Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine

Abstract

Personalized medicine strives to deliver the ‘right drug at the right dose’ by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based Pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver [(AAD)2] methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the Quality by Design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry.

Application of in Silico Tools in Clinical Practice using Ketoconazole as a Model Drug

“…In the clinical environment PBPK models have gained much importance to enable personalized medicine and to assess drug-drug/ drug-disease interactions 20,[60][61][62][63] . For these purposes, its usefulness rely on its ability to determine the importance of subpopulations and to optimize the formulation to obtain the targeted drug plasma concentration profile 60 . Nevertheless, not much attention has been drawn to the utility of computer models when designing alternative clinical approaches.…”

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

“…We simulated four clinical scenarios from therapeutic dose to 70-fold overdose situations and compared the simulation results with clinically observed QT prolongation or TdP. Utilisation of quantitative systems models to simulate absorption, distribution, and elimination of a single drug or combination of drugs, generally referred to as physiologically based pharmacokinetics (PBPK) models, have already been well established in defining or refining appropriate dosage recommendations in regulatory submissions (23)(24)(25)(26). However, utilisation of such a quantitative systems approach to simulate therapeutic response or toxicity events is not widely explored, probably due to the limited availability of sufficiently verified systems toxicology models and/or the availability of suitable input and quantitative systems (physiology) data to parameterise the model.…”

On the analysis of complex biological supply chains: From process systems engineering to quantitative systems pharmacology

“…This framework should encompass all steps from discovery to formulation, manufacturing, delivery, in vivo assessment and response at the individual level. We recently articulated how we envision these type of “global” modeling structures enable the development and delivery of precision and personalized health delivery, eventually bridging the gap across all scales of QSP (Hartmanshenn et al, 2016). There is significant work that remains to be accomplished in many areas.…”