Pharmacokinetics/pharmacodynamics PK/PD

Colburn WA. Combined pharmacokinetic/ pharmacodynamic (PK/PD) modelling. /Clin Pharmacol 1988 28 769-71. 

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. 

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. 

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). 

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]. 

Tsuchihashi, M. Harashima, H. Kiwada, H. Development of a pharmacokinetic/pharmacodynamic (PK/PD)-simulation system for doxorubicin in long circulating liposomes in mice using peritoneal P388. J. Controlled Release. 1999, 61 (1-2), 9-19. 

Derendorf H, Meibohm B. Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships Concepts and perspectives. Pharma Res. 1999 16(2) 176-185. 

There are several approaches to population model development that have been discussed in the literature (7, 9, 15-17). The traditional approach has been to make scatterplots of weighted residuals versus covariates and look at trends in the plot to infer some sort of relationship. The covariates identified with the scatterplots are then tested against each of the parameters in a population model, one covariate at a time. Covariates identified are used to create a full model and the final irreducible, given the data, is obtained by backward elimination. The drawback of this approach is that it is only valid for covariates that act independently on the pharmacokinetic (PK) or pharmacokinetic/pharmacodynamic (PK/PD) parameters, and the understanding of the dimensionality of the covariate diata is not taken into account. 

---