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Population pharmacokinetic modelling to assess clinical drug–drug interaction between AZD 7325 and midazolam
Author(s) -
Zhou D.,
Lu Z.,
Sunzel M.,
Xu H.,
AlHuniti N.
Publication year - 2014
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12152
Subject(s) - drug , midazolam , pharmacokinetics , medicine , pharmacology , drug drug interaction , population , drug interaction , environmental health , sedation
Summary What is known and objective AZD 7325 is a selective gamma‐amino‐butyric acid ( GABA A ) α2, 3 receptor modulator. The aims of this analysis were to develop population pharmacokinetic ( PPK ) models of AZD 7325 and midazolam and to assess the induction effect of AZD 7325 on CYP 3A4 with midazolam as a substrate. Methods Drug–drug interaction data of AZD 7325 and midazolam from 24 healthy subjects were available for model development. PPK models were developed in a sequential manner using NONMEM . Both AZD 7325 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 AZD 7325 and midazolam, respectively. The induction of CYP 3A by AZD 7325 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 CYP 3A4. Results and discussion The population estimates for AZD 7325 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 CYP 3A4 enzyme was 197 h, with 57% IIV . What is new and conclusion The PPK models developed adequately described the clinical observation of AZD 7325‐mediated CYP 3A4 enzyme induction with midazolam as a probe. The model could provide basis for the rational dosing of AZD 7325 in clinical practice.