Oral Olanzapine Disposition in Adolescents with Schizophrenia or Bipolar I Disorder A Population Pharmacokinetic Model

• Published in: Paediatric drugs Vol. 12; no. 3; pp. 201 - 211
• Main Authors: Lobo, Evelyn D., Robertson-Plouch, Carol, Quinlan, Tonya, Hong, Quan, Bergstrom, Richard F.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2010; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Administration, Oral; Adolescent; Adult; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - therapeutic use; Benzodiazepines - administration & dosage; Benzodiazepines - blood; Benzodiazepines - pharmacokinetics; Benzodiazepines - therapeutic use; Bipolar disorder; Bipolar Disorder - drug therapy; Bipolar Disorder - metabolism; Dosage and administration; Drug therapy; Female; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Models, Biological; Multicenter Studies as Topic; Olanzapine; Original Research Article; Pediatrics; Pharmacokinetics; Pharmacotherapy; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - metabolism; Sex Characteristics; United States; Oral Olanzapine; Olanzapine; Population Pharmacokinetic Model; Interpatient Variability; Parameter Sensitivity Analysis
• DOI: 10.2165/11532580-000000000-00000
• ISSN: 1174-5878

Background Olanzapine is an atypical antipsychotic approved for the treatment of adults and adolescents (aged 13–17 years) with schizophrenia or bipolar I disorder (manic or mixed episodes). Objectives To characterize the pharmacokinetics of olanzapine in adolescents, to estimate the sources of variability, and to identify significant co-variates. In addition, olanzapine pharmacokinetic parameters in adolescents were compared with those in adults to guide appropriate dosing recommendations for adolescent patients. Methods A population pharmacokinetic modeling study was performed. The majority of pharmacokinetic data for the model came from a multicenter, open-label study in which 4.5 weeks of oral olanzapine 2.5-20 mg once daily was administered to a total of 105 patients aged 13–17 years (41.1–148 kg) who had a diagnosis of schizophrenia or bipolar I disorder. Four blood samples at steady state were obtained from each patient. Olanzapine concentrations in plasma were determined using a validated high-performance liquid chromatography method with electrochemical detection. Similar data from 11 adolescents from three previous studies were also included. A pharmacokinetic model was developed and the potential effects of patient characteristics (sex, bodyweight, age, ethnic origin) were investigated using a nonlinear mixed effects modeling program. The distributions of pharmacokinetic parameters for olanzapine in adolescents were compared with those previously reported in adults (n = 912, diagnosis of schizophrenia, olanzapine 5–20 mg/day) using the Kolmogorov-Smirnov 2-sample test. A visual predictive check was performed using Monte Carlo simulations on an external validation dataset. Results The pharmacokinetics of oral olanzapine in adolescent patients were described by a one-compartment pharmacokinetic model. The typical model estimates were 13.6 L/h (70 kg female patient) for oral clearance (CL/F) and 899 L for oral volume of distribution (V/F). Interpatient variability (40.5% for CL/F, 65.4% for V/F) and residual error (27%) were moderate. Bodyweight and sex had a significant influence on CL/F, which was lower in patients with lower weights and approximately 30% higher in males than females. Olanzapine exposure was typically 27% higher in adolescents versus adults. Approximately 77% of adolescents and adults had comparable CL/F values and 69% had comparable V/F values. Conclusions The pharmacokinetics of oral olanzapine in adolescent patients are similar to those in adults, and are linear in the dosage range of 2.5-20 mg/day. Given the small magnitude of co-variate effects and the interpatient variability, dose adjustments based on bodyweight or sex are not necessary in adolescents.