unlikely to occur outside industrial settings, which largely precludes their development with relation to drugs of abuse.…”

Section: Introductionmentioning

confidence: 99%

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Fantegrossi

2006

Psychopharmacology

View full text Add to dashboard Cite

Rationale: Many animal models relevant to the persistent effects of drugs of abuse necessitate the application of interspecies dose scaling procedures to approximate drug administration regimens in humans, but drug self-administration procedures differ in that they allow animal subjects to control their own drug intake. Objectives: This report reviews the reinforcing effects of 3,4-methylenedioxymethamphetamine (MDMA), its enantiomers, and several structural analogs in rhesus monkeys, paying particular attention to the pharmacological mechanisms of such reinforcing effects, the development of structure activity relationships among these compounds, the stability of MDMA self-administration behavior over time, and the persistent effects of selfadministered MDMA on monoamines. Results: The methylenedioxy amphetamine congeners MDMA, 3, 4-methylenedioxyamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, and N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine function as reinforcers in rhesus monkeys, maintaining self-administration behavior greater than that engendered by contingent saline but less than that engendered by traditional psychostimulants. These findings are remarkable as structurally distinct serotonergic hallucinogen-like drugs do not maintain reliable selfadministration in laboratory animals. During prolonged MDMA self-administration, MDMA-maintained responding progressively weakens, and MDMA eventually fails to maintain significant self-administration. The neurochemical correlates of this effect have not yet been identified. Conclusions: Procedures in which MDMA and related compounds are self-administered can be established in rhesus monkeys. These techniques can be used to engender contingent MDMA exposure without resorting to controversial methods of interspecies dose scaling. As such, further application of self-administration methods may provide important new insights into the persistent effects of MDMA on brain and behavior in nonhuman primates.

show abstract

Application of Full Physiological Models for Pharmaceutical Drug Candidate Selection and Extrapolation of Pharmacokinetics to Man

Cited by 87 publications

References 9 publications

Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs

Prediction of Human Pharmacokinetics Using Physiologically Based Modeling: A Retrospective Analysis of 26 Clinically Tested Drugs

Development and Application of Physiologically Based Pharmacokinetic-Modeling Tools to Support Drug Discovery

Reinforcing effects of methylenedioxy amphetamine congeners in rhesus monkeys: are intravenous self-administration experiments relevant to MDMA neurotoxicity?

Contact Info

Product

Resources

About