Introduction to Pharmacokinetics
N. F. Gray in Basic Pharmacokinetics, 2012
Pharmacokinetics and its related elds have numerous applications in all stages of the drug development process. This includes studying of the drug pharmacokinetic behavior in different animal species, which can be utilized to predict the absorption, distribution, metabolism, and elimination of the drug in humans. Also, designing and preparing a suitable dosage forms of the drug for use in the preclinical and clinical phases of drug development. Moreover, identication of the range of blood drug concentration, which is associated with the optimal therapeutic effect and minimum toxicity. In addition to determination of the factors that affect the drug pharmaco kinetic behavior in the different patient populations, which is important for individualiza tion of drug therapy to achieve the optimal therapeutic outcome in all patients. The following discussion covers a brief introduction to the general principles of the eld of pharmacokinetics and its related elds.
Nonlinear Pharmacokinetics
N. F. Gray in Basic Pharmacokinetics, 2012
In the previous discussion of the pharmacokinetic behavior of drugs after single and multiple drug administration by different routes, it was assumed that the drug absorption, distribution, and elimination processes follow rst-order kinetics. In this case, the drug CLT, Vd, k, and t1/2 are constant irrespective of the administered dose, that is, dose independent and concentration independent. After administration of increasing doses of the drug, the plasma drug concentration-time proles during the elimination phase are parallel when plotted on the semilog scale. Also, the AUC of the drug from 0 to ∞ after a single drug administration is directly proportional to the administered dose, which is known as the principle of superposition. Furthermore, at steady state during multiple drug administration, the AUC from 0 to τ and the average drug concentration are directly proportional to the administered dose. The drug is said to follow linear or dose-independent pharmacokinetics when there is a linear relationship between the dose and AUC after single dose administration and the dose and steady-state concentration during multiple drug administration.
The Role of Pharmacokinetics in Drug Development
Allen Cato, Allen Sutton, Allen Cato III in Clinical Drug Trials and Tribulations, Revised and Expanded, 2002
Pharmacokinetics, a branch of biopharmaceutics, is a part of the pharmaceutical sciences that describes the relationship between the processes of drug absorption, distribution, metabolism (biotransformation), and excretion (ADME) to the time course of therapeutic or adverse effects of drugs (1). Efficacy is determined by the drug concentration at the site of action, which generally is correlated with the drug concentration in the blood. The ultimate goal of pharmacokinetics is to characterize the sources of variability in the concentration-time profile which may be correlated with variability in efficacy and adverse events. Pharmacokinetics can be used to guide dosage regimen selection and thereby optimize pharmacological effects and minimize toxicological effects when a drug is administered to an individual patient. Thus, while the basic pharmacokinetic properties of a drug are identified during the earliest stage of clinical drug development, the many factors affecting the pharmacokinetics in the patient population must be identified throughout the drug development process to enable proper dose selection for individuals.
Toward a new age of cellular pharmacokinetics in drug discovery
Published in Drug Metabolism Reviews, 2011
Fang Zhou, Jingwei Zhang, Peng Li, Fang Niu, Xiaolan Wu, Guangji Wang, Michael S. Roberts
Pharmacokinetics, pharmacology, and toxicology are the major determinants of the success or failure of candidates during drug development. Because inappropriate pharmacokinetics often leads to inefficacy, even toxicity, pharmacokinetics studies have been regarded as crucial components in drug preclinical and clinical research. However, new data increasingly reveal that drug concentrations in plasma or tissues cannot totally explain the efficacy of drug on the target organ. For most drugs that interact with targets localized in cells, intracellular penetration, accumulation, distribution, and elimination are important parameters governing the efficacy in the target cells. So, there is a pressing need to clarify the cellular pharmacokinetics and thus evaluate the efficacy of drugs in the target cells. This review provides a general overview regarding current knowledge about cellular pharmacokinetics in some specific cells and also summarizes the factors that can influence cellular pharmacokinetics. It concludes by discussing potential strategies for optimizing cellular pharmacokinetics and advocating that global cellular pharmacokinetics studies be conducted in future research toward improving drug efficacy.
Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke
Published in Expert Opinion on Drug Metabolism & Toxicology, 2011
Andrew D Greenhalgh, Kayode Ogungbenro, Nancy J Rothwell, James P Galea
Introduction: There is increasing recognition of the importance of translational pharmacokinetics in stroke research, lack of which has been cited as one of the main contributing factors to failure of Phase III trials. Areas covered: The article reviews the translational issues in administration, distribution and sampling in the pharmacokinetics of putative therapeutic drugs in stroke. In addition, the role of translational pharmacometrics in drug development is discussed. The review uses the anti-inflammatory agent, IL-1 receptor antagonist, as an example. The reader will gain an insight into the pitfalls that are commonplace in translating pharmacokinetics from the preclinical to the clinical scenario. The reader will also gain an understanding of the complexities of blood–central nervous system (CNS) barriers in relation to brain pharmacokinetics and the increasing use of translational pharmacometrics in stroke research. Expert opinion: The translation of preclinical to clinical pharmacokinetics is a discipline that is traditionally overlooked and is likely to be a key factor responsible for failure of clinical trials. With a clear comprehensive insight into the benefits and limitations of translational pharmacokinetics in stroke, translational pharmacokinetics can be safely used to enhance the efficacy of clinical trials in stroke and their likelihood of success.
Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy relationships
Published in Expert Opinion on Drug Metabolism & Toxicology, 2021
ABSTRACT Introduction: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice. Areas covered: This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities. Expert opinion: Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients’ optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.
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