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SGS Exprimo is now extending services to also include physiologically based pharmacokinetic modelling and simulation, PBPK M&S

The history of PBPK can be traced back to the 1930s when Torsten Teorell described how the body could be divided in a series of tissues connected by the circulatory system and how the body handles the behavior of drugs as an interconnected system. This mechanistic view of pharmacokinetics was presented as a series of mathematical equations (Teorell T, 1937). The concept of PBPK was however not applied within pharmacokinetics until the 1970s (Harrison and Gibaldi, 1977). Since then PBPK has been used mainly by the environmental risk community, but a more widespread interest for use in risk assessment and drug industry was observed after 2002 (Rowland et al., 2011).

In short, the PBPK models are based on that the whole organism is treated as a closed circulatory system, consisting of compartments linked with blood flow. The distribution of drugs between tissues within the body is described by plasma coefficients derived from physicochemical properties of the drug. Anatomical, physiological, biochemical and chemical information is incorporated to model complex ADME processes. The model can take into account intrinsic factors such as demographic characteristics, as well as extrinsic factors such as drug-drug interactions, environmental factors and life-style for example (Huang and Rowland, 2012).

Today PBPK simulations are becoming increasingly used particularly in the field of drug-drug interactions. At the annual meeting of the population approach group in Europe (PAGE) this year, it was presented that the number of submissions to and requests by regulatory authorities have risen (https://www.page-meeting.org/default.asp?abstract=7390). Aspects of the draft EMA Guideline, focusing specifically on PBPK Modelling and Simulation, were also discussed (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/clinical_pharmacology_pharmacokinetics/general_content_001729.jsp&mid=WC0b01ac0580032ec5).

The use of PBPK is expected to continue growing in all phases of drug development. During drug discovery the approach is utilized in the screening of compounds, even before animal testing, with respect to their anticipated pharmacokinetic behavior in order to minimize risk of failure during drug development. PBPK simulations of concentration-time profiles in organs influencing the pharmacokinetics of the drug are valuable also for subsequent PKPD analysis, elucidating possible accumulation effects or target-specific PKPD. Such PBPK/PD evaluations may provide crucial information regarding potency and safety. During clinical development PBPK can be a tool to appreciate differences in pharmacokinetics between populations, taking into account demographic characteristics, ethnic origins and diseases.    

The Bayer PBPK software suite for PBPK simulation has been released as open-source software, a further encouragement to move into this direction (https://www.exprimo.com/article/pk-sim-and-mobi-now-opensource).

 

 

References

Teorell T, 1937. Kinetics of distribution of substances administered to the body.I. The extravascular modes of administration. Arch.Int.Pharmacodyn.Ther.57:202-5.

Harrison and Gibaldi, 1977. Physiologically based pharmacokinetic model for digoxin disposition in dogs and its preliminary application to human. J. Pharm. Sci. 66(12):1979-83

Rowland et al., 2011. Physiologically based pharmacokinetics in drug development and regulatory science: A workshop report (Georgetown University, Washington DC, May 29-30, 2002). Annu. Rev. Pharmacol. Toxicol. 52:45-73

Huang and Rowland, 2012. The role of physiologically based pharmacokinetic modeling in regulatory review, Nature. 91:3.

(https://www.page-meeting.org/default.asp?abstract=7390)

Qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation (Draft Guideline). (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/clinical_pharmacology_pharmacokinetics/general_content_001729.jsp&mid=WC0b01ac0580032ec5

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