Pharmacodynamics parameters

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. 

There has been tremendous progress in the identification of pharmacokinetic and pharmacodynamic parameters in chronically ill infants and children. 

Obviously, if the clinical mirror approach to bioequivalency testing gains momentum, we may expect to see more quantification of clinical response in bioequivalency studies. In some instances pharmacodynamic parameters that are amenable to precise quantification are easily identified. Thus, if we are working with an antihypertensive drug, measurement of blood pressure using an electronic sphygnomanometer is an obvious option. However, for many drugs there is no simple way to quantify pharmacodynamic response. In some cases we may have to rely, to some extent at least, on patient diaries [41]. Such techniques are open to criticism of subjectivity and imprecision. 

Renwick (1991, 1993) analyzed interindividual differences of healthy volunteers by comparing the maximum and mean values of pharmacokinetic parameters (7 substances) and pharmacodynamic parameters (6 substances). The data indicated that toxicokinetic differences were slightly greater than toxicodynamic differences. With one exception, the ratios between the maximum and mean value for a substance s kinetic parameter ranged from 1.8 to 4.2 with most values between 3 and 4, and it was concluded that a factor of 3-4 would be sufficient to consider toxicokinetic differences for 99% of the healthy, adult population and for 80% of the substances. The ratios between the maximum and mean value for a substance s dynamic parameter ranged from 1.5 to 6.9 with most values between 1.7 and 2.7. Based on the analyses, Renwick proposed to subdivide the interindividual factor of 10 into a factor of 4 for pharmacokinetic differences and a factor of 2.5 for pharmacodynamic differences. The aim of the subdivision of the 10-fold factor was to allow the incorporation of suitable compound-specific data for one particular aspect of uncertainty. 

Do not substitute subcutaneous administration of/Avonex for IM administration. Subcutaneous and IM administration have been observed to have nonequivalent pharmacokinetic and pharmacodynamic parameters. 

The treatment of the data proceeds as a two step procedure. First, a suitable PK model is fitted to the concentration-time data. Then a PD model is fitted to the data as described by the PK model, simultaneously solving for pharmacodynamic parameters (e.g. max. 50% s) and the effect compartment parameter eO-... 

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. 

Until recently, only a few studies have utilized human lymphocytes or Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) derived from the CEPH to identify heritable traits related to drug sensitivity or other drug-induced pharmacodynamic parameters (3,4). However, these studies are providing evidence for the broad applicability of this approach to pharmacogenomic research. 

Contradicting results were reported for GFJ when administered with caffeine. One study reported no changes in AUC, blood pressure, and heart rate (173). A second study reported increases in AUC and half-life. However, no assessment of pharmacodynamic parameters was performed (89). Furthermore, GFJ increased the fraction absorbed and the percentage of excreted dextromethorphan (28). The above-mentioned interactions can be considered weak regarding the overall exposure. Furthermore, dextromethorphan has a broad therapeutic window. The interactions of GFJ with caffeine and dextromethorphan do not seem to be of clinical relevance. 

Table 3-1 Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs.

Pharmacokinetic and Pharmacodynamic Parameters for Insulin and Glucose Following Rectal Administration of Insulin, SNAP, and Carboxy-PTIO... 

Figure 1.3 Plots showing two different scenarios caused by time- or state-varying pharmacokinetic or pharmacodynamic parameters.

Includes herbal medications whose pharmacodynamic parameters have been delineated at the molecular level Provides clinical materials, pharmacological concepts, and ancient wisdom about appropriate usage of drugs Presents state-of-the-art and newly designed diagrams to provide an account of how these medications work... 

Table 3-1. Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs. (See Speight Holford, 1997, for a More Comprehensive Listing.)...

Craig, W. A. (1998) Pharmacokinetic/ pharmacodynamic parameters rationale for antibacterial dosing of mice and men. Clin Infect Dis. 26, 1-10. 

Quinones-Torrelo, C., Sagrado, S., Villanueva-Camanas, R.M., and Medina-Hernandez, M.J., Retention pharmacokinetic and pharmacodynamic parameter relationships of antihistamine drugs using biopartitioning micellar chromatography, J. Chromatogr. B, 761, 13-26, 2001. 

In actual practice, nonlinear regression is used to fit a suitable pharmacokinetic model described by the function c (t) to time—concentration data. Then, the estimated parameters are used as constants in the pharmacodynamic model to estimate the pharmacodynamic parameters. Alternatively, simultaneous fitting of the model to the concentration-effect—time data can be performed. This is recommended as c (t) and E (t) time courses are simultaneously observed. 

It is also worthy of mention the work on the pharmacodynamics of midazolam in rats of Cleton et al. [575]. These authors found that the rate of change in plasma concentration is an important determinant of midazolam pharmacodynamics. In addition, the relationship found between the rate of change of blood concentration and the values of the different pharmacodynamic parameters is rather complex. These findings indicate that in vivo a homeostatic control mechanism is operative that may modify the sensitivity to midazolam and whose activation is largely influenced by the rate of presentation of the drug in blood. 

For the purposes of simplicity, the description of each study is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety (and pharmacodynamic) parameters are also studied. 

While formulation interactions often are subject to in vitro investigations, the section below presents a particular example of an in vivo formulation interaction study (CPMP/EWP/QWP/1401/98 2002) a potential interaction of a drug in medical practice frequently given concomitantly with another drug (i.e. both mixed in a syringe) was subject to a clinical study which is illustrated below. For the purposes of simplicity, the description is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety and pharmacodynamic parameters were also studied. 

To identify which pharmacokinetic and pharmacodynamic parameters of a drug are likely to be affected by different types of liver disease... 

However, pH does not always influence the rate or extent of absorption. For example, McElnay et al. found that captopril pharmacodynamic parameters (blood pressure, heart rate, and plasma renin activity) did not differ significantly between buffered and unbuffered sublingual administration, suggesting that manipulation of pH had little effect. It was, therefore, proposed that a mechanism other than passive diffusion was involved in the buccal absorption of this drug. 

Tolerance Model For some drugs, pharmacodynamic parameters like max and ECsn may appear to vary over time, resulting in changes in pharmacological response despite the presence of constant concentrations at the effect site. Tolerance is characterized by a reduction in pharmacological response after repeated or continuous drug exposure. The complex mechanism of tolerance may involve receptor pool depletion, decrease in receptor affinity, and up- or down-regulation. 

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