Pharmacokinetics pharmacodynamics versus

Time-varying. Figure 1.3 shows two possible Cp versus time plots that could arise from a pharmacokinetic/pharmacodynamic system where Cl (bottom panel) or receptor density (top panel) varies sinusoidally... 

In a separate study, pharmacokinetic-pharmacodynamic modeling of the psychomotor and amnesic effects of a single oral dose of lorazepam 2 mg was investigated in 12 healthy volunteers in a randomized, double-blind, placebo-controlled, two-way, crossover study using the following tasks choice reaction time, immediate and delayed cued recall of paired words, and immediate and delayed free recall and recognition of pictures (12). The delayed recall trials were more impaired than the immediate recall trials similar observations were made with the recognition versus recall tasks. 

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. 

FIGURE 3.6 Compartmental analysis for different terms of volume of distribution. (Adapted from Kwon, Y., Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists, Kluwer Academic/Plenum Publishers, New York, 2001. With permission.) (a) Schematic diagram of two-compartment model for compound disposition. Compound is administrated and eliminated from central compartment (compartment 1) and distributes between central compartment and peripheral compartment (compartment 2). Vj and V2 are the apparent volumes of the central and peripheral compartments, respectively. kI0 is the elimination rate constant, and k12 and k21 are the intercompartmental distribution rate constants, (b) Concentration versus time profiles of plasma (—) and peripheral tissue (—) for two-compartmental disposition after IV bolus injection. C0 is the extrapolated concentration at time zero, used for estimation of V, The time of distributional equilibrium is fss. Ydss is a volume distribution value at fss only. Vj, is the volume of distribution value at and after postdistribution equilibrium, which is influenced by relative rates of distribution and elimination, (c) Time-dependent volume of distribution for the corresponding two-compart-mental disposition. Vt is the starting distribution space and has the smallest value. Volume of distribution increases to Vdss at t,s. Volume of distribution further increases with time to Vp at and after postdistribution equilibrium. Vp is influenced by relative rates of distribution and elimination and is not a pure term for volume of distribution. 

Greenblatt DJ, Shader RI Long-term administration of benzodiazepines pharmacokinetic versus pharmacodynamic tolerance. Psychopharmacol Bull 22 416 23, 1986... 

Dershwitz M, Walsh JL, Morishige RJ, Connors PM, Rubsamen RM, Shafer SL, Rosow CE (2000) Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology 93 619-628. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

Two different aspects have to be considered in the answer economic and scientific. An economic interest to have a variety of products in the market exists on the part of those pharmaceutical companies that have developed and marketed or are developing antipsychotics. Consequently, their advertising places the emphasis on the special features and advantages of individual medications, even though the differences between many products are not always very relevant clinically. Nevertheless, the differences that actually exist between products with regard to their pharmacokinetic and pharmacodynamic properties are of scientific interest, especially those related to the effects of atypical versus typical antipsychotics ... 

TABLE 5.4. General pharmacokinetic and pharmacodynamic features of protein versus chemical drugs... 

Miotto K, McCann M, Basch J, Rawson R ling W (2002). Naltrexone and dysphoria fact or myth American Journal of Addictions, 11, 151-60 Mitchell TB, White JM, Somogyi AA Bodmer F (2003). Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence. Drug and Alcohol Dependence, 11, 85-94 Mitchell TB, White JM, Somogyi AA Bochner F (2004). Slow-release oral morphine versus methadone a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction, 99, 940-5 Mitka M (2003). Office-based primary care physicians called on to treat the new addict. Journal of the American Medical Association, 290, 735-6... 

The variability in composition is because these are natural products and often are not pure extracts of a single chemical. Instead, they often contain multiple chemicals that may contribute to different beneficial or adverse effects. Composition may also vary as a function of what part of the plant is used to make the product (e.g., the root versus the stalk). In contrast to patented medications, there is no requirement to prove safety or efficacy to market it. There is also no requirement to define the basic pharmacology of the product. Hence, there is often little substantive knowledge about the pharmacodynamics or the pharmacokinetics of the compound or constituents. 

Burger F, Scholtz H, Frick AD, Becker RHA (2004) Pharmacodynamics (PD) and Pharmacokinetics (PK) of Insulin Glulisine (GLU) Versus Insulin Lispro (IL) and Regular Human Insulin (RHI) in Patients with Type 1 Diabetes. Abstract and poster presentations at the annual american diabetes congress ADA (American Diabetes Association)... 

The most common approach to in vivo pharmacokinetic and pharmacodynamic modeling involves sequential analysis of the concentration versus time and effect versus time data, such that the kinetic model provides an independent variable, such as concentration, driving the dynamics. Only in limited situations could it be anticipated that the effect influences the kinetics, for example effects on blood flow or drug clearance itself. 

Chiou, W.L. (2001) The rate and extent of oral bioavailability versus the rate and extent of oral absorption clarification and recommendation of terminology. J Pharmacokinetics and Pharmacodynamics, 28, 3-6. 

T. D. Egan, C. F. Minto, D. J. Hermann, J. Barr, K. T. Muir, and S. L. Shafer, Remifentanil versus alfentanil comparative pharmacokinetics and pharmacodynamics in healthy adult volunteers. Anesthesiology 84(4) 821-833 (1996). 

The result is that a much more empirical approach is used to describe the relationship between concentration and effect in clinical pharmacology studies. After a pharmacodynamic experiment has been conducted, concentration-effect plots are generated. The shape of the concentration-effect curve is used to determine which pharmacodynamic model will be used to describe the data. Because of this, the pharmacodynamic models used in a clinical pharmacology study are deterministic in the same way that the shape of the serum-concentration-versus-time curve determines which pharmacokinetic model is used in clinical pharmacokinetic studies. 

Age. The pharmacokinetic and pharmacodynamic effects of a drug can be influenced by age, and drug metabolism plays an important role in understanding the differences observed. Differences between the levels of metabolism enzymes for the fetal and neonatal (first 4 weeks postpartum) liver versus the adult liver have been observed in both animal and human studies (125). At birth, total CYP levels are approximately 30%of adult levels and glucuronidation activity is at 10-30% of adult levels. Interestingly, sulfotransferase activity in neonates seems to be comparable with that in adults. 

Both the rate and extent of drug distribution across tissue barriers can have a profound impact on pharmacokinetic and pharmacodynamic properties. The extent of drug distribution manifests itself locally as the tissue to plasma (or blood) concentration ratio. Collectively, the extent of distribution into all the tissues results in the apparent volume of distribution. Simply put, the pharmacokinetic parameter volume of distribution reflects the ratio of individual tissue to plasma drug concentration weighed for tissue volume. The rate of distribution (together with the extent of distribution) can influence the shape of the plasma versus time profile for a drug, which can give rise to differences in elimination half-life as well as onset and duration of action. 

Rembratt A, Grangaard-Jensen C, Senderovitz T, et al. (2004). Pharmacokinetics and pharmacodynamics of desmopressin administred orally versus intravenously at daytime versus night-time in healthy men aged 55-70 years. Eur. J. Clin. Pharmacol. 60 397-402. 

In the future, the choice between developing the racemate of a chiral drug versus single enantiomers will largely depend on a critical evaluation of their chiral characteristics with respect to their pharmacodynamic, pharmacokinetic, and toxicological effects. The potential for stereoselectivity in skin permeation due to stereochemical interactions between chiral drug, chiral excipients, and the biomembranes has generally been overlooked. Nevertheless, extrapolation of enantioselectivity in the permeation of enantiomers from in vitro data to in vivo behavior (permeation, disposition, and efficacy) is important and should be carried out carefully. 

For some dmgs, we can link the parameters and equations of pharmacokinetics to those of pharmacodynamics, resulting in a PKPD model which can predict pharmacological effect over time. This concept is discussed in more detail later in this chapter. (Equation 17.7 is a typical PKPD equation.) Figure 17.3 depicts the relationship of effect versus time for the dmg albuterol (salbuta-mol) and contrasts this with a superimposed plot of plasma dmg concentration versus time. 

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