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Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury.

Ho SS, McLachlan AJ, Chen TF, Hibbs DE, Fois RA - CPT Pharmacometrics Syst Pharmacol (2015)

Bottom Line: We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI.Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015).Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy (A15), University of Sydney Sydney, NSW, Australia.

ABSTRACT
Immune-mediated drug-induced liver injury (IMDILI) can be devastating, irreversible, and fatal in the absence of successful transplantation surgery. We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI. Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015). Eleven of these drugs, along with their known and proposed metabolites, constituted a training set used to develop a four-point pharmacophore model (sensitivity 75%; specificity 85%). Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

No MeSH data available.


Related in: MedlinePlus

Adjusted reporting odds ratio (with 95% CI) for drugs significantly associated with immune-mediated drug induced liver injury as identified from Australia's postmarketing adverse drug reaction surveillance system (P < 0.00015, Bonferroni adjusted).
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fig02: Adjusted reporting odds ratio (with 95% CI) for drugs significantly associated with immune-mediated drug induced liver injury as identified from Australia's postmarketing adverse drug reaction surveillance system (P < 0.00015, Bonferroni adjusted).

Mentions: Multivariate logistic regression identified 18 drugs (representing 12 drug classes) that were significantly associated with IMDILI (P < 0.00015, Bonferroni-adjusted limit for significance) (Figure2). Seven of these drugs had fewer than four reports in the database or had molecular weight >500 Da and were excluded from subsequent analyses.


Relationships Between Pharmacovigilance, Molecular, Structural, and Pathway Data: Revealing Mechanisms for Immune-Mediated Drug-Induced Liver Injury.

Ho SS, McLachlan AJ, Chen TF, Hibbs DE, Fois RA - CPT Pharmacometrics Syst Pharmacol (2015)

Adjusted reporting odds ratio (with 95% CI) for drugs significantly associated with immune-mediated drug induced liver injury as identified from Australia's postmarketing adverse drug reaction surveillance system (P < 0.00015, Bonferroni adjusted).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544056&req=5

fig02: Adjusted reporting odds ratio (with 95% CI) for drugs significantly associated with immune-mediated drug induced liver injury as identified from Australia's postmarketing adverse drug reaction surveillance system (P < 0.00015, Bonferroni adjusted).
Mentions: Multivariate logistic regression identified 18 drugs (representing 12 drug classes) that were significantly associated with IMDILI (P < 0.00015, Bonferroni-adjusted limit for significance) (Figure2). Seven of these drugs had fewer than four reports in the database or had molecular weight >500 Da and were excluded from subsequent analyses.

Bottom Line: We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI.Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015).Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmacy (A15), University of Sydney Sydney, NSW, Australia.

ABSTRACT
Immune-mediated drug-induced liver injury (IMDILI) can be devastating, irreversible, and fatal in the absence of successful transplantation surgery. We present a novel approach that combines the methods of pharmacoepidemiology with in silico molecular modeling to identify specific features in toxic ligands that are associated with clinical features of IMDILI. Specifically, from pharmacovigilance data multivariate logistic regression identified 18 drugs associated with IMDILI (P < 0.00015). Eleven of these drugs, along with their known and proposed metabolites, constituted a training set used to develop a four-point pharmacophore model (sensitivity 75%; specificity 85%). Subsequently, this information was combined with information from immune-pathway reviews and genetic-association studies and complemented with ligand-protein docking simulations to support a hypothesis implicating two putative targets within separate, possibly interacting, immune-system pathways: the major histocompatibility complex within the adaptive immune system and Toll-like receptors (TLRs), in particular TLR-7, which represent pattern recognition receptors of the innate immune system.

No MeSH data available.


Related in: MedlinePlus