Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Predictive markers linking drug efficacy to clinical outcome are a key component in the drug discovery and development process. In HIV infection, two different measures, viral load decay and phenotypic assays, are used to assess drug efficacy in vivo and in vitro. For the newly introduced class of integrase inhibitors, a huge discrepancy between these two measures of efficacy was observed. Hence, a thorough understanding of the relation between these two measures of drug efficacy is imperative for guiding future drug discovery and development activities in HIV. In this article, we developed a novel viral dynamics model, which allows for a mechanistic integration of the mode of action of all approved drugs and drugs in late clinical trials. Subsequently, we established a link between in vivo and in vitro measures of drug efficacy, and extract important determinants of drug efficacy in vivo. The analysis is based on a new quantity—the reproductive capacity—that represents in mathematical terms the in vivo analog of the read-out of a phenotypic assay. Our results suggest a drug-class specific impact of antivirals on the total amount of viral replication. Moreover, we showed that the (drug-)target half life, dominated by immune-system related clearance processes, is a key characteristic that affects both the emergence of resistance as well as the in vitro–in vivo correlation of efficacy measures in HIV treatment. We found that protease- and maturation inhibitors, due to their target half-life, decrease the total amount of viral replication and the emergence of resistance most efficiently.

show abstract

“…distr , see e.g. [72], where . Finally, we assume that on average each virus contains 2 viral RNAs (which are measured [viral RNA/mL] plasma).…”

Section: Resultsmentioning

confidence: 99%

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

2010

Self Cite

View full text Add to dashboard Cite

show abstract

“…The permeability is determined by the diffusion coefficient, a measure of the rate of entry into the cytoplasm depending on the molecular weight or size of a molecule, the partition coefficient and the cell membrane thickness. The partition coefficient for a compound is dependent on the physiochemical properties, such as lipophilicity and acid/base properties, where highly lipophilic and uncharged compounds will have a high partition coefficient and a high permeability and will readily diffuse across the cell membrane (5,11,12). Macromolecules, however, are characterised by limited passage across cell membranes due to their size and charge.…”

Section: From Organ To Whole Body: the Generic Pbpk Modelsmentioning

confidence: 99%

Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules

Thygesen

Macheras

Peer³

2009

Pharm Res

View full text Add to dashboard Cite

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

show abstract

“…Valuable tools for our understanding of the interplay between various pharmacokinetic parameters include either the simulation of drug time-course profiles within the framework of specific body models that are described through solving systems of differential equations, or the fitting of the corresponding equations to experimental concentration-time data (Huisinga et al 2006;von Kleist and Huisinga 2007). Here, both simulation and modeling are required to address a number of key questions at the various stages of the drug-development process (Bonate 2006;Lave et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Explicit reformulations of the Lambert W-omega function for calculations of the solutions to one-compartment pharmacokinetic models with Michaelis–Menten elimination kinetics

Goličnik

2011

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

The exact closed-form solutions to the integrated rate equations for one-compartment pharmacokinetic models that obey Michaelis-Menten elimination kinetics were derived recently (Tang and Xiao in J Pharmacokin Pharmacodyn 34:807-827, 2007). These solutions are expressed in terms of the Lambert W(x)-omega function; however, unfortunately, most of the available computer programs are not set up to handle equations that involve the W(x) function. Therefore, in this article, I provide alternative explicit analytical equations expressed in terms of elementary mathematical functions that accurately approximate exact solutions and can be simply calculated using any optional standard software.

show abstract

Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Cited by 27 publications

References 31 publications

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

Drug-Class Specific Impact of Antivirals on the Reproductive Capacity of HIV

Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules

Explicit reformulations of the Lambert W-omega function for calculations of the solutions to one-compartment pharmacokinetic models with Michaelis–Menten elimination kinetics

Contact Info

Product

Resources

About