title: [Rational estimation of drug dosage through pharmacometric modeling: The case of a long-acting depot antipsychotic].
abstract: Drug manufacturer seeking authorization to bring a newly medicinal compound to the market (Market Authorization Application) have to undertake various studies, each of them providing a specific report. It is however essential to know how to pool results in order to understand the behavior of the drug in all the situations likely to be encountered in clinical practice. The exploitation of these data is now carried out through pharmacometric analyzes which aim at quantifying the exposure and the response of a drug over time. These methods (named "population approach") are based on non-linear mixed effects model and therefore, on the identification of a mathematical model. A first step is to model the variations in concentrations over time by integrating the physio-pathological characteristics of the patients. At this stage, the Bayesian analysis is essential to identify and select the factors of interindividual variability. This pharmacokinetic (PK) modeling allows us to obtain the prescribed dose for each patient, but also their exposure. The second step consists in defining the relationship between exposure and effect: pharmacodynamic (PD) modeling. In psychiatry, the response can be the receptors' occupancy rate or the evolution of a clinical score (BPRS, PANSS…) over time. The final PK-PD model defines the target exposure, that is to say, the concentration values required to achieve maximum effect on the score studied without risking over-exposure. Ultimately, a Monte Carlo simulation will be conducted which will test the expected response for different doses and will facilitate a rational choice in dosage. Assessing the process behind the transition from an oral to a long-acting injectable form of an active ingredient such as aripiprazole can be done by following the same protocol. A 10- to 30-mg per day therapeutic range has thus been identified. The model incorporates all the identified factors of variability of aripiprazole (drug interactions and genetic polymorphism of the P450 2D6 cytochrome) and showed that with an injectable sustained release form, a monthly dose of 400mg would allow 90% of patients to gain exposure in the therapeutic range. In case of a drug inhibition and/or of a slow metabolizing profile, dosage adjustment is necessary.
authors.affiliation: Service de pharmacologie clinique, CAP-TV, hôpital Sainte-Marguerite, AP-HM, 270, boulevard Sainte-Marguerite, 13271 Marseille, France; Aix-Marseille université, Inserm, Sesstim U912, 13006 Marseille, France. Electronic address: nicolas.simon@ap-hm.fr.
authors.forename: N
authors.initials: N
authors.lastname: Simon
authors.affiliation: SHU Psychiatrie adultes, hôpital Sainte-Marguerite, 13274 Marseille cedex 9, France.
authors.forename: J-M
authors.initials: JM
authors.lastname: Azorin
mesh_terms: D000284:Administration, Oral; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000068180:Aripiprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D001499:Bayes Theorem; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D006801:Humans; D040541:Marketing; D008962:Models, Theoretical; D009010:Monte Carlo Method; D057285:Precision Medicine
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D000068180:Aripiprazole
keywords: Antipsychotics; Antipsychotiques atypiques; Aripiprazole; Modeling; Modélisation; Nonmem; Pharmacocinétique; Pharmacodynamic; Pharmacodynamique; Pharmacokinetics