Editorial

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Pharmacokinetic–pharmacodynamic
modeling and it is relevance in the drug
discovery
Sunil Kumar Dubey*,1 , Kommera Sai Pradyuth1 , Sreehari Krishna Kulkarni1 & Gautam
Singhvi1
1
Industrial Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India
*Author for correspondence: [email protected]

First draft submitted: 20 October 2018; Accepted for publication: 21 November 2018; Published online:
12 December 2018

Keywords: clinical trial • discovery • drug • modeling • pharmacodynamics • pharmacokinetics

The need for development of a relationship between the pharmacokinetics (PK) and pharmacodynamics (PD)
parameters of a drug is essential in estimating the complete profile of the drug. The correlation between these two
can bring about great success in the process of drug discovery. The fitting correlation between PK and PD of the
drug through different mathematical approaches can be aptly brought about by the introduction of PK/PD models.
Hence, the development of different PK/PD models to aid in drug discovery has gained importance, which has
led to the establishment of several models like the linear model, nonlinear model, Emax model and Hill model [1].
The model wherein the drug concentration is relatively linear to the response shown by the drug is called as
linear PD model. The model wherein the drug does not show a linear relationship between the concentration and
the response, thereby switching the data into a logarithmic form is encouraged is called nonlinear model. The
Emax model is also known as the hyperbolic model is a function of the Michaelis–Menten equation for saturable
process and accounts for maximal drug effects. This model is significant in depicting the nonlinear concentration–
response relations. Hill model is also known as Sigmoidal Emax model accounts for the drugs that show the steeper
relationships of PD and PK properties. This model establishes the dose and kinetic relationships through the
introduction of shape factor to diminish the deviations from perfect hyperbola [1].
Drug discovery and development is a very long process that involves high risks and budget all along its pathway.
Hence, different pioneers involved in drug development require a sophisticated model that can help them identify
the probability of drug clearing the regulatory phases, in the early stages of drug development. The advent of PK/PD
models created a speculation of such model, but the use of PK/PD models in the process of drug development has
been limited in its early times as it needed to overcome the issues pertaining to the drug distribution in the body,
protein binding and tolerance. But the applications of these models through scientific and rational approach have
now created interest among scientists who develop PK/PD models for drug discovery and development. It can be
profoundly said that the relevance of the PK/PD modeling in the process of drug discovery is enormous as it can
efficiently decrease the cost involved in the whole drug discovery process.
The prediction of drug response in correlation with the concentrations by using different PK/PD models can be
used from the stages of early drug-discovery process, including preclinical studies [2]. Prediction of oral bioavailability
and safety concentrations can be successfully achieved through implementation of the PK/PD modeling in the
preclinical development of the drug discovery. Hence, it can be concluded that PK/PD modeling can also be used
to study the distribution of the drugs within the body in the preclinical drug-development process. It is also a
vital tool that helps in anticipating the crucial aspects with reference to drug properties, thereby providing a scope
for decision-making, regarding the changes that are possible for increasing the success rate of drug discoveries [3].
Prediction of clinical potency and optimal sampling procedures can be successfully established using PK/PD
models. It is also an important tool that can be used during early Phase II trials of the drug discovery as it helps in
designing the drug-disease model to characterize the different PK properties of the drug in response to its effect.

10.4155/ipk-2018-0004 
C 2018 Newlands Press Int. J. Pharmacokinet. (2018) 3(3), 91–92 ISSN 2053-0846 91
Editorial Dubey, Pradyuth, Kulkarni, & Singhvi

It also helps in bolstering the testimony of the drug safety and efficacy [4]. It also aids in the entry of the modified
drug formulations into the market by providing an evidence for the characteristics of the drugs [4].
The applications of the PK/PD modeling are not limited to the early process of the drug discovery but are also
found in the later stages of the drug discovery where it can be used for dose selection and dosage regimen. The
PK/PD models also help in attributing the impact of the covariables in the process of drug development. The
PK/PD models can be efficiently used to test the study designs in the Phase IIa/IIb. Hence, all these applications
along with different studies indicating the importance of the PK/PD modeling has resulted in positioning the
PK/PD-based studies on the epitome of the different tools used in the process of the drug discovery. It was
successfully established that in vitro static and dynamic kill curves obtained through the PK/PD models have been
fruitful in the correlation of in vivo effects in the animal models [5]. Clewe et al. showed that the development
of pharmacometric model for tuberculosis was successfully able to correlate the change in bacterial numbers for
various bacterial states [6]. Hence, it can be concluded that the antibiotic effect of a drug can be efficiently correlated
with the help of the PK/PD modeling, thereby aiding in the establishment of the dosage regimen. Translational
PK/PD modeling strengthens the confidence of profitably evaluating the proof of mechanism in humans and
helps in increasing the success rate of the drug discovery [7]. The impact of dosage regimens on the therapeutic
concentration ranges can be studied using these models. The population studies through PK/PD modeling can be
useful in retrieving data that can ensure the probability of drug passing the clinical trials. The PK/PD studies also
ensure validation of the population-based studies in Phase III clinical trials. It can also become an important aid in
population studies, wherein the available population size is limited.
The development of PK/PD models has garnered the attention of different multinational companies as its
significance can be efficiently utilized in each stage of the drug discovery process. The PK/PD models, through
establishing the drug PK and PD relationships accurately, have increased the success rate of the drug discovery and
development in recent times. It is also established that the budget involved in the pathway of the drug developmental
process can be consequently restricted as the anticipation of drug success can be made in the early stages. Hence,
all these wide ranges of applications using PK/PD models can bring about glorious results in the drug discovery
process.

Financial & competing interests disclosure

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92 Int. J. Pharmacokinet. (2018) 3(3) future science group