Translational pharmacology: the key to ensuring safe and effective dosing

Toxicokinetics (TK) is generation of kinetic data for systemic exposure and toxicity assessment of the drug. These studies help us to estimate the observed toxicity to that dose. TK evaluation is very important in drug development phase in both regulatory and scientific perspective. There are several guidelines to conduct TK study in animals recommended by regulatory bodies (OECD). TK evaluation is useful in selection of dose, dosing form, alternative dosing route, evaluation of toxicological mechanism, and also used for the setting safe dose level in clinical phases. This TK studies also used to reduces the animal number (replacement, reduction and refinement). On the other hand, TK data are practically used for the purpose of drug discovery such as lead-optimization and candidate-selection. Email：marketing@medicilon.com.cn Web:www.medicilon.com

The relationship between dose, systemic exposure, and both safety and efficacy are the most important elements in biopharmaceutical / drug development. The key is to attain adequate systemic exposure to mediate a clinically effective response while avoiding a level of exposure that results in toxicity. Understanding these relationships constitutes the central dogma of product development from preclinical studies and on through to phase I, II, and III clinical trials, and is still important in post-marketing studies and pharmacovigilance.

In order to proceed successfully through clinical development, it is necessary to accurately assess and demonstrate a favorable risk/benefit relationship at each milestone. This begins at the preclinical level, where appropriate pharmacodynamic, safety pharmacology, pharmacokinetic, toxicology and toxicokinetic studies are performed in various animal species.

The results of these studies are used to demonstrate proof-of-concept for the proposed indication and to support safety for first-in-human administration in a phase 1 clinical trial. These preclinical study results are also used to determine the no-observable-adverse-effect level (NOAEL) and estimate the Maximum Safe Clinical Starting Dose that are then used for determining the dose range to be tested in the phase 1 clinical trial. The FDA depends on the preclinical pharmacology-toxicology programme to support safety and plan the phase 1 clinical trial. Results of the preclinical pharmacology-toxicology programme are submitted to the FDA as part of an Investigational New Drug (IND) Application to support the proposed first-in-human clinical trial. The focus of the FDA's clinical reviewers when assessing a phase 1 IND application is whether the first-in-human clinical study is designed to demonstrate safety in a small number of subjects without putting these subjects at unnecessary risk.

Preclinical and Clinical Pharmacokinetic/Pharmacodynamic Studies

Preclinical and clinical PK/PD studies permit optimal translation of dose from animal studies to clinical trials and finally to clinical practice. PK/PD analysis shouldn't be performed as an afterthought or simply to meet regulatory requirements, but rather carried out with careful planning from early development through product approval. The fundamental principle of translational pharmacology is to design pharmacokinetic and toxicokinetic studies in the preclinical setting and early phase 1 clinical trials with the purpose of accurately and effectively modelling the dosing so that critical clinical trials maximise their chance of success with respect to both safety and efficacy. The goal of translational pharmacology is not simply to design preclinical studies to demonstrate safety for first-in-human clinical administration, but to design studies that, together with phase 1 clinical data, will be used to maximise the chances of success in the phase 2 and phase 3 clinical trials. Preclinical, first-in-human and other phase 1 studies can be particularly suitable to PK/PD analyses since a range of dose levels are often assessed and blood sampling tends to be intensive (data rich). Depending on the therapeutic area, biomarker data can be incorporated into such studies easily and biomarkers can help bridge animal and human pharmacology, toxicity/safety evaluation, dose selection, patient selection. The use of biomarkers can be an integral part of reducing the risk of phase 2 trial failure. Later in clinical development, data gathered across clinical trials can characterise the relationships between dose, safety, efficacy, biomarkers and population covariates.

This data helps define dosing guidelines for use in clinical practice following approval. Biomarkers play a key role in accelerated approval. There is a need and critical role that PK/PD assessments and modelling can play in increasing the chances for success in the development process. Particularly for an oncology drug, it's a therapeutic area that has one of the highest failure rates (estimated at 90 per cent).