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An S‐warfarin and AZD1981 interaction: in vitro and clinical pilot data suggest the N‐deacetylated amino acid metabolite as the primary perpetrator
Author(s) -
Grime Ken,
Pehrson Rikard,
Nordell Pär,
Gillen Michael,
Kühn Wolfgang,
Mant Timothy,
Brännström Marie,
Svanberg Petter,
Jones Barry,
Brealey Clive
Publication year - 2017
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13102
Subject(s) - metabolite , pharmacology , in vitro , pharmacokinetics , active metabolite , hepatocyte , excretion , in vivo , cytochrome p450 , drug interaction , chemistry , biology , biochemistry , metabolism , microbiology and biotechnology
Aim AZD1981 is an orally bioavailable chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N‐deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite‐dependent drug–drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N‐deacetylated AZD1981 is responsible for the observed interaction. Methods The excretion and biotransformation of [ 14 C]‐AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice‐daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed. Results The excretion balance study showed N‐deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time‐dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S‐warfarin area under the plasma concentration–time curve increased, on average, 1.4‐fold [95% confidence interval (CI) 1.22, 1.50] and 2.4‐fold (95% CI 2.11, 2.64) after 100 mg ( n = 13) and 400 mg ( n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction. Conclusions N‐deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug–drug interactions, with weak time‐dependent inhibition exacerbated by efficient hepatic uptake being the cause.