Free whitepapers on Pharmacogenomics and Drug Transporters

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Pharmacogenomics - Drug Disposition, Drug Targets, and Side Effects
It is well recognized that different patients respond in different ways to the same medication. These differences are often greater among members of a population than they are within the same person at different times (or between monozygotic twins).

Drug Transporters in ADME
Pharmaceutical companies are investing research time into understanding and modelling of drug transporters to better predict drug-drug interactions and toxicities. Whilst understanding drug-drug interactions can enhance study efficiency and drug efficacy, the challenges presented by drug transporters are complex.

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Drug transporters and their role in drug interactions and toxicity

Background

Drug transporters have gained prominent attention from almost everyone involved in drug development across the globe in the last two decades. Researchers now have a fair understanding of the vital role played by drug transporters in drug absorption, distribution, metabolism and excretion (ADME). Attention has been drawn towards their involvement in drug interactions and toxicity. Improvement in clinical translation of in vitro and preclinical transport studies and increased impact of regulatory authorities for better understanding of transport interactions (draft EMEA guidance and 2010 ITC whitepaper) are also stressed.

A range of various drug transporters is present in the human body. Most important of these include transporters expressed particularly in the endothelium of the blood–brain barrier and in the epithelia of the liver, intestine, and kidney during drug development. These drug transporters are specific to their substrates. However, the number of substrates specific to each transporter may vary. For example, a transporter may be specific for only one substrate while another may act as a transporter for three substrates. At a particular site,  distribution of each of these transporters varies, entailing the different physiological functions and sometimes the pathological reaction. Lack or absence of these transporters can result in numerous genetic disorders. The bioavailability of drugs with less permeability and absorption can be enhanced by the use of transporters involved in the absorption or else by restricting the transporters required for the efflux system.

Thanks to fresh developments in molecular biology in gene cloning and other techniques, molecular level characteristics and distribution of transporters can be studied. Over the years, the major cause of failure for late stage therapeutic entities during drug development has been drug-induced organ toxicity. In vitro screening of molecular compounds can be done to ascertain the effect of drugs on various pathways or mechanisms that might be linked to drug toxicity. However, very few negative in vivo outcomes can be predicted in this manner; as in the case for most of the models, the in vivo conditions cannot be replicated.

The two major conditions required to determine the organ specificity for toxicity are increasing the concentration and delivery of drugs to the target. Much progress has already been made in deducing the role of these drug transporters in drug safety and efficacy. For the human genome, over hundreds of transporters have been discovered. Examples include the two most important superfamilies, namely, the ATP binding cassette and the solute carrier (abbreviated as ABC and SLC, respectively).


Since a lot of research has been done with focus on interaction of drugs and their metabolites, scientists have simultaneously developed a huge range of literature on the topic. Several of these studies suggest the in vivo role of drug transporters in the drug’s disposition, efficacy and some negative responses. Models for in vivo demonstration of the role of drug transporters include a number of animal species, commonly knockout (KO) mice. In humans, loss-of-function genetic variants have also been used. The in vivo role of many ABC and SLC transporters has been elucidated using such studies. Many such studies have proved the role of  transporters along with several drug-metabolizing enzymes (DMEs) during ADME. Clinical pharmacokinetic drug-drug interaction studies also support genetic polymorphism of DMEs.

Read more about:

    Overview of drug transporters:

• P glycoprotein (P-gp)
• BCRP
• OCTs and OATs
• OATPs

1. Issues on Drug Development
2. Future Directions
3. Conclusion

Click here for the complimentary 5-page article: Drug Transporters.

INTERESTED IN THIS TOPIC? Access free information, more articles and whitepapers as well as details on the Clinically Relevant Drug Transporters Congress, click here: 2nd International Congress Clinically Relevant Drug Transporters

Guideline on Clinical Investigation of Immunosuppressants for solid Organ Transplantation

The aim of this guideline is to provide guidance on the clinical development of compounds for the prevention and treatment of allograft rejection in solid organ transplantation.

The immune system is vital for the human body and immunosuppression in organ transplantation should be as selective as possible, to minimise the risk of over-immunosuppression which can cause increased risks of infections and malignancies. Many problems exist in currently approved regimens: Treatments are often very complex, e.g. quadruple immunosuppression, and vary over time for each patient. This complexity also increases the risk for low patient compliance. Therapeutic margins can be very narrow and there are considerable risks of over- as well as of under immunosuppression. The pharmacokinetic interaction potential is high and causes problems (decreased efficacy, increased toxicity) as transplant patients are often on multiple other drugs. Many widely used immunosuppressive protocols in transplants performed in low numbers,  i.e., lung, bowel and islet transplantation, are not approved for that indication.

Different treatment settings and modalities, such as type of organ transplantation (renal, liver, heart, lung, etc.) type of therapy (induction, initial, maintenance, tolerance induction), type of allograft rejection (hyperacute, acute, subacute, ‘chronic’ and/or (steroid) resistant) and type of pathophysiology (cellular or humoral type of rejection) are distinguished. Many different immunosuppressive drugs and a number of different combinations are currently available and new agents are under development. Other treatment concepts that are explored include steroid withdrawal or total avoidance of steroids, drug minimisation and induction of tolerance.

This document considers these circumstances and provides guidance for proper development of new immunosuppressant for solid organ transplantation. Potential claims provided reflect principal aims of management of transplanted allograft with immunosuppressant. Baseline subject characteristics and selection criteria of subjects considers immunological and global transplantation risk assessment; both of donor/transplant and recipient. Primary efficacy criteria are provided in general terms and are seen as constructed by composed and/or co-primary endpoints only. Guidance on pharmacokinetic and pharmacodynamic investigations reflects mainly specific pathophysiology during peri-transplantation period, co-therapies and monitoring strategies. Exploratory trials should reflect concepts of immunosuppression for investigated agent or process and base strong rationale for confirmative investigations. Guidance on confirmatory trials is provided mainly for  major transplantation areas, such as renal, liver, heart, lung and pancreas transplantation. Specific areas with limited experience gathered
up till now, such as development of minor transplantation areas as well as choice of non-approved comparators are recommended to be guided by European regulatory advice procedures. Special issues in paediatric, elderly population and in case of certain infections during peri-transplantation period are advised to be investigated by tailored trials. Clinical safety investigation should reflect certain essential
characteristics of immunosuppression in solid organ transplantation, such as life-long lasting treatment in a population with extensive co-morbidity. Specific factors to be considered include proper time for assessment of infectogenic and cancerogenic potential, risk of premature death due to primary disease and overlapping safety signals.

This document should be conceived as general guidance and should be read in conjunction with other EU and ICH guidelines that apply to the subject (see Section 3 ‘Legal basis’). Due to the dynamics of the field, frequent revisions and amendments are foreseen.
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This document provides guidance for proper development of new immunosuppressant for solid organ transplantation. Potential claims provided reflect principal aims of management of transplanted allograft with immunosuppressant. Baseline subject characteristics and selection criteria of subjects considers immunological and global transplantation risk assessment; both of donor/transplant and recipient.

The 15-page Guideline on clinical investigation of immunosuppressants for solid organ transplantation can be downloaded here: Guideline on clinical investigation of immunosuppressants for solid organ transplantation