Translational pharmacology and drug 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

Understanding these relationships constitutes the central dogma of product development from pre-clinical 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 favourable risk/benefit relationship at each milestone. This begins at the pre-clinical 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 I clinical trial. These pre-clinical 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 I clinical trial.

The FDA depends on the pre-clinical pharmacology-toxicology programme to support safety and plan the phase I clinical trial. Results of the pre-clinical 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 I 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.

Although safety is the main focus in the pre-clinical studies and early clinical trials, the sponsor should also be thinking in terms of defining the relationship between dose, exposure and efficacy. Historically, one of the main reasons for the high rate of drug attrition in clinical development was undesirable pharmacokinetics (PK); from 1964 to 1985, approximately 39 per cent of drug candidates in the UK failed clinical development due to their PK characteristics.

This is no longer a major issue due to improved approaches to drug design and candidate selection increasing the bioavailability of chemical entities. More recently, phase II clinical trials most often fail because insufficient attention was paid to accurately translating pre-clinical efficacy findings to clinical doses that are not just safe, but have a high chance of demonstrating efficacy. The incidence of failure due to efficacy in phase II clinical trials is increasing based on an analysis of 2008-2010 data. The report indicates that 51 per cent of 87 phase II trials conducted between 2008 and 2010 clearly failed because of efficacy. It notes that an additional 29 per cent were categorised as failures due to 'strategic' reasons that likely resulted from failures due to efficacy (as well as safety). Thus, the overwhelming majority of phase II failures were related to efficacy.

The use of biomarkers can plan an integral part in reducing the risk of phase II trial failure

Pre-clinical and clinical PK/PD studies

Pre-clinical 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 PK and toxicokinetic studies in the pre-clinical setting and early phase I 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 pre-clinical studies to demonstrate safety for first-in-human clinical administration, but to design studies that, together with phase I clinical data, will be used to maximise the chances of success in the phase II and phase III clinical trials.

Pre-clinical, first-in-human and other phase I 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 II 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 a 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).

Key observations

There has been insufficient attention paid to PK/PD analysis and modelling, which too often contributes to the failure of phase II trials. We advise conducting careful planning and study design in order to achieve robust PK/PD data from pre-clinical and phase I clinical studies, which is critical to designing successful phase II and III clinical trials. For small companies, efforts to move forward with additional clinical studies following failure of a phase II clinical trial can be associated with significant difficulties and delays that often prove unsustainable.