Year : 2014 | Volume
: 140 | Issue : 4 | Page : 575--577
Drug - drug interactions for therapeutic biologics
Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry 605 006, India
Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry 605 006
|How to cite this article:|
Adithan C. Drug - drug interactions for therapeutic biologics.Indian J Med Res 2014;140:575-577
|How to cite this URL:|
Adithan C. Drug - drug interactions for therapeutic biologics. Indian J Med Res [serial online] 2014 [cited 2020 Apr 10 ];140:575-577
Available from: http://www.ijmr.org.in/text.asp?2014/140/4/575/146294
Drug - drug interactions for therapeutic biologics , H. Zhou, B. Meibohm, editors (Wiley- Blackwell, UK) 2013. 386 pages. Price: not mentioned
This book gives a comprehensive and systematic overview of drug-drug interactions (DDIs) of therapeutic biologics. Experts and professional authors have discussed their sharp views on various critical aspects, right from the stage of drug development to the detailed mechanisms of DDIs and associated complications, involving the use of biologics. Considering the growing prevalence of polypharmacy and the amplifying use of biologics, understanding the basic mechanisms of potential interactions is the need of the hour. This book covers the various strategies for assessment of DDIs including model based and model independent methods, in vitro methods, and selection of animal models for determining the clinical interactions of therapeutic proteins (TPs).
The initial chapter discusses about the increasing usage of biotherapeutic agents in pre-existing therapeutic regimens and the unawareness of clinically relevant drug interactions (DIs). The survey by Biotechnology Industry Organization (BIO) among its member companies showed that a majority of the companies did not have any internal strategy for evaluating therapeutic protein-drug interaction (TP-DI) and the studied interactions did not warrant any clinical dose adjustment. This scenario indicates the pressing need for risk-based assessment strategy for TP-DIs.
The second chapter mainly focuses on the ADME pathways of therapeutic proteins and the mechanisms of pharmacokinetic and pharmacodynamics based TP-DIs. After discussing the critical points about the absorption, distribution, catabolism and excretion of therapeutic proteins, the authors have discussed in detail about the potential mechanisms of TP-DIs. They have classified TP-DIs into two broad categories, PK-based DIs, which are due to direct competition, inhibition or inhibition of drug ADME mechanisms and PD-based DIs, which involve modulation of targets by the drugs used in combinations. Both of these mechanisms can affect safety and efficacy outcomes, especially if a drug has narrow therapeutic index.
It is interesting to know that in contrary to PK-DIs, PD-DIs are very common. Drugs used in combination with biologics can increase their exposure levels either by decreasing the immunological mediated or target mediated clearance which in turn can affect the safety and efficacy of the drug. The impact of PD based TP-DIs due to changes in immunological clearance, target mediated drug disposition and cytokine-cytochrome P450 modulation effects are discussed in detail with relevant examples. In the final section of this chapter, the authors have discussed the various strategies and challenges for assessing risks of TP-DIs in clinical development of TPs. Question-based strategy is considered as a better method for assessing TP-DIs in clinical development, as it gives the potential impact of TP-DIs on safety/efficacy outcomes and whether this impact warrants clinical dose adjustment or therapeutic drug monitoring (TDM).
The next chapter compares various DI strategies routinely used for small molecule drugs (SMDs) and the feasibility of using the same in biologics. The detailed description of alterations (induction and inhibition) in drug metabolizing enzymes and transporters involved in the PK of small molecule drugs and biologics is given along with the comparison of relevant PK of SMDs and biologics.
Chapters 4 to 7 discuss the various methods for assessing the DDIs of TPs in detail. To start with, the model independent and model dependent methods have been discussed, enumerating the practical relevance of these methods for assessing biologics compared to small drug molecules. The model independent methods include in vitro screening, dedicated DDI studies and cocktail DDI studies, and model dependent methods include population PK/PD based DDI studies. Following this, the utility of in vitro methods, various assays used and the individual assessment of the effect of cytokines on cytochrome P450 enzymes, phase II drug metabolizing enzymes and drug transporters are discussed.
The next chapter discusses the concept of using animal models for determining the clinical DDIs involving TPs. This chapter mainly concentrates on the selection of an appropriate animal model, designing an animal study for DDI studies involving biologics, utility of disease models and the challenges faced. After pre-clinical approach, the authors continue with the cocktail approach and its utility in DDI assessment for TPs. In this approach, the phenotyping substances are given together in a cocktail to test the effect of drugs at a single occasion. For performing such studies with biologics, beyond the appropriate selection of phenotyping metrics, it should be ensured that there is no relevant interaction between the individual components of phenotyping cocktail. If the interaction cannot be ruled out, the cocktail has to be split up and the interacting substance should be administered on a different day of the study. This chapter also highlights the special features and guidelines for performing such studies along with some published studies done with TPs using this approach.
The challenges in conducting TP-DI studies for oncology and non-oncology TPs were discussed separately in the subsequent chapter. Three types of studies are commonly encountered in TP-DI research areas, including screening studies, estimation studies and dedicated studies. A few additional insights to be considered for designing TP-DI studies with regards to the study population (usually diseased population and not healthy volunteers), selection of drugs, types of study design, regimen selection, sampling scheme, choosing an end-point, sample size, data analysis have also been discussed in separate sections.
The subsequent chapter compares the conventional DDI assessment with population pharmacokinetics. Though the conventional method is the most robust and least controversial in approach, population PK has a distinct advantage since it has the ability to integrate information from multiple sources. DDI assessment in phase III clinical studies using confirmatory population PK model is discussed in detail with example. In chapter 10 on scientific perspectives of TP-DI studies, the authors discuss the implications of labelling change with examples of drugs which include DDI information in their labels.
Chapters 11 to 14 describe the design and conduction of some TP-DI studies in diseased population. The design of pre-clinical and clinical studies for tocilizumab, recombinant monoclonal antibody of IgG (used in rheumatoid arthritis) is discussed in chapter 11. The clinical evaluation of DDIs involving concomitant drugs used by these patients, such as omeprazole, dextromethorphan, methotrexate, etc., has been done. The following chapters review the concept of DDI with etanercept-fusion protein, cytokines and anticytokine TPs, growth factors and hormones as examples for evaluating DDI studies. DDIs for nucleic acid based derivatives have been explored separately in chapter 15. The appendix gives a useful compilation of DDI monographs involving therapeutic biologics either as victims or perpetrators based on current US labelling information and scientific literature.
In conclusion, this book gives a comprehensive and detailed description of DDIs involving TPs. There is a uniform flow of information, gradually boosting the knowledge of the reader from basic concepts to certain advanced topics that are neatly discussed in simple language. This book can be a good resource of information for understanding certain complex concepts in DDIs, especially useful for scientists, clinical pharmacologists, researchers in pharmaceutical and biotech industries, who are involved in the drug development process.