Pharmacodynamics pharmacokinetic correlations

Calculated molecular properties from 3D molecular fields of interaction energies are a novel approach to correlate 3D molecular structures with pharmacodynamic, pharmacokinetic and physico-chemical properties. The novel VolSurf descriptors quantitatively characterize size, shape, polarity, hydrophobicity and the balance between them. 

Dowell JA, Stogniew M, Krause D, Henkel T. (2003) Anidulafungin (ANID) pharmacokinetic (PK)/Pharmacodynamic (PD) correlation Treatment of esophageal candidiasis. 43rd Interscience Conference of Antimicrobial Agents and Chemotherapy Abstract A-1578. 

There was no correlation between the in vivo and in vitro antimalarial activity. This may be due to pharmacodynamics/pharmacokinetics (biotransformation and bioavailability) of the constituents and the active compounds in vivo. However, both extracts had similar survival times (14.0 and 15.0 days) to that of the reference drug CQ (p > 0.05). 

Pharmacokinetic and Pharmacodynamic Parameters Correlating with Antibacterial Activity... 

H. Derendorf and G. Hochhaus, Handbook of Pharmacokinetic / Pharmacodynamic Correlation, CRC Press, Boca Raton, FL, 1995. 

IV iron preparations have different pharmacokinetic profiles, which do not correlate with pharmacodynamic effect. 

Pharmacokinetics and ADME Correlation with Pharmacodynamics Low dose High dose General Toxicity... 

Pharmacokinetic/pharmacodynamic model using nonlinear, mixed-effects model in two compartment, best described time course of concentration strong correlation with creatinine clearance predicted concentration at the efi ect site and in reduction of heart rate during atrial fibrillation using population kinetic approach... 

Pharmaceutical firms have to reexamine their strategies to devise means to increase their drug pipelines for continuous streams of products. The high failure rates of Investigational New Drugs during clinical trials (see Exhibit 5.8) necessitate the development of better assay systems and animal models that correlate closely with human pharmacodynamics and pharmacokinetics. The study of pharmacogenomics will be crucial to address this issue. 

The relationship between toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) parameters is a difficult one and somewhat poorly characterized. The key targets of HDACi are unknown and predicting which patients will respond to HDACi therapy is difficult. Correlation between surrogate markers (for example, levels of acetylated histones in peripheral blood mononuclear cells [PBMNC] pre- and post-dosing) is not always in keeping with measured PK profiles. 

Limitations of semm levels pharmacokinetic parameters determined in blood are not closely indicative of the situation in the central compartment (here the CNS) serum levels are not correlated with activity (pharmacodynamics) in general, only the mother molecule is assayed although its metabolites may be active or toxic the relationship between concentration (PK) and activity (PD) is often complex assays of free forms would be more pertinent. 

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

Perez-Reyes et al.8 estimated that only 32% of a dose of cocaine base placed in a pipe is actually inhaled by the smoker. Cone9 compared the pharmacokinetics and pharmacodynamics of cocaine by the intravenous, intranasal, and smoked routes of administration in the same subjects. Venous plasma cocaine concentrations peaked within 5 min by the intravenous and smoked routes. Estimated peak cocaine concentrations ranged from 98 to 349 ng/ml and 154 to 345 ng/ml after intravenous administration of 25-mg cocaine hydrochloride and 42-mg cocaine base by the smoked route, respectively. After dosing by the intranasal route (32 mg cocaine hydrochloride) estimated peak plasma cocaine concentrations ranged from 40 to 88 ng/ml after 0.39 to 0.85 h.9 In this study, the average bioavailability of cocaine was 70.1% by the smoked route and 93.7% by the intranasal route. Jenkins et al.10 described the correlation between pharmacological effects and plasma cocaine concentrations in seven volunteers after they had smoked 10 to 40 mg cocaine. The mean plasma... 

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. 

Cortes JE et al (2009) Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 23 1537-1544... 

Billemont B, et al. (2009) Correlation of sorafenib plasma concentrations and clinical toxicity a prospective population pharmacodynamic and pharmacokinetic study. J Clin Oncol 27 (No 15 S) (May 20 Suppl, el4585)... 

Cox, E.H. et al. Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of synthetic opioids in the rat correlation with the interaction at the mu-opioid receptor. J Pharmacol Exp Ther 1998, 284 1095-1103. 

It was found that pharmacokinetic-pharmacodynamic correlation in mice demonstrated that plasma concentrations of > 40 pmol/L after pazopanib (30 mg/kg p.o.) inhibited VEGF-induced VEGFR2 phosphorylation for more than 8 h. The mean plasma concentrations were 153.9,47.5,41.1, 17.4, and 4.3 pmol/L at times of 1,4, 8, 16, and 24 h. 

Derendorf, H. and Hochhaus, G., Handbook of Pharmacokinetic/Pharmacodynamic Correlation, CRC, 1995. 

Bioequivalence and -avalibility can be assessed in vitro, for example in dissolution tests for controlled release forms, or in vivo in experimental animals in pharmacokinetic and/or pharmacodynamic studies. The results should be correlated with the pharmacological effects in the target organism. If the modified product is not bioequivalent or shows different therapeutic effects, clinical studies will be necessary. Products which have a narrow therapeutic ratio (e.g. a less than twofold difference between the minimum toxic and minimum effective concentration in the body 21 CFR 320) require clinical studies under all circumstances. 

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