Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
One of the most effective ways in which regulatory agencies communicate with sponsors and guide drug development is through the issuance of guidances or guidelines. These can be issued domestically ...in a given region such as the United States by the Food and Drug Administration (FDA) or internationally through the International Conference on Harmonization. Currently, there are over 400 final or draft guidances that can be found through the FDA website. The development of guidances proceeds through a process known as Good Guidance Practices, which is intended to assure that there is an appropriate level of meaningful public participation in the development of guidance. In the past 10 years, clinical pharmacology guidances covering important areas have been issued, including pharmacokinetic data in patients with renal and hepatic impairment, dose‐response studies, and drug‐drug interactions.
Clinical Pharmacology & Therapeutics (2007) 81, 298–304. doi:10.1038/sj.clpt.6100054
Individualization of drug therapy, described as tailoring drug selection and drug dosing to a given patient, has been an objective of physicians and other health‐care providers for centuries. An ...understanding of the pathogenesis of the disease, the mechanism of action of the drug, and exposure–response relationships provides the framework for individualization. There are many approaches to individualization: selecting an antibiotic based on minimum effective concentrations and bacterial sensitivity, population (sparse sample) pharmacokinetics, therapeutic drug monitoring and, more recently, pharmacogenomics. The goal of individualization is to optimize the efficacy of a drug, minimize its toxicity, or both. With the growth of technology and databases, drug–disease–trial models and simulation have become useful for integrating information from many different domains. Physiology‐based pharmacokinetic (PBPK) models have provided a mechanistic approach to individualization, and clinical trial designs such as those involving enrichment have also enabled individualization. In the future, “‐omics” technologies, vaccines, ex vivo gene therapy, and the so‐called “diseases‐in‐a‐dish” will provide additional strategies to achieve individualization.
Clinical Pharmacology & Therapeutics (2012); 92 4, 458–466. doi:10.1038/clpt.2012.113
Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or ...lowering the risk of toxicity. Model‐informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large‐scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become “widespread clinical practice,” among those, wider interdisciplinary collaborations and the necessity for further evidence‐based efficacy and cost–benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.
A systems pharmacology model typically integrates pharmacokinetic, biochemical network, and systems biology concepts into a unifying approach. It typically consists of a large number of parameters ...and reaction species that are interlinked based upon the underlying (patho)physiology and the mechanism of drug action. The more complex these models are, the greater the challenge of reliably identifying and estimating respective model parameters. Global sensitivity analysis provides an innovative tool that can meet this challenge.
CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 69–79; doi:10.1002/psp4.6; published online 25 February 2015
The US Food and Drug Administration (FDA) is currently developing a guidance for industry to replace a previous guidance, “Pharmacokinetics in Patients With Impaired Renal Function—Study Design, Data ...Analysis, and Impact on Dosing and Labeling” (renal guidance) issued in May 1998. The impact of the 1998 renal guidance was assessed following a survey of 94 new drug applications (NDAs) for small‐molecule new molecular entities (NMEs) approved over the past 5 years (2003–2007). The survey results indicate that 57% of these NDAs included renal impairment study data, that 44% of those with renal data included evaluation in patients on hemodialysis, and that 41% of those with renal data resulted in recommendation of dose adjustment in renal impairment. In addition, the survey results provided evidence that renal impairment can affect the pharmacokinetics of drugs that are predominantly eliminated by nonrenal processes such as metabolism and/or active transport. The latter finding supports our updated recommendation to evaluate pharmacokinetic/pharmacodynamic alterations in renal impairment for those drugs that are mainly eliminated by nonrenal processes, in addition to those that are mainly excreted unchanged by the kidney.
Clinical Pharmacology & Therapeutics (2009); 85, 3, 305–311 doi:10.1038/clpt.2008.208
Transporters are membrane‐bound proteins that control the access of endogenous and xenobiotics (drugs) to various sites in the human body. They influence drug pharmacokinetics and pharmacodynamics ...(both benefit and risk) by affecting a drug's absorption, distribution, metabolism (via control of access to metabolizing enzymes), and excretion (ADME) and by controlling drug concentrations at the site of action. Like metabolizing enzymes, transporters have binding sites that are saturable and can be inhibited or induced.
Clinical Pharmacology & Therapeutics (2011) 89 4, 481–484. doi:10.1038/clpt.2010.359
This commentary focuses on the status of oral anticoagulants, namely, warfarin and the novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban.
The market for molecular diagnostic tests is predicted to grow at extraordinary rates over the next 10 years, fueled by pharmacogenetics and the elusive dream of personalized medicine. The challenge ...is managing the expectations of the medical community and the public at large that have already been set by speculation, promises, and the repeated exposure to headlines about genetic discoveries. Personalized medicine is a paradigm that exists more in conceptual terms than in reality, with only a few marketed drug–test companion products and not very many actual clinical practices set up to personalize medicine in the way that supporters have intended. Nevertheless, the reality of personalized medicine has become more imminent because of the increased awareness of the shortcomings in the delivery of drugs with adequate benefit/risk to patients, a better molecular understanding of how to optimize drug selection and dosing, and an increased demand for integrating more clinically relevant genetic information into the drug development process to improve both innovation and productivity. This paper focuses on personalized medicine by (1) looking at some converging changes taking place in the health‐care landscape that are creating a scientific and social infrastructure to enable personalized medicine, (2) considering challenges that need to be addressed with regard to clinical evidence standards for validating genotype–phenotype associations, and (3) considering how clinical pharmacology can help construct a rational personalized medicine framework. As therapeutic experts, clinical pharmacologists can work to assure that “good therapeutics follows good diagnostics”. They are well equipped to provide timely genetic education to others and to interpret genetic data so that actionable decisions, especially about drug dosing in individual patients, can be implemented in clinical practice.
Clinical Pharmacology & Therapeutics (2007) 81, 807–816. doi:10.1038/sj.clpt.6100204
Many intrinsic and extrinsic factors can affect an individual patient's drug exposure and response.1 The US Food and Drug Administration (FDA) has published a number of guidances that recommend how ...and when to evaluate these factors during drug development.2 The most recent FDA draft guidance on drug interactions3 provides advice for in vitro and in vivo drug interaction studies, including suggestions for study design, dosing strategies and analysis, and interpretation of data for medical product labels. The draft guidance3 updated the FDA's recommendations on the evaluation of important cytochrome P450 (CYP) enzyme‐ and transporter‐based drug interactions during drug development.
Clinical Pharmacology & Therapeutics (2010) 87 4, 497–503. doi:10.1038/clpt.2009.308
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