Physiologically based pharmacokinetic (PBPK) approach has received value in recent years due to provision of new opportunities for the estimation of systemic drug concentrations in both healthy and diseased populations (1). The PBPK simulation has been used to predict inter-individual changes accompanied with the absorption, distribution, metabolism and excretion (ADME) of administered drugs (2). Not to mention that by allowing an opportunity to associate pathophysiological variabilites associated with a disease, the PBPK model helps the construction of drugâ??disease models (3).
When a PBPK model is constructed and evaluated, because of to its mechanistic nature, it can easily be extended to special populations and medications (4). Hence, the PBPK approach can be very efficient in predicting ADME of administered drugs in clinically important diseases such as psychosis.
Schizophrenia is a complicated illness with great differences in presentation, response to treatment and trajectory (5) . This suggests the presence of more than one cause and the existence of many interplaying factors which lead to the development of schizophrenia (6). So far, etiology of schizophrenia has been still unknown (7). However, a combination of genetic, physiological processes and certain environmental risk factors is believed to contribute to the development of this disease (8). Schizophrenia is regarded as the most dangerous of all psychiatric illnesses, from which approximately 1% of the worldâ??s population are affected, regardless to cultures and ethnicities (9). The manifestation of schizophrenia can be attenuating, disturbing the skills of cognition, social affairs which may lead personality to loss (7). As such, schizophrenia presents a huge social and financial burden to patients and health care systems (10).
Olanzapine is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is usually classed with the atypical antipsychotics, the newer generation of antipsychotics (11). It appears to have slightly greater effectiveness in treating schizophrenia (especially the negative symptoms) and a lower risk of causing movement disorders than typical antipsychotics. Olanzapine, however, has a higher risk of causing metabolic side effects like weight gain and type 2 diabetes than the typical antipsychotics (12).
Olanzapine is structurally similar to clozapine and quetiapine. It is chemically classified as a thienobenzodiazepine. It is believed to work by blocking, or antagonizing, the dopamine D2 receptor which is an action it shares with all presently-approved antipsychotics (13). Like most other atypical antipsychotics olanzapine also strongly antagonizes the 5-HT2A receptor, which may partially underpin its reduced propensity for causing movement disorders. Despite its close structural relation to traditional benzodiazepine anxiety-relieving medications, it possesses no affinity for the GABAA receptor, its anxiety-relieving effect is mediated through its effect on dopamine and 5HT receptors (14).
Olanzapine is practically insoluble in water (15), exhibiting extensive first pass metabolism, such thatonly 40% reaching the circulation. its half-life ranges from 21 to 54 hours, and apparent plasma clearance ranges from 12 to 47 L/hr. Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein (16). Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6 (17).
This research aimed to establish and validate the PBPK model, which describes the pharmacokinetic parameters of olanzapine in healthy adults. Also, the effect of age, obesity and liver disease on the pharmacokinetics of the drug was studied.
