**3.4.2 PK-PG model**

Poblational analysis of the index, testosterone/creatinine in urine, using Kernel`s test , have allowed us to detect 3 different populations, as a result of combination of the different polymorphisms affecting the genes that encode CYP3A, CYP2B6, and NAT2, obtaining from the application of the equation 2, the following equi-effective dose ratio:

> DOSE genotype : wild type 2 or 4 DOSE genotype : polimorphic type

in dependence of the variant alleles present (Lozano et al 2008b, 2009b).

#### **3.5 Lamotrigine**

Lamotrigine is a drug specifically used for epilepsy but also is effective as a mood stabilizer in treating bipolar depression, one of the most intractable stages of this disorder. Its iatrogenic effects, rare but extremely serious, such as Stevens-Johnson syndrome or Lyell syndrome, usually appear at 2-8 weeks of starting treatment. With unknown mechanism of action, it is believed that acts on sodium channels, its use is reserved for prevention of depressive episodes in bipolar disorder.

Lamotrigine is eliminated from the body by the action of the UGT1A4 enzyme, competing with bilirubin for the formation of their respective conjugates with glucuronide acid. Taking advantage of this interaction over UGT1A4, we can use bilirubin plasma levels as a indicator of plasma Lamotrigine concentration (French 2004; Lees & Leach 1993; Pellock 1999; Ramsay et al 1991; Rogawski & Löscher 2004).

The influence of bilirubin and other inhibitors of the UGT1A4 enzyme, on plasma concentrations of Lamotrigine, is calculated assuming a Michaelis-Menten kinetics, using equation 4, and a competitive inhibition model, as follows:

$$\Delta\left[L\text{tg}\right] = \frac{\Delta\left[Bil\right]}{\left[E\_o\right]^2 \mathcal{K}\_{\mathcal{M}\_{\text{Idg}}} \mathcal{K}\_{\mathcal{M}\_{\text{Sil}}}} \tag{6}$$

(Eo = [UGT], KM = Michaelis-Menten Constant) (Bil= Bilirrubina, Ltg= Lamotrigina, Inh= Inhibidor)

allowing us to conclude that the main factors affecting Cp of Lamotrigine are the amount of UGT enzyme (Eo) and KM values of inhibitors with respect to those of Lamotrigine and Bilirubin, according to the following relation:

$$\frac{\Delta\left[L\text{tg}\right]}{\Delta\left[Inh\right]} = \frac{K\_{M\_{\text{ho}}}}{K\_{M\_{\text{lo}}}} \tag{7}$$

This method described above allows the analysis of the main factors affecting competitive inhibition between two substrates, such as: UGT enzyme concentration, exponentially, and KM value of substrates (Lozano et al 2009a, 2009b, 2010d).

#### **3.5.1 PK-PG model**

168 Biomarker

The ability of opioid drugs to reduce serum testosterone levels, also, can be effectively used as a measure to assess the pharmacological activity of Methadone. Therefore, indirect assessment of the Methadone concentration in the biophase, can be accomplished by using the test of depletion of testosterone or test of depletion of LH that, also, seems to be specific for narcotic effect and correlates well with changes in testosterone levels (Kosterlitz & Warp

Methadone, among other opiate drugs, causes a decrease in the value of index, testosterone/creatinine in urine, in a dose-dependent manner. We can dose Methadone by increasing o decreasing the daily dosage to reach index values of 20-30 mg / g, the Clinical

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 its Clinical

Poblational analysis of the index, testosterone/creatinine in urine, using Kernel`s test , have allowed us to detect 3 different populations, as a result of combination of the different polymorphisms affecting the genes that encode CYP3A, CYP2B6, and NAT2, obtaining from

> DOSE genotype : wild type 2 or 4

Lamotrigine is a drug specifically used for epilepsy but also is effective as a mood stabilizer in treating bipolar depression, one of the most intractable stages of this disorder. Its iatrogenic effects, rare but extremely serious, such as Stevens-Johnson syndrome or Lyell syndrome, usually appear at 2-8 weeks of starting treatment. With unknown mechanism of action, it is believed that acts on sodium channels, its use is reserved for prevention of

Lamotrigine is eliminated from the body by the action of the UGT1A4 enzyme, competing with bilirubin for the formation of their respective conjugates with glucuronide acid. Taking advantage of this interaction over UGT1A4, we can use bilirubin plasma levels as a indicator of plasma Lamotrigine concentration (French 2004; Lees & Leach 1993; Pellock 1999; Ramsay

The influence of bilirubin and other inhibitors of the UGT1A4 enzyme, on plasma concentrations of Lamotrigine, is calculated assuming a Michaelis-Menten kinetics, using

DOSE genotype : polimorphic type

the application of the equation 2, the following equi-effective dose ratio:

in dependence of the variant alleles present (Lozano et al 2008b, 2009b).

1968; Lozano et al 2008b, 2009b; Snyder 1975).

Surrogate Endpoint. (Lozano et al 2008b, 2009b).

Surrogate Endpoint, using equation 2

depressive episodes in bipolar disorder.

et al 1991; Rogawski & Löscher 2004).

equation 4, and a competitive inhibition model, as follows:

**3.4.1 PK-PD model** 

**3.4.2 PK-PG model** 

**3.5 Lamotrigine** 

Is based on individual genetic polymorphisms which can alter the enzymatic activity of UGT1A1: The enzyme that conjugates bilirubin is called uridindifosfoglucuronato glucuronosyltransferase,UGT, and its production is regulated by a promoter that can have a mutation that causes decreased production of this enzyme. The amounts of UGT, in Gilbert's syndrome, are reduced until 30% of the normal value. The genetic defect is in the insertion of an extra base pair in the promoter TATA box in the gene encoding the enzyme UGT and that is located on chromosome 2 (Bosma et al 1995). Gilbert's syndrome, therefore, is a disease in which there is a high bilirubin level and the values in these patients ranging between 20 mmol/dl and 80 mmol/dl, obtaining from the application of the equation 6, the following equi-effective dose ratio for Lamotrigine:

$$\frac{\text{DOSE} \left(\text{genotype} : \text{will type}\right)}{\text{DOSE} \left(\text{genome} : \text{Gilbert's syndrome}\right)} = 2$$

(Lozano et al 2009a, 2009c, 2010d).

#### **3.6 New antiepileptics**

The new generation of AEDs such as Topiramate, Oxcarbazepine, Gabapentin, and Levetiracetam, acts by enhancing GABAergic neurotransmission: The gamma-aminobutyric acid, GABA, has 2 types of receptors, A and B. When GABA binds to GABAA receptor, facilitates the passage of chlorine, negatively charged ion, inside the cell through chloride channels. This influx of chloride increases the negativity of the cell (ie, a resting potential more negative membrane) causing it a greater difficulty to reach the action potential resulting, finally, in a cell stabilization (Barnard et al 1998; Kravitz et al 1963; Krnjević & Schwartz 1967; Sieghart & Sperk 2002; Takeuchi & Onodera 1972; Takeuchi & Takeuchi 1967, 1969).

Biomarkers and Therapeutic Drug Monitoring in Psychiatry 171

of all the most innovative techniques in pharmacokinetics, pharmacodynamics and

1. Estimate their pharmacokinetic and pharmacodynamic parameters, using for this purpose, PK-PD, PK-PD and PG-PG modelling, and quantitative analysis of dose-effect

2. Quantify the effect of different genetic polymorphisms of CYP450, receptors and

3. Identify, using Kernel`s test, the different phenotypes and subpopulations originated in the different dose-response and metabolic behavior, such as the EM, PM and UM

In conclusion, the use of Biomarkers in PK, PD and PG modelling, in continuos developing, has provided us with the adequate tools to choose the best therapeutic strategy and calculate optimal dose, in order to improve the therapeutic drug monitoring of psychiatric drugs, relapses, drug side effects and clinical outcome of the most common psychiatric diseases. http://cpmc.coriell.org/Sections/Medical/DrugsAndGenes\_mp.aspx?PgId=216.

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The GABAergic transmission, may be increased or facilitated, by direct binding of an agonist, such as progesterone, benzodiazepines, barbiturates, to the GABAA receptors and its subsequent activation; by blocking the presynaptic uptake of GABA by Tiagabine; by inhibiting the metabolism of GABA by GABA-transaminase, such as Vigabatrin and Valproate, or by increasing GABA synthesis modulating the enzyme glutamic acid decarboxylase, GAD, responsible for the decarboxylation of glutamate to GABA, as is the case of Gabapentin and other AEDs that enhance the production of GABA and causes a down-regulation of glutamate. For Felbamate, whose exact mechanism is unknown, it is known that exerts its effect on the GABA receptor and by antagonizing the NMDA receptor, while, Topiramato locks the sodium channels of voltage-gated and increases the activity of GABA through the activation of some subtype of GABA receptors, antagonizing some subtype of glutamate receptor and inhibiting the enzyme carbonic anhydrase, particularly isozymes II and IV (Kapetanovic et al 1998; Kume al 1994).

The GH plasma levels, also, have been used as a Surrogate Marker of noradrenergic transmission and, more recently, as evidence of 5HT1a and 5HT1b/d1 receptor activation, being this another example of how one Surrogate Marker serves as measure for very different effects in the CNS (Dinan 1996; Facchinetti et al 1994; Herdman et al 1994; Laakman al 1990; Mota et al 1997).
