title: Population pharmacokinetic modelling to assess clinical drug-drug interaction between AZD7325 and midazolam.
abstract: OBJECTIVE
  AZD7325 is a selective gamma-amino-butyric acid (GABAA )α2, 3 receptor modulator. The aims of this analysis were to develop population pharmacokinetic (PPK) models of AZD7325 and midazolam and to assess the induction effect of AZD7325 on CYP3A4 with midazolam as a substrate.
  
  
  METHODS
  Drug-drug interaction data of AZD7325 and midazolam from 24 healthy subjects were available for model development. PPK models were developed in a sequential manner using NONMEM. Both AZD7325 and midazolam pharmacokinetics were described by two-compartment models, and a transit compartment absorption model and a first-order absorption model were applied for the absorption of AZD7325 and midazolam, respectively. The induction of CYP3A by AZD7325 was described by a transit enzyme model, where the elimination of midazolam was proportionally linked to the enzyme amount. Simulations were performed to predict dosing regimens to account for the induction of CYP3A4.
  
  
  CONCLUSIONS
  The population estimates for AZD7325 clearance, intercompartmental clearance, central and peripheral volume were 36, 29·2 L/h, 169 and 392 L, respectively, with interindividual variability (IIV) of 35% and 24% for clearance and central volume. Midazolam clearance, intercompartmental clearance, central and peripheral volume were estimated to be 62·7, 34·7 L/h, 133 and 146 L, respectively, with 43% IIV for clearance. The estimated mean transit time for induction of the CYP3A4 enzyme was 197 h, with 57% IIV.
  
  
  CONCLUSIONS
  The PPK models developed adequately described the clinical observation of AZD7325-mediated CYP3A4 enzyme induction with midazolam as a probe. The model could provide basis for the rational dosing of AZD7325 in clinical practice.
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca LP, Wilmington, DE, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhou
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Sunzel
authors.forename: H
authors.initials: H
authors.lastname: Xu
authors.forename: N
authors.initials: N
authors.lastname: Al-Huniti
mesh_terms: D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D013997:Time Factors
chemical_list: C576237:4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide; D018757:GABA Modulators; D006574:Heterocyclic Compounds, 2-Ring; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam
keywords: drug interaction; enzyme induction; population pharmacokinetics