Pharmacokinetics and pharmacodynamic PK-PD

Ultimately rapid methods are needed to obtain data adequate at each stage of drug discovery. At candidate selection level the extrapolation from animals to man, through the integration of pharmacokinetics and pharmacodynamics (PK/PD), becomes crucial for success [62, 63]. Such HT methods are currently being implemented and further developed in the pharmaceutical and biotechnology industry. 

More recently, Hayashi et al. reported the results of pharmacokinetic and pharmacodynamic (PK/PD) analysis for rhG-CSF (lenograstim) after s.c. administration... 

Brenn et al. [ 153] compared the efficacy of antibiotics commonly used in dental and oral clinical practice in application to the bacteria most frequently isolated in odontogenic infections (S. viridans, Peptostreptococcus spp, Prevotella intermedia, Porphyromona gingivalis and Fusobacterium nucleatum) based on pharmacokinetic and pharmacodynamic (PK/PD) analyses (effect of the human body upon the drug, reflected by the plasma concentration profile-pharmacokinetics, and the effect of the drug upon the body, as defined by the minimum inhibitory concentration, or MIC-pharmacodynamics). Antibiotics commonly used in dental practice, such as erythromycin, metronidazole or azithromycin, were found to be ineffective in apphcation in over 30% of the strains (39.1%, 50.5% and 33.2%, respectively) [154]. 

Drag => PK -I- PD => Individualized Dose Also pharmacogenetics (PG) can be integrated into a common concept, and be figured as pharmacokinetic (PK) and pharmacodynamic parameters (PD) for the individual patient. 

Human pharmacology (Phase I) Assess tolerance Define/describe pharmacokinetics and pharmacodynamics Explore drug metabolism and drug interactions Estimate activity Dose-tolerance studies Single and multiple dose PK and/or PD studies Drug interaction studies... 

To Study interactions between proteins and drugs, an available tool is the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) Associated Protein Database (see Table 1.5). The database contains information about relevant proteins, functions, similarities, substrates and hgands, tissue distributions, and other features of targets. Eor the understanding of pharmacokinetic (PK) and pharmacodynamic (PD) features, some available resources are listed in Table 1.5. For example, the Pharmacokinetic and Pharmacodynamic Resources site provides links to relevant software, courses, textbooks, and journals (see Note 5). For quantitative structure-activity relationship (QSAR), the QSAR Datasets site collects data sets that are available in a structural format (see Table 1.5). 

At the beginning of the project, it is often difficult to have a precise idea of the projected therapeutic dose. Projects usually start with an estimated average potency of 1 mg/kg, once daily dose as an optimal approach. When initial pharmacokinetic/ pharmacodynamic (PK/PD) data becomes available one can better refine the TCP. Table 3.1 gives some guidelines on how to adjust the solubility requirement depending on the therapeutic dose and compound permeability. 

Using human physiology and in vitro data and clinically relevant input parameters (i.e., metabolic stability in human hepatocytes and microsomes as well as prothrombin time measured in various batches of human plasma) the model was extended to human. This human PK/PD model was then used to investigate the impact of the various physicochemical, pharmacokinetic and pharmacodynamic properties on the anticoagulant profile (i.e., prothrombin time) expected in man. 

Danhof, M., de, L., Elizabeth, C.M., Delia, P., Oscar, E., Ploeger, B.A. and Voskuyl, R.A. (2008) Mechanism-based pharmacokinetic-pharmacodynamic PK-PD modeling in translational drug research. Trends in Pharmacological Sciences, 29, 186-191. 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

The primary objective of the early efLcacy studies is to validate the pharmacology model with a compound that is known to interact with the desired receptor and develop the Pharmacokinetics-Pharmacodynamics (PK-PD) relationship for further screening during lead optimization (Neervan-nan, 2006). It is essential that the excipients selected forthe vehicle do not interfere with the measured end points especially, for a disease-relevant animal model that has no clinically effective drugs to validate an animal model. In this situation, vehicles should be used as negative controls in the studies. 

Meibohm, B., and Derendorf, H. (1997). Basic concepts of pharmacokinetic/ pharmacodynamic (PK/PD) modelling. Int. J. Clin. Pharmacol. Ther. 35 401-413. 

Fig. 1.3 Pharmacokinetic/pharmacodynamic (PK/PD) modeling as combination of the classic pharmacological disciplines pharmacokinetics and pharmacodynamics (from [5]).

Fig. 1.4 Examples of the application of pharmacokinetic/pharmacodynamic (PK/PD) concepts in preclinical and clinical drug development (from [10]).

Therefore, this review of pharmacokinetic/pharmacodynamics (PK/PD) correlation will include investigations between the effective concentrations at the target sites of antisense oligonucleotides with each of the pharmacological effects discussed above. Moreover, an establishment of the correlation between plasma equilibrium concentrations with concentrations at the target sites is pertinent, enabling plasma concentrations to be used as a surrogate in clinical studies to establish relationships between pharmacodynamics and pharmacokinetics. 

Various hyphenated LC-MS-based assays, using either the electrospray ionization (ESI) or the atmospheric pressure chemical ionization (APCI) interface, have been developed and applied in the clinical setting in order to support pharmacokinetic (PK), pharmacogenetic-pharmacokinetic (PG-PK), and pharmacokinetic-pharmacodynamic (PK-PD) studies in BC patients under tamoxifen therapy (Table 3). 

Oral dmg product formulation and manufacturing process development can use a hierarchical approach to meeting three conditions based on, in order of importance, bioavailability, stability, and manufacturability. The bioavailability of a drug product is the most critical condition and must meet established criteria or the product is not viable. Dmg substance properties such as salt form, solubility, and particle size can significantly affect pharmacokinetic and pharmacodynamic performance of a product. The dosage form platform, formulation design, and manufacturing process can also affect the PK/PD profile of a product. Therefore, all selections must maintain the required pharmacokinetic/pharmacodynamic outcome and work within these confines to achieve a stable and robust product/process. 

In this case study a simulation strategy, based on a mechanistic PK/PD model, was developed to predict the outcome of the first time in man (FTIM) and proof of concept (POC) study of a new erythropoietin receptor agonist (ERA). A description of the erythropoiesis model, along with the procedures to scale the pharmacokinetics and pharmacodynamics based on preclinical in vivo and in vitro information is presented. The Phase I study design is described and finally the model-based predictions are shown and discussed. 

In general, multiple (up to 30-40) blood samples can be obtained per subject to measure dmg and metabolite concentrations as well as biomarkers in these phase I clinical trials. Furthermore, pharmacodynamic measurements can be included to get a first impression on the drug effect in humans, however, limited by the fact that healthy volunteers were studied and not patients. As strict inclusion and exclusion criteria are used, the demographic characteristics of the healthy volunteers do not provide sufficient spread to investigate the effect of intrinsic factors. Therefore, phase I trials provide very rich data to develop pharmacokinetic and pharmacodynamic models on biomarker, but cannot be used to develop models for efficacy, safety, influence of patient factors on PK and/or PD and disease progression. 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

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