The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.

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Pharmacokinetics and dosage adjustment in patients with renal dysfunction

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.

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on "how PBPK modeling can be applied in industry" focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.

Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective.

A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity

Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms “PBPK” and “physiologically based pharmacokinetic model” to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

https://dmd.aspetjournals.org/content/dmd/early/2015/10/06/dmd.115.065920.full.pdf

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

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.

T. C. Wu

Papers

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications