PHARMACOKINETIC DRUG INTERACTIONS. DRUGS REMOVED FROM THE MARKET DURING THE 1990s DRUGCATEGORYREASON Astemizoleantihistamineserious metabolic drug intxns

PHARMACOKINETIC PHARMACOKINETIC DRUG INTERACTIONSDRUG INTERACTIONS

DRUGS REMOVED FROM THE MARKET DRUGS REMOVED FROM THE MARKET DURING THE 1990sDURING THE 1990s

DRUG CATEGORY REASONAstemizole antihistamine serious metabolic

drug intxnsBromfenac analgesic hepatotoxicityDexfenfluramine anorectic cardiovascular toxFelbamate anticonvulsant aplastic anemiaFlosequinan vasodilator increased mortalityGrepafloxacin antibiotic proarrhythmicMibefradil Ca channel blocker serious drug intxnsTemafloxacin antibiotic severe ADRTerfenadine antihistamine serious drug intxnTravafloxacin antibiotic hepatotoxicity

Source: J Clin Pharmacol 40:1093, 2000

I. GENERAL CONSIDERATIONSI. GENERAL CONSIDERATIONSA. CONCEPT OF A THERAPEUTIC WINDOWA. CONCEPT OF A THERAPEUTIC WINDOW

Toxicity Desired

log Concentration

Probability of Response

B. EPIDEMIOLOGICAL CONSIDERATIONSB. EPIDEMIOLOGICAL CONSIDERATIONS

HOSPITALIZED PATIENTS EXPERIENCING AN HOSPITALIZED PATIENTS EXPERIENCING AN ADVERSE REACTIONADVERSE REACTION

Drug Class % Pts with ReactionAntihypertensives 12Anticoagulants 11Antimicrobials 6Antiarrhythmics 4Antiinflammatory 3Diuretics 3Analgesics 2

Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.


Effect of the Number of Drugs a Patient Receives on Effect of the Number of Drugs a Patient Receives on the Frequency of Adverse Drug Reactionsthe Frequency of Adverse Drug Reactions

Number Antihypertensives Anticoagulants 0-5 9 7 6-10 9 811-15 18 1516-20 23 18

Data from: May FE et,al. Drug interactions and multiple drug administration. Clin Pharmacol Ther 22:323, 1977.


Prospective study of 237 patients treated with warfarin Prospective study of 237 patients treated with warfarin analyzed for determination of whether or not a drug analyzed for determination of whether or not a drug interaction occurred with concurrent chloral hydrateinteraction occurred with concurrent chloral hydrate

All patients who received chloral hydrate 237 during warfarin therapyThose patients who received chloral hydrate for at least 3 consecutive days 69 Impossible to evaluate (unstable/change therapy) 28 Potentiation of anticoagulant action 22 No observable interaction 19

Data from: Koch-Weser J. Hemorrhagic reactions and drug interactions in 500 warfarin treated patients. Clin Pharmacol Ther 14:139-146, 1973.

C. TYPE OF INTERACTIONC. TYPE OF INTERACTION

UnidirectionalUnidirectional

A B

BidirectionalBidirectional

A B

D. CLASSIFICATION OF MECHANISMD. CLASSIFICATION OF MECHANISM

ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTION

Complexation/ChelationComplexation/Chelation

Example: antacids + tetracyclineExample: antacids + tetracycline

Impact: tetracycline complexes with Impact: tetracycline complexes with divalent cations forming an insoluble divalent cations forming an insoluble complexcomplex




Altered GI TransitAltered GI Transit

Example: anticholinergics + acetaminophenExample: anticholinergics + acetaminophen

Impact: delay in absorption of acetaminophenImpact: delay in absorption of acetaminophen




Altered GI TransitAltered GI Transit

Altered Gastric pHAltered Gastric pH

Example: H-2 blockers + ketoconazoleExample: H-2 blockers + ketoconazole

Impact: dissolution of ketoconazole is Impact: dissolution of ketoconazole is decreased, resulting in reduced decreased, resulting in reduced absorptionabsorption


ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM

Induction of MetabolismInduction of Metabolism

Example: phenobarbital + warfarinExample: phenobarbital + warfarin

Impact: phenobarbital increases the Impact: phenobarbital increases the metabolism of warfarin, resulting in metabolism of warfarin, resulting in reduced anticoagulationreduced anticoagulation


ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISM

Induction of MetabolismInduction of Metabolism

Inhibition of MetabolismInhibition of Metabolism

Example: cimetidine + theophyllineExample: cimetidine + theophylline

Impact: cimetidine reduces the clearance Impact: cimetidine reduces the clearance of theophylline causing an increase in of theophylline causing an increase in adverse effectsadverse effects


ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCE

Increase in Renal Blood FlowIncrease in Renal Blood Flow

Example: hydralazine + digoxinExample: hydralazine + digoxin

Impact: hydralazine increases the renal Impact: hydralazine increases the renal clearance of digoxinclearance of digoxin



Increase in Renal Blood FlowIncrease in Renal Blood FlowInhibition of Active Tubular SecretionInhibition of Active Tubular Secretion

Example: probenecid + penicillinExample: probenecid + penicillin

Impact: probenecid prolongs the half-life Impact: probenecid prolongs the half-life of penicillin, allowing single dose therapyof penicillin, allowing single dose therapy



Increase in Renal Blood FlowIncrease in Renal Blood FlowInhibition of Active Tubular SecretionInhibition of Active Tubular SecretionAlterations in Tubular ReabsorptionAlterations in Tubular Reabsorption

Example: antacids + aspirinExample: antacids + aspirin

Impact: antacids reduce the tubular Impact: antacids reduce the tubular reabsorption of salicylate via an increase reabsorption of salicylate via an increase in urine pHin urine pH


ALTERATIONS IN ABSORPTIONALTERATIONS IN ABSORPTIONALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN HEPATIC METABOLISMALTERATIONS IN RENAL CLEARANCEALTERATIONS IN RENAL CLEARANCEALTERATIONS IN PLASMA PROTEIN ALTERATIONS IN PLASMA PROTEIN BINDINGBINDING

Example: phenytoin + valproic acidExample: phenytoin + valproic acid

Impact: protein binding of valproic acid is Impact: protein binding of valproic acid is reduced and total Css decreasedreduced and total Css decreased

II. ALTERATIONS IN ABSORPTIONII. ALTERATIONS IN ABSORPTIONA.A. Mediated by binding or chelation of drug inMediated by binding or chelation of drug in the gastrointestinal tractthe gastrointestinal tract

HO

HO carbidopa

HO

HO

COOH

NH2

L-dopa

NH-NH2

CH3

COOH

Effect of ferrous sulfate (325 mg) on plasma levodopa and carbidopa concentrations after ingestion of Sinemet (100/25) in patients with Parkinson's disease. Concentrations shown are mean values without (tirangles) and with (circles) ferrous sulfate administration simultaneously.

Adapted from Campbell NRC et al: Br J clin Pharmacol 30:599-605, 1990

Effect of Antacids on Iron Absorption from a Multivitamin. Antacid was ingested immediately after multivitamin ingestion. Data from: O'Neil-Cutting MA, Crosby WH. The effect of antacids on the absorption of simultaneously ingested iron. JAMA 255:1468- 1470, 1986.

COMPOUNDS DEMONSTRATED COMPOUNDS DEMONSTRATED TO BIND WITH IRONTO BIND WITH IRON

ACETAMINOPHENACETAMINOPHEN MINOXIDILMINOXIDILAMPICILLINAMPICILLIN NALIDIXI ACIDNALIDIXI ACIDCAPTOPRILCAPTOPRIL NORFLOXACINNORFLOXACINCARBIDOPACARBIDOPA PENICILLAMINEPENICILLAMINECIPROFLOXACINCIPROFLOXACIN RIFAMPINRIFAMPINETHAMBUTOLETHAMBUTOL TETRACYCLINETETRACYCLINEFOLIC ACIDFOLIC ACID THYROXINETHYROXINEINDOMETHACININDOMETHACIN SALICYLIC ACIDSALICYLIC ACIDLEVODOPALEVODOPAMETHYLDOPAMETHYLDOPA

B. Mediated by alterations in gastric emptying B. Mediated by alterations in gastric emptying or gastrointestinal transit or gastrointestinal transit

1

2

3

4

5

6

7

8

9

10

11

Fasting Fed

GRT

(hr)

Effect of food on Effect of food on gastric residence time gastric residence time (GRT) of the (GRT) of the Heidelberg capsule Heidelberg capsule administered to administered to healthy male (circles) healthy male (circles) and female (squares).and female (squares). Reproduced from: Mojaverian Reproduced from: Mojaverian P et al. Effect of food on the P et al. Effect of food on the absorption of enteric coated absorption of enteric coated aspirin: Correlation with aspirin: Correlation with gastric residence time. gastric residence time. Clin Clin Pharmacol Ther Pharmacol Ther 41:11-17, 41:11-17, 1987.1987.

Reproduced from: Rowland M,Tozer TN. Reproduced from: Rowland M,Tozer TN. Clinical Pharmacokinetics – Concepts and ApplicationsClinical Pharmacokinetics – Concepts and Applications , 3, 3rdrd edition, edition, 1995, p.2711995, p.271

Effect of sumatriptan on acetaminophen Effect of sumatriptan on acetaminophen absorption in patients with migrainesabsorption in patients with migraines

ParameterParameter APAP aloneAPAP alone with Sumatriptan p value with Sumatriptan p value

CCmaxmax (mg/L) (mg/L) 36.3 (10.9) 36.3 (10.9) 18.3 (6.7) 18.3 (6.7) 0.001 0.001

ttmaxmax (hr) (hr) 1.4 (0.4) 1.4 (0.4) 2.7 (1.0) 2.7 (1.0) 0.001 0.001

tt1/21/2 (hr)(hr) 2.3 (0.7) 2.3 (0.7) 3.0 (1.4) 3.0 (1.4) NS NS

AUCAUC0-1.50-1.5 26.9 (9.5) 11.8 (3.7)26.9 (9.5) 11.8 (3.7) 0.001 0.001

AUCAUC0-30-3 62.3 (14) 33.1 (12.9)62.3 (14) 33.1 (12.9) 0.001 0.001

AUCAUC0-80-8 109 (37) 78.8 (31.3)109 (37) 78.8 (31.3) NS NS

Data from: Rani PU, et al. Sumatriptan delays paracetamol Data from: Rani PU, et al. Sumatriptan delays paracetamol absorption in migraine patients. absorption in migraine patients. Clin PharmacokinetClin Pharmacokinet 11:300- 11:300-304, 1996.304, 1996.

III. ALTERATIONS IN DRUG METABOLISMIII. ALTERATIONS IN DRUG METABOLISM

A. InductionA. Induction

int

int

int

uubO

uubH

uubHH

CLf

DoseFAUC

CLfQ

CLfQCL

Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and Effect of phenobarbital (60 mg qd) on dicumarol plasma concentrations and prothrombin time. prothrombin time. From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels From: Cucinell SA, et al. Lowering effect of phenobarbital on plasma levels

of dicumarol and diphenylhydantion. of dicumarol and diphenylhydantion. Clinical Pharmacology & TherapeuticsClinical Pharmacology & Therapeutics 6:420-429, 1965. 6:420-429, 1965.

Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. Reproduced from: Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. NEJMNEJM 304:1466, 1981. 304:1466, 1981.

From: Rowland M, Tozer TN. Ibid. p. 282.From: Rowland M, Tozer TN. Ibid. p. 282.

Effect of cimetidine on the clearance on diazepam (D), Effect of cimetidine on the clearance on diazepam (D), desmethyldiazepam (DZD), chlordiazepoxide (CZD) and desmethyldiazepam (DZD), chlordiazepoxide (CZD) and oxazepam (OXM). CZD values are x10, while OXM values are oxazepam (OXM). CZD values are x10, while OXM values are 1/10.1/10. Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. Data from: Somogyi A, Gugler R: Drug interactions with cimetidine. Clin Clin PharmacokinetPharmacokinet 7:23, 1982. 7:23, 1982.

B. InhibitionB. Inhibition

Summary of studies assessing effect of quinolones on theophylline Summary of studies assessing effect of quinolones on theophylline clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak clearance. Data from: Edwards DJ, Bowles SK, Svensson CK, Rybak MJ. MJ. Clin PharmacokinetClin Pharmacokinet 15:194, 1988. 15:194, 1988.

FACTORS WHICH ALTER HEPATIC BLOOD FLOWFACTORS WHICH ALTER HEPATIC BLOOD FLOW

Increased FlowIncreased Flow•GlucagonGlucagon•IsoproterenolIsoproterenol•PhentolaminePhentolamine•PhenobarbitalPhenobarbital•PGEPGE•Supine postureSupine posture•High-protein mealHigh-protein meal•Viral hepatitisViral hepatitis

Decreased FlowDecreased Flow•PropranololPropranolol•NorepinephrineNorepinephrine•AnestheticsAnesthetics•LabetalolLabetalol•Upright postureUpright posture•HypovolemiaHypovolemia•CHFCHF•cirrhosiscirrhosis

Effect of changing posture on liver Effect of changing posture on liver blood flow and lidocaine clearanceblood flow and lidocaine clearance

ParameterParameter SupineSupine Sitting/tiltedSitting/tilted

QQHH (mL/min) (mL/min) 1100 (167)1100 (167) 765 (106) 765 (106)

CL (mL/min)CL (mL/min) 602 (101) 475 (109) 602 (101) 475 (109)

Data presented as mean (SD)Data presented as mean (SD)From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine From: Feely J, et al. Effect of hypotension on liver blood flow and lidocaine disposition. disposition. N Engl J MedN Engl J Med 307:866-869, 1982. 307:866-869, 1982.

V. ALTERATIONS IN RENAL CLEARANCEV. ALTERATIONS IN RENAL CLEARANCEA. Renal Blood FlowA. Renal Blood Flow

Effect of vasodilators on hemodynamics, renal function and digoxin renal Effect of vasodilators on hemodynamics, renal function and digoxin renal excretion. CI - cardiac index,; PAH - excretion. CI - cardiac index,; PAH - pp-aminohippuric acid clearance; RBF --aminohippuric acid clearance; RBF -renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et renal blood flow; and Dig CLr - digoxin renal clearance. Data from Cogan JJ, et al. al. CirculationCirculation 64:973, 1981. 64:973, 1981.

B. Active Tubular SecretionB. Active Tubular Secretion

B. Urine pHB. Urine pH

Renal clearance of salicylate in 11 yo child with rheumatic fever treated Renal clearance of salicylate in 11 yo child with rheumatic fever treated with an antacid. Data from Levy G, Lampman T, Kamath BL, with an antacid. Data from Levy G, Lampman T, Kamath BL, Garrettson LK. Decreased serum salicylate concentrations in children Garrettson LK. Decreased serum salicylate concentrations in children with rheumatic fever treated with antacid. with rheumatic fever treated with antacid. N Engl J MedN Engl J Med 293:323-325, 293:323-325, 1975.1975.

VI. ALTERATIONS IN PROTEIN BINDINGVI. ALTERATIONS IN PROTEIN BINDING

From: Rowland M, Tozer TN. Ibid, p. 274.From: Rowland M, Tozer TN. Ibid, p. 274.

Reproduced from: Rowland M, Tozer TN. Reproduced from: Rowland M, Tozer TN. Ibid, p. 280Ibid, p. 280

From: Rowland M, Tozer TN. Ibid, p. 275.From: Rowland M, Tozer TN. Ibid, p. 275.

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PHARMACOKINETIC DRUG INTERACTIONS. DRUGS REMOVED FROM THE MARKET DURING THE 1990s DRUGCATEGORYREASON Astemizoleantihistamineserious metabolic drug intxns