**2.3 The PD-PG models**

160 Biomarker

4. Poblational models, are used to solve the problem of inter and intra-individual variability in the therapeutic response to a drug. In PK and PD models, the kinetic parameters of each individual are modeled in terms of the fixed effect observed, and other of random nature, while PK-PD poblational models, based on nonlinear mixed effects analysis, characterize the pharmacokinetic parameters and concentration-effect relationship, in poblational terms more than individual. Thus, in PK and PK-PD poblational models, we need to know in advance the average behaviour of pharmacokinetic parameters in target population, to identify and assess demographic, pathophysiological and environmental factors, affecting population under study and, finally, evaluate the inter and intraindivual variability through the variation coefficient of the PK parameters and their residual components (Dominguez-Gil & Lanao 1999;

Consist of mathematical expressions that describe the quantitative relationship between the drug dose necessary to achieve the same response intensity of a Biomarker or Surrogate Marker, for each one of the different genotypes phenotypically actives present in a

Pharmacogenetic models, PK-PG, are used to adapt the therapeutic use of different drugs to the idiosyncrasy of each patient and their genetic characteristics, increasing its efficiency and minimizing their side effects. Approximately 20-90% of the interindividual variability in drug response is consequence of individual genotype and variants that encode different

Single Nucleotide Polymorphisms, SNPs, have been associated with substantial changes in the metabolism or in the effect of a drug, and therefore are being used to predict the clinical response to a drug of an individual. For the biotransformation of a drug, there are over 30 families of metabolizers enzymes belonging the family of cytochrome P-450, whose genetic polymorphisms normally lead to a functional changes in the encoded protein, resulting in

a. Poor Metabolizers, PM: The encoded enzyme has no activity, the metabolic activity is very reduced or absent and the phenotype is predicted by the presence of two inactive alleles. b. Intermediate Metabolizers, IM: The encoded enzyme has its activity decreased, the phenotype is predicted by the presence of two alleles with decreased activity, or a

c. Extended metabolizers, EM: They are carriers of one active gene copy at least, have a normal metabolic activity and phenotype is predicted from the combination of two active alleles. For some genes, the presence of one active allele combined with one allele with decreased activity or allele with no activity, causes that the metabolic activity was

d. Ultrafast Metabolizers, UM: They have a double metabolic capacity and the phenotype is predicted by the presence of three or more functional alleles or the presence of two inducible alleles http://cpmc.coriell.org/Sections/Medical/DrugsAndGenes\_mp

Carrier proteins of drugs play an important role in regulating the absorption, distribution and excretion of many drugs. Within the ATP-binding cassette family, P-glycoprotein,

combination of a reduced activity allele and a allele with no activity.

polymorphs of the enzymes that metabolize and / or transport drugs.

Schnider et al 1996).

individuals with different phenotypes:

**2.2 The PK-PG models** 

population.

normal.

.aspx?PgId=216).

PD-PG models, consist of mathematical expressions that describe the quantitative relationship between the response intensity of a Biomarker or Surrogate Marker, to a single dose of the drug, and the different genotypes phenotypically actives present in a specific population.

Pharmacogenetic models, PD-PG, are used to adapt the therapeutic use of different drugs to the idiosyncrasy of each patient and their genetic characteristics, increasing its efficiency and minimizing their side effects. Approximately 20-90% of the interindividual variability in drug response is consequence of individual genotype and variants that encode different polymorphs of therapeutic targets.

Genetic polymorphisms with indirect effects on the response to drugs are those that affect to a genes encoding proteins that often are involved in the mechanisms of the drug disposition, producing alterations in the response to treatment only under certain situations.

Therefore, both PK -PG and PD-PG models are used to describe the genotype-phenotype, gene-concentration and gene-dose correlations, necessary to achieve an optimal pharmacotherapy (Brockmöller & Tzvetkov 2008, Tsai & Hoyme 2002; Weinshilboum & Wang 2006).
