Computing with evidence: Part I: A drug-mechanism evidence taxonomy oriented toward confidence assignment

We present a new evidence taxonomy that, when combined with a set of inclusion criteria, enable drug experts to specify what their confidence in a drug mechanism assertion would be if it were supported by a specific set of evidence. We discuss our experience applying the taxonomy to representing drug-mechanism evidence for 16 active pharmaceutical ingredients including six members of the HMG-CoA-reductase inhibitor family (statins). All evidence was collected and entered into the Drug-Interaction Knowledge Base (DIKB); a system that can provide customized views of a body of drug-mechanism knowledge to users who do not agree about the inferential value of particular evidence types. We provide specific examples of how the DIKB's evidence model can flag when a particular use of evidence should be re-evaluated because its related conjectures are no longer valid. We also present the algorithm that the DIKB uses to identify patterns of evidence support that are indicative of fallacious reasoning by the evidence-base curators.

[1]  P. Neuvonen,et al.  The effect of ingestion time interval on the interaction between itraconazole and triazolam , 1996, Clinical pharmacology and therapeutics.

[2]  N McKoy,et al.  Systems to rate the strength of scientific evidence. , 2002, Evidence report/technology assessment.

[3]  S. Hall,et al.  The interaction of diltiazem with simvastatin , 2000, Clinical pharmacology and therapeutics.

[4]  Terry A Jacobson,et al.  Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. , 2004, The American journal of cardiology.

[5]  P. Neuvonen,et al.  Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole , 1994 .

[6]  Marc Berg,et al.  Overriding of drug safety alerts in computerized physician order entry. , 2006, Journal of the American Medical Informatics Association : JAMIA.

[7]  A. Hiller,et al.  A potentially hazardous interaction between erythromycin and midazolam , 1993 .

[8]  B. Knollmann,et al.  Critical evaluation of handheld electronic prescribing guides for physicians , 2004 .

[9]  P. Neuvonen,et al.  Diltiazem enhances the effects of triazolam by inhibiting its metabolism , 1996, Clinical pharmacology and therapeutics.

[10]  George Hripcsak,et al.  Viewpoint Paper: Clinical Decision Support and Electronic Prescribing Systems: A Time for Responsible Thought and Action , 2005, J. Am. Medical Informatics Assoc..

[11]  A. Dane,et al.  The effect of fluconazole on the pharmacokinetics of rosuvastatin , 2002, European Journal of Clinical Pharmacology.

[12]  Linda Gavendo,et al.  The incidence of adverse drug events in two large academic long-term care facilities. , 2005, The American journal of medicine.

[13]  S. Preskorn,et al.  How drug-drug interactions can impact managed care. , 2004, The American journal of managed care.

[14]  F. Scharpf,et al.  Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam. , 1996, Arzneimittel-Forschung.

[15]  Julie M. Fiskio,et al.  Research Paper: Characteristics and Consequences of Drug Allergy Alert Overrides in a Computerized Physician Order Entry System , 2004, J. Am. Medical Informatics Assoc..

[16]  D. Kazierad,et al.  Comparison of midazolam and simvastatin as cytochrome P450 3A probes , 2006, Clinical pharmacology and therapeutics.

[17]  T Ishizaki,et al.  A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: In vivo evidence for the involvement of CYP3A4 in alprazolam metabolism , 1996, Clinical pharmacology and therapeutics.

[18]  Russ B. Altman,et al.  Application of Information Technology: A Statistical Approach to Scanning the Biomedical Literature for Pharmacogenetics Knowledge , 2004, J. Am. Medical Informatics Assoc..

[19]  P. Kollman,et al.  Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[20]  A. Mazzu,et al.  Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin , 2000, Clinical pharmacology and therapeutics.

[21]  Darrell R. Abernethy,et al.  Notes of the American Society for Clinical Pharmacology and Therapeutics , 1991 .

[22]  P. Hansten,et al.  Drug interaction management , 2003, Pharmacy World and Science.

[23]  L. Ereshefsky,et al.  Pharmacokinetic and Pharmacodynamic Interactions of Oral Midazolam with Ketoconazole, Fluoxetine, Fluvoxamine, and Nefazodone , 2003, Journal of clinical pharmacology.

[24]  George A. Miller,et al.  WordNet: A Lexical Database for English , 1995, HLT.

[25]  G. Amsden,et al.  A Study of the Interaction Potential of Azithromycin and Clarithromycin with Atorvastatin in Healthy Volunteers , 2002, Journal of clinical pharmacology.

[26]  Fumiyoshi Yamashita,et al.  In silico approaches for predicting ADME properties of drugs. , 2004, Drug metabolism and pharmacokinetics.

[27]  Ira J. Kalet,et al.  Modeling Drug Mechanism Knowledge Using Evidence and Truth Maintenance , 2007, IEEE Transactions on Information Technology in Biomedicine.

[28]  P. Neuvonen,et al.  Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole , 1994, Clinical pharmacology and therapeutics.

[29]  Joshua M. Stuart,et al.  Integrating genotype and phenotype information: an overview of the PharmGKB project , 2001, The Pharmacogenomics Journal.

[30]  A. D. Rodrigues,et al.  Oxidative metabolism of clarithromycin in the presence of human liver microsomes. Major role for the cytochrome P4503A (CYP3A) subfamily. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[31]  Bruce Kaplan,et al.  Evaluation of Drug Interaction Software to Identify Alerts for Transplant Medications , 2005, The Annals of pharmacotherapy.

[32]  Jennifer L. Donovan,et al.  Comparative CYP3A4 Inhibitory Effects of Venlafaxine, Fluoxetine, Sertraline, and Nefazodone in Healthy Volunteers , 2004, Journal of clinical psychopharmacology.

[33]  J S Harmatz,et al.  Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. , 1996, The Journal of pharmacology and experimental therapeutics.

[34]  Akihiro Hisaka,et al.  General Framework for the Quantitative Prediction of CYP3A4-Mediated Oral Drug Interactions Based on the AUC Increase by Coadministration of Standard Drugs , 2007, Clinical pharmacokinetics.

[35]  Russ B. Altman,et al.  A Resource to Acquire and Summarize Pharmacogenetics Knowledge in the Literature , 2004, MedInfo.

[36]  J S Barrett,et al.  Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment. , 2005, International journal of clinical pharmacology and therapeutics.

[37]  Kyoung-Ah Kim,et al.  Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects , 2006, Clinical pharmacology and therapeutics.

[38]  James Pustejovsky,et al.  Robust Relational Parsing Over Biomedical Literature: Extracting Inhibit Relations , 2001, Pacific Symposium on Biocomputing.

[39]  C. Masimirembwa,et al.  An Experimental Pharmacokinetic Computer Program to Predict Potential Drug-Drug Interactions , 2009 .

[40]  P. Neuvonen,et al.  Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations , 1998, Clinical pharmacology and therapy.

[41]  Paul D. Martin,et al.  The effect of erythromycin on the pharmacokinetics of rosuvastatin , 2003, European Journal of Clinical Pharmacology.

[42]  P. Neuvonen,et al.  Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid , 1996, Clinical pharmacology and therapeutics.

[43]  J. Ahonen,et al.  Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam , 2009, European Journal of Clinical Pharmacology.

[44]  K. Otani,et al.  Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam , 1998, Psychopharmacology.

[45]  M. Leider Goodman & Gilman's The Pharmacological Basis of Therapeutics , 1985 .

[46]  P. Neuvonen,et al.  Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. , 2003, British journal of clinical pharmacology.

[47]  D. Greenblatt,et al.  Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences , 1998, Clinical pharmacology and therapeutics.

[48]  D. Osherson,et al.  Comparison of confirmation measures , 2007, Cognition.

[49]  Ervina Resetar,et al.  Case Report: Implementing a Commercial Rule Base as a Medication Order Safety Net , 2005, J. Am. Medical Informatics Assoc..

[50]  Jouni Ahonen,et al.  The Effect of the Systemic Antimycotics, Itraconazole and Fluconazole, on the Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Midazolam , 1996, Anesthesia and analgesia.

[51]  R. Herman,et al.  Drug interactions and the statins. , 1999, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[52]  Bill Gurley,et al.  Assessing the Clinical Significance of Botanical Supplementation on Human Cytochrome P450 3A Activity: Comparison of a Milk Thistle and Black Cohosh Product to Rifampin and Clarithromycin , 2006, Journal of clinical pharmacology.

[53]  John R Horn,et al.  Proposal for a New Tool to Evaluate Drug Interaction Cases , 2007, The Annals of pharmacotherapy.

[54]  S. Hall,et al.  The interaction of diltiazem with lovastatin and pravastatin , 1998, Clinical pharmacology and therapeutics.

[55]  Volker Haarslev,et al.  Racer: A Core Inference Engine for the Semantic Web , 2003, EON.

[56]  J. Gorski,et al.  The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin , 1998, Clinical pharmacology and therapeutics.

[57]  Jonathan M. Teich,et al.  AMIA Position Paper: Clinical Decision Support in Electronic Prescribing: Recommendations and an Action Plan: Report of the Joint Clinical Decision Support Workgroup , 2005, J. Am. Medical Informatics Assoc..

[58]  P. Neuvonen,et al.  Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole , 1998, Clinical pharmacology and therapeutics.

[59]  Helen Pilmore,et al.  Potentially fatal interaction between diltiazem and statins. , 2004, Annals of internal medicine.

[60]  S. Olson,et al.  Erythromycin Coadministration Increases Plasma Atorvastatin Concentrations , 1999, Journal of clinical pharmacology.

[61]  D. Greenblatt,et al.  Inhibition of triazolam clearance by macrolide antimicrobial agents: In vitro correlates and dynamic consequences , 1998, Clinical pharmacology and therapeutics.

[62]  Mark S. Tuttle,et al.  NCI Thesaurus: Using Science-Based Terminology to Integrate Cancer Research Results , 2004, MedInfo.

[63]  Peter D. Karp,et al.  An Evidence Ontology for Use in Pathway/Genome Databases , 2003, Pacific Symposium on Biocomputing.

[64]  J. Houston,et al.  In vitro cytochrome P450 inhibition data and the prediction of drug‐drug interactions: Qualitative relationships, quantitative predictions, and the rank‐order approach , 2005, Clinical pharmacology and therapeutics.

[65]  P. Neuvonen,et al.  Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin. , 1998, British journal of clinical pharmacology.

[66]  Anthony J Avery,et al.  Incidence and Possible Causes of Prescribing Potentially Hazardous/Contraindicated Drug Combinations in General Practice , 2005, Drug safety.

[67]  H. van de Waterbeemd,et al.  ADMET in silico modelling: towards prediction paradise? , 2003, Nature reviews. Drug discovery.

[68]  J. Backman,et al.  Dose of midazolam should be reduced during diltiazem and verapamil treatments. , 1994, British journal of clinical pharmacology.

[69]  P. Neuvonen,et al.  Effect of itraconazole on the pharmacokinetics of atorvastatin , 1998, Clinical pharmacology and therapeutics.

[70]  R B Smith,et al.  A pharmacokinetic drug interaction between erythromycin and triazolam. , 1986, Journal of clinical psychopharmacology.

[71]  Aasma Shaukat,et al.  Simvastatin–Fluconazole Causing Rhabdomyolysis , 2003, The Annals of pharmacotherapy.

[72]  Ira J. Kalet,et al.  Qualitative Pharmacokinetic Modeling of Drugs , 2005, AMIA.

[73]  D E Salazar,et al.  Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. , 1995, Journal of clinical psychopharmacology.

[74]  Walter E. Haefeli,et al.  Information deficits in the summary of product characteristics preclude an optimal management of drug interactions: a comparison with evidence from the literature , 2005, European Journal of Clinical Pharmacology.

[75]  L. Wienkers,et al.  Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[76]  Steffen Bauer,et al.  Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. , 1999, Pharmacogenetics.

[77]  P. Bonnabry,et al.  Quantitative Drug Interactions Prediction System (Q-DIPS) , 2001, Clinical pharmacokinetics.

[78]  K Ohashi,et al.  Enhanced effect of triazolam with diltiazem. , 1997, British journal of clinical pharmacology.

[79]  Howard L. Bleich,et al.  Technical Milestone: Medical Subject Headings Used to Search the Biomedical Literature , 2001, J. Am. Medical Informatics Assoc..

[80]  T K Hazlet,et al.  Performance of community pharmacy drug interaction software. , 2001, Journal of the American Pharmaceutical Association.

[81]  P. Neuvonen,et al.  Effect of fluconazole on plasma fluvastatin and pravastatin concentrations , 2000, European Journal of Clinical Pharmacology.

[82]  A. Laupacis,et al.  Drug-drug interactions among elderly patients hospitalized for drug toxicity. , 2003, JAMA.

[83]  Russ B Altman,et al.  Indexing pharmacogenetic knowledge on the World Wide Web. , 2003, Pharmacogenetics.