**3.3.2.1 PK-PD model**

166 Biomarker

the PM phenotype in homozygous and for IM phenotype in heterozygous, when to present (Zhou 2008), obtaining from the application of the equation 2, the following equi-effective

The poblational analysis of PRL values, using Kernel`s test, allowed us to detect two subpopulations, sex-linked, and related to an alteration of the dopaminergic and / or serotonergic pathways, caused by a combination of polymorphisms of the genes encoding receptors 5-HT2a , D2, and SERT, among others, obtaining from the application of the

> DOSE genotype : wild type 0.4 / 2.5 DOSE genotype : polimorphic type

Since the HPA axis regulation appears altered in patients with schizophrenia, its modulation may be relevant for the control of symptoms in schizophrenia and antipsychotic treatment response. Otherwise, cortisol can be used as surrogate of the 5HT2a receptor blockade, the receptor that has manifested itself as the most important in the serotonergic regulation of HPA axis and, thus, can be used as Surrogate Marker for dosing antipsychotics that act predominantly on the serotonergic pathways (Marx & Lieberman 1998; Meltzer et al 2001; Morrow et al 1995). Moreover, the alteration of the HPA axis, induced by antipsychotic with capacity for serotoninergic antagonism, that bind strongly to receptors 5-HT2a/2c, can be used to modulate the response of cortisol and, eventually, to suppress the axis and to cause a decrease of the corticotropin-releasing factor, CRF, and the adrenocorticotropin hormone,

Clozapine and Olanzapine, a 5HT2a antagonists, show strong affinity for some dopamine receptors, but weak ability to antagonize the D2 receptor, a receptor that modulates the neuroleptic activity. Evidence has shown that cortisol levels achieved in individuals treated with olanzapine and clozapine are dose dependent and directly proportional to the plasma

Not only Olanzapine and Clozapine have shown a dose-dependent effect on the plasma cortisol levels, Risperidone also has significant effects but less pronounced compared with Olanzapine and Clozapine, whereas, Haloperidol has more modest effects. Olanzapine and Clozapine produce a cortisol increases, Δ-delta, up to 4-5 times higher than those produced by Haloperidol, while, risperidone produces a cortisol increases almost 1.5 times greater than observed with Haloperidol. Therefore, antipsychotics dosage are suitable to be

concentrations of these drugs, at the start of antipsychotic treatment and along it.

monitored by using cortisol plasma levels (Girdler et al 2001).

 DOSE CYP2D6 phenotype : EM <sup>3</sup> DOSE CYP2D6 phenotype : PM

dose ratios:

(Lozano et al 2007, 2010c).

**3.3.2 Clozapine and olanzapine** 

**3.3.1.3 PD-PG model** 

 DOSE CYP2D6 phenotype : EM 1.5 DOSE CYP2D6 phenotype : IM and

equation 2, the following equi-effective dose ratio:

ACTH (Morrow et al 1995; Patchev et al 1994).

in men and women, respectivily (Lozano et al 2007, 2010c).

Mechanistic-model. Clozapine and Olanzapine, among other antipsychotics, cause an increase plasma cortisol levels in a dose-dependent manner, so the daily dosage has to be increased or decreased in order to reach cortisol plasma levels of 19.6 ± 6.6 mcg / dL and 18.3 ± 5.3 mcg / dL, the Clinical Surrogate Endpoint for Clozapine or Olanzapine, respectively (Lozano et al 2007, 2008a, 2010c, 2011a).

Once the steady-state and a pharmacological response, ranging between the 20-80% of maximal effect, is reached, we can estimate the optimal dose required to achieve cortisol values of 19.6 ± 6.6 mcg / dL and 18.3 ± 5.3 mcg / dL, the Clinical Surrogate Endpoints for Clozapine or Olanzapine, respectively, using equation 2 (Lozano et al 2008a, 2011a).
