PMID- 29381228
OWN - NLM
STAT- MEDLINE
DCOM- 20190624
LR  - 20210109
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 84
IP  - 5
DP  - 2018 May
TI  - Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the 
      evaluation of drug-drug interactions: a case study with repaglinide.
PG  - 972-986
LID - 10.1111/bcp.13533 [doi]
AB  - AIMS: Statistically significant positive correlations are reported for the 
      abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, 
      the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual 
      variabilities of clearance and drug-drug interactions (DDIs) for repaglinide 
      using physiologically based pharmacokinetic (PBPK) modelling. METHODS: PBPK 
      modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual 
      populations were generated assuming intercorrelations between hepatic 
      CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A 
      repaglinide PBPK model was used to predict PK parameters in the presence and 
      absence of gemfibrozil in virtual populations, and the results were compared with 
      a clinical DDI study. RESULTS: Coefficient of variation (CV) of oral clearance 
      was 52.5% in the absence of intercorrelation between CYP3A4-CYP2C8 abundances, 
      which increased to 54.2% when incorporating intercorrelation. In contrast, CV for 
      predicted DDI (as measured by AUC ratio before and after inhibition) was reduced 
      from 46.0% in the absence of intercorrelation between enzymes to 43.8% when 
      incorporating intercorrelation: these CVs were associated with 5th/95th 
      percentiles (2.48-11.29 vs. 2.49-9.69). The range of predicted DDI was larger in 
      the absence of intercorrelation (1.55-77.06) than when incorporating 
      intercorrelation (1.79-25.15), which was closer to clinical observations 
      (2.6-12). CONCLUSIONS: The present study demonstrates via a systematic 
      investigation that population-based PBPK modelling incorporating intercorrelation 
      led to more consistent estimation of extreme values than those observed in 
      interindividual variabilities of clearance and DDI. As the intercorrelations more 
      realistically reflect enzyme abundances, virtual population studies involving 
      PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.
CI  - (c) 2018 The British Pharmacological Society.
FAU - Doki, Kosuke
AU  - Doki K
AUID- ORCID: 0000-0003-2497-0063
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, 
      University of Manchester, Manchester, UK.
AD  - Department of Pharmaceutical Sciences, Faculty of Medicine, University of 
      Tsukuba, Ibaraki, Japan.
FAU - Darwich, Adam S
AU  - Darwich AS
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, 
      University of Manchester, Manchester, UK.
FAU - Achour, Brahim
AU  - Achour B
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, 
      University of Manchester, Manchester, UK.
FAU - Tornio, Aleksi
AU  - Tornio A
AUID- ORCID: 0000-0001-5713-5692
AD  - Department of Clinical Pharmacology, University of Helsinki and Helsinki 
      University Hospital, Helsinki, Finland.
FAU - Backman, Janne T
AU  - Backman JT
AD  - Department of Clinical Pharmacology, University of Helsinki and Helsinki 
      University Hospital, Helsinki, Finland.
FAU - Rostami-Hodjegan, Amin
AU  - Rostami-Hodjegan A
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy & Optometry, 
      University of Manchester, Manchester, UK.
AD  - Simcyp Limited (A Certara Company), Sheffield, UK.
LA  - eng
PT  - Journal Article
DEP - 20180306
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Carbamates)
RN  - 0 (Cytochrome P-450 CYP2C8 Inhibitors)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Piperidines)
RN  - 668Z8C33LU (repaglinide)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C8)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - Q8X02027X3 (Gemfibrozil)
SB  - IM
MH  - Adult
MH  - Carbamates/*pharmacokinetics
MH  - Clinical Trials as Topic/statistics & numerical data
MH  - Computer Simulation
MH  - Cytochrome P-450 CYP2C8/*metabolism
MH  - Cytochrome P-450 CYP2C8 Inhibitors/pharmacology
MH  - Cytochrome P-450 CYP3A/*metabolism
MH  - Drug Interactions
MH  - Female
MH  - Gemfibrozil/*pharmacology
MH  - Humans
MH  - Hypoglycemic Agents/pharmacokinetics
MH  - Male
MH  - Microsomes, Liver/metabolism
MH  - Models, Biological
MH  - Piperidines/*pharmacokinetics
MH  - Young Adult
PMC - PMC5903242
OTO - NOTNLM
OT  - PBPK model
OT  - correlation
OT  - drug-drug interactions
OT  - interindividual variability
OT  - repaglinide
EDAT- 2018/01/31 06:00
MHDA- 2019/06/25 06:00
PMCR- 2019/05/01
CRDT- 2018/01/31 06:00
PHST- 2017/09/03 00:00 [received]
PHST- 2017/12/21 00:00 [revised]
PHST- 2018/01/21 00:00 [accepted]
PHST- 2018/01/31 06:00 [pubmed]
PHST- 2019/06/25 06:00 [medline]
PHST- 2018/01/31 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - BCP13533 [pii]
AID - 10.1111/bcp.13533 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2018 May;84(5):972-986. doi: 10.1111/bcp.13533. Epub 2018 
      Mar 6.