FDA Decision Tree Base on In Vitro Studies

Substrate:

- If not a substrate ! stop and label accordingly

- If a substrate ! conduct in vivo studies with potent inhibitor (s)/inducer(s) ! adjust dose and/or label accordingly

Inhibitor/inducer:

- If not an inhibitor/inducer ! stop and label accordingly

- If an inhibitor/inducer ! conduct in vivo studies, adjust dose and/or label accordingly

Table 5.12. Human oral in vivo substrates (fm for that particular enzyme), inhibitors and inducers for P450 isoforms

P450

isoform

Substrate (fm)

Inhibitor

Inducer

CYP1A2

Theophylline, caffeine

Fluvoxamine

Smoking

CYP2B6

Efavirenz

Clopidogrel

Rifampin

CYP2CS

Repaglinide (0.49a),

Gemfibrozil

Rifampin

rosiglitazone (0.5a)

CYP2C9

Warfarin (0.85b),

Fluconazole,

Rifampin

tolbutamide (0.85b)

amiodarone

CYP2C19

Omeprazole,

Omeprazole,

Rifampin

esomprazole,

fluvoxamine,

lansoprazole,

moclobemide

pantoprazole

CYP2D6

Desipramine (0.97c,

Paroxetine,

Not induced

0.877d),

quinidine,

dextromethorphan,

fluoxetine

atomoxetine

CYP2E1

Chlorzoxazone

Disulfiram

Ethanol

CYP3A

Midazolam (0.94e),

Atazanavir,

Rifampin,

buspirone (0.99f),

clarithromycin,

carbamazepine

felodipine (0.81e),

indinavir,

lovastatin (0.9g,

itraconazole,

0.99a), eletriptan,

ketoconazole,

sildenafil (0.9h),

nefazodone,

simvastatin (0.99a),

nelfinavir,

triazolam (0.92e)

ritonavir,

saquinavir,

telithromycin

Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/

DevelopmentResources/DrugInteractionsLabeling/ucm081177.htm#inVivo visited last August 1, 2010

aHinton LK et al. (2008) Pharm Res 25:1063-74

bMiners JO, Birkett DJ (1998) Br J Clin Pharmacol 45:525-538

cRowland YK et al. (2004) Drug Metab Dispos 32:1522

dIto et al. (2005) Drug Metab Dispos 33:837-844

eBrown HS et al. (2005) Br J Clin Pharmacol 60(5):508-18

fGaletin A et al. (2006) Drug Metab Dispos 34:166-75

gShitara Y, Sugiyama Y (2006) Pharmacol Ther 112:71-105

hHouston, Galetin (2008) Current Drug Metab (2008) 9:940-951

References

Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (&) and the concentration of inhibitor which causes 50 per cent inhibition (iso) of an enzymatic reaction. Biochem Pharmacol 22:3099-3108 FDA Draft Guidance for Industry on Drug Interaction Studies-Study design, data analysis, and implication for dosing and labeling. September 2006 Kanamitsu SI, Ito K, Sugiyama Y (2000) Quantitive prediction of in vivo drug-drug interactions from in vitro data based on physiological phar-macokinetics:use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharm Res 17:336-343 Mayhew BS, Jones DR, Hall SD (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 metabolic intermediate complex formation. Drug Metab Dispos 28:1031-1037 McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepa-tocytes. Drug Metab Dispos 34:1291-1300 Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, Tremaine LM (2006) The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions. J Pharmacol Exp Ther 316:336-348

Obach RS, Walsky RL, Venkatakrishnan K (2007) Mechanism-based inac-tivation of human cytochrome P450 enzymes and the prediction of drug-drug interactions. Drug Metab Dispos 35:246-255 Walsky RL, Obach RS (2004) Validated assays for human cytochrome P450

activities. Drug Metab Dispos 32:647-660 Wang Y-H (2010) Confidence assessment of the Simcyp time-based approach and a static mathematical model in predicting clinical drug-drug interactions for mechanism-based CYP3A inhibitors. Drug Metab Dispos 38:1094-1104 Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A (2008) Cytochrome P450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab 9:384-393 Zhao P, Kunze KL, Lee CA (2005) Evaluation of time-dependent inactiva-tion of CYP3A in cryopreserved human hepatocytes. Drug Metab Dispos 33:853-861

Further Readings

Cozza KL, Armstrong SC, Oesterheld JR (2003) Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, Ugts, P-Glycoproteins, 2nd edn. American Psychiatric Publishing, Washington, DC Kenny JR, McGinnity DF, Grime K, Riley RJ (2008) Utilizing of in vitro Cytochrome P450 inhibition data for projection clinical drug-drug interactions. Wiley, New York Levy RH, Thummel KE, Trager WF (2000) Metabolic Drug Interactions. Lippincott Williams & Wilkins, Philadelphia

Rodrigues AD (2008) Drug-Drug Interactions, 2nd edn. Marcel Dekker, New York

Segel IH (1993) Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. Wiley, New York Walsky RL, Boldt SE (2008) In vitro cytochrome P450 inhibition and induction. Curr Drug Metab 9:1-12

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