title: Population pharmacokinetics of risperidone and 9-hydroxyrisperidone in patients with acute episodes associated with bipolar I disorder.
abstract: A population model was developed with the aim to simultaneously describe risperidone and 9-hydroxyrisperidone pharmacokinetics; to obtain estimates for pharmacokinetic parameters and associated inter- and intra-individual variability of risperidone and 9-hydroxyrisperidone; and to evaluate the influence of patient demographic characteristics and other factors on risperidone, 9-hydroxyrisperidone, and active moiety pharmacokinetics. Data were obtained from 407 patients enrolled in four Phase 1 (serial blood sampling) and three Phase 3 trials (sparse sampling), representing dosage regimens ranging from 4 mg single dose to flexible 1-6 mg once daily. A pharmacokinetic model with two-compartment submodels for risperidone and 9-hydroxyrisperidone disposition and a sequential zero- and first-order absorption pathway was selected based on prior knowledge. A mixture model was incorporated due to CYP2D6 polymorphism of risperidone conversion to 9-hydroxyrisperidone. Patient characteristics tested as potential covariates were: age, sex, race, body weight, lean body mass, body mass index, creatinine clearance, liver function laboratory parameters, study, and carbamazepine comedication. The quasi-clearance of active moiety (the sum of risperidone and 9-hydroxyrisperidone) was simulated and linear regression performed to identify significant covariates. The selected pharmacokinetic model described the plasma concentration-time profiles for risperidone and 9-hydroxyrisperidone quite well and was able to determine each patient's phenotype. Covariates significantly affecting the pharmacokinetics were carbamazepine comedication, and study because the proportion of patients assigned to the intermediate metabolizer status decreased from single to multiple dosing while the proportion assigned to extensive metabolizer status increased. Covariates with limited and clinically irrelevant effects on active moiety concentrations were patient phenotype, race, and total protein. Carbamazepine also decreased active moiety concentrations.
authors.affiliation: Division of Janssen Pharmaceutica N.V., Johnson & Johnson Pharmaceutical Research & Development, 2340, Beerse, Belgium. avermeul@prdbe.jnj.com
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Piotrovsky
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Ludwig
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism*; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019992:Databases as Topic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000097:blood / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000068882:Paliperidone Palmitate; D010641:Phenotype; D011159:Population Surveillance; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D018967:Risperidone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets
chemical_list: D014150:Antipsychotic Agents; D007555:Isoxazoles; D011743:Pyrimidines; D013607:Tablets; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate