Effects of Liver Disease on Pharmacokinetics

Transcription

1 Eects o Liver Disease on Pharmacokinetics Jan J.L. Lertora, M.D., Ph.D. Director linical Pharmacology Program October 31, 2013 National Instittes o Health linical enter GOALS o Eects o Liver Disease Lectre Estimation o Hepatic learance Eect o Liver Disease on Elimination: - RESTRITIVELY Eliminated Drgs - NON-RESTRITIVELY Eliminated Drgs Other Eects o Liver Disease: - Renal Fnction - Drg Distribtion - Drg Response Modiication o Drg Therapy in Patients with Liver Disease ADDITIVITY o learances E R NR ESTIMATED FROM PLASMA LEVEL- VS.-TIME URVE ESTIMATED FROM REOVERY OF DRUG IN URINE ESTIMATED AS E - R 1

2 ALULATION OF H l H l E l R ASSUMES H = NR l FIK EUATION E So l A - V A A - V A E A = ONENTRATION ENTERING LIVER V = ONENTRATION LEAVING LIVER = HEPATI BLOOD FLOW Derivation o ROWLAND EUATION (I) Blood Flow () a WELL- STIRRED OMPART- V, MENT V, v v v = FRATION OF DRUG THAT IS UNBOUND = HEPATI EARANE IN ABSENE OF BINDING RESTRITION 2

3 Derivation o ROWLAND EUATION (II) Blood Flow () a v V, v d V ν dt a v MASS BALANE EUATION : v Derivation o ROWLAND EUATION (III) Blood Flow () a v atsteady state: a v so : V, v a v a thereore: ER a v a v v v 0 ROWLAND EUATION WELL-STIRRED OMPARTMENT H E TWO LIMITING ASES: RESTRITIVELY METABOLIZED DRUGS ( >> U): H NON-RESTRITIVELY METABOLIZED DRUGS (U >> ): H 3

4 RESTRITIVELY and NON-RESTRITIVELY Eliminated Drgs RESTRITIVELY METABOLIZED DRUGS: Phenytoin Wararin Theophylline NON-RESTRITIVELY METABOLIZED DRUGS: Lidocaine Propranolol Morphine HEPATI FIRST-PASS METABOLISM E A V A IF E = 1: V = 0 IF E = 0: V = A V A PORTAL VEIN HEPATI VEIN NON-RESTRITIVELY Eliminated Drgs l H ER FOR : ER A - V A 1, V 0 BUT : F 1- ER, So F 0 THESE DRUGS HAVE EXTENSIVE FIRST-PASS METABOLISM 4

5 AUTE VIRAL HEPATITIS Acte inlammatory condition Mild and transient changes related to extent o disease in most cases. Inreqently severe and lminant May become chronic and severe hanges in drg disposition less than in chronic disease Hepatic elimination retrns to normal as disease resolves HRONI LIVER DISEASE Usally related to chronic alcohol se or viral hepatitis Irreversible hepatocyte damage Decrease in SERUM ALBUMIN concentration Decrease in INTRINSI EARANE o drgs Intrahepatic and extrahepatic shnting o blood rom nctioning hepatocytes FIBROSIS disrpts normal hepatic architectre NODULES o regenerated hepatocytes orm RESTRITIVELY Metabolized Drgs: Eects o LIVER DISEASE H ALBUMIN H FREE ON. NO HANGE PORTOSYSTEMI SHUNTING 5

6 [PHENYTOIN] μg/ml RESTRITIVELY Metabolized Drgs: Eect o PROTEIN BINDING hanges SS H DOSE / H FOR RESTRITIVELY ELIMINATED DRUGS : FREE ON. SS DOSE / FREE and TOTAL PHENYTOIN Levels (DOSE = 300 MG/DAY) H INT = BOUND [PHENYTOIN] FREE [PHENYTOIN] 2 0 NORMAL RENAL FUNTION FUNTIONALLY ANEPHRI RESTRITIVELY Metabolized Drgs : Eect o PROTEIN BINDING hanges 6

7 % NORMAL INTRINSI EARANE- RESTRITIVELY Metabolized Drgs: Eects o LIVER DISEASE H H FREE ON. ALBUMIN NO HANGE PORTOSYSTEMI SHUNTING Role o YP ENZYMES in Hepatic Drg Metabolism RELATIVE HEPATI ONTENT OF YP ENZYMES YP2D6 2% YP2E1 7% % DRUGS METABOLIZED BY YP ENZYMES YP % YP 29 YP 2 17% YP 1A2 OTHER 36% 14% YP 1A2 14% YP2D6 23% 12% YP 3A4-5 26% YP 3A4-5 33% YP2E1 5% RESTRITIVELY Metabolized Drgs: Eect o IRRHOSIS on YP2D GLUURONIDATION YP3A YP219 YP1A2 NORMAL MILD MODERATE SEVERE 7

8 % NORMAL FUNTION - PUGH-HILD ASSIFIATION O Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SORE 1 POINT 2 POINTS 3 POINTS ENEPHALOPATHY GRADE 0 1 or 2 3 or 4 ASITES ABSENT SLIGHT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTHROMBIN TIME (seconds > control) > 10 ASSIFIATION OF INIAL SEVERITY INIAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 orrelation o Lab Test Reslts with Impaired YP Enzyme Fnction The entral Problem: There is no laboratory test o liver nction that is as sel or giding drg dose adjstment in patients with liver disease as is the estimation o creatinine clearance in patients with impaired renal nction. orrelation o SPEIAL TESTS o Liver Fnction with HILD-PUGH SORES* INDOYANINE GREEN EARANE GALATOSE ELIMINATION APATY SORBITOL EARANE 20 ANITPYRINE BREATH TEST 0 NORMAL MILD MODERATE SEVERE * Data rom Herold, et al. Liver 2001;21:

9 PITTSBURGH OKTAIL Approach* DRUG AFFEINE HLORZOXAZONE DAPSONE DEBRISOUIN MEPHENYTOIN ENZYME YP 1A2 YP 2E1 YP 3A + NAT2 YP 2D6 YP 219 * From: Frye RF, et al. lin Pharmacol Ther 1997;62: RESTRITIVELY Metabolized Drgs: Eects o Liver Disease H ALBUMIN H FREE ON. NO HANGE PORTOSYSTEMI SHUNTING Eects o HEPATI SHUNTING on ROWLAND EUATION* H P T T T T = TOTAL BLOOD FLOW TO LIVER P = BLOOD FLOW PERFUSING LIVER T P = SHUNT BLOOD FLOW FOR RESTRITIVELY ELIMINATED DRUGS: T >>, H = ( P / T ) * From: McLean A, et al. lin Pharmacol Ther 1979;25:

10 RESTRITIVELY Metabolized Drgs: Eects o Hepatic Shnting* SEVERITY T P P / T ANTIPYRINE H (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. lin Pharmacol Ther 1979;25: NON-RESTRITIVELY Metabolized Drgs: Eects o Liver Disease H H F ALBUMIN NO HANGE* NO HANGE NO HANGE NO HANGE HEPATI PERFUSION * HOWEVER, NOTE THAT FREE ONENTRATION IS NON-RESTRITIVELY Metabolized Drgs: Eects o Liver Disease H H F ALBUMIN NO HANGE* NO HANGE NO HANGE NO HANGE HEPATI PERFUSION HOWEVER, MAY NO LONGER BE >> 10

11 NON-RESTRITIVELY Metabolized Drgs: Eects o Liver Disease H H F ALBUMIN NO HANGE* NO HANGE NO HANGE NO HANGE HEPATI PERFUSION Eects o Hepatic Shnting on Rowland Eqation* H P T T T T = TOTAL BLOOD FLOW TO LIVER P = BLOOD FLOW PERFUSING LIVER T P = SHUNT BLOOD FLOW FOR NON-RESTRITIVELY ELIMINATED DRUGS: l >> T, H = ( P / T ) T = P * From: McLean A, et al. lin Pharmacol Ther 1979;25: NON-RESTRITIVELY Metabolized Drgs: Eects o Decreased Liver Persion* SEVERITY T P P / T IG H (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. lin Pharmacol Ther 1979;25:

12 Inlence o PORTOSYSTEMI SHUNTING on Oral Bioavailability (F) RESTRITIVELY Eliminated Drgs: Little change NON-RESTRITIVELY Eliminated Drgs: SHUNTING may markedly increase extent o drg absorption (F) IRRHOSIS Aects Exposre to Some NON-RESTRITIVELY Metabolized Drgs ABSOLUTE BIOAVAILABILITY ONTROLS (%) IRRHOTIS (%) RELATIVE EXPOSURE IRRHOTIS/ONTROL IV ORAL MEPERIDINE PENTAZOINE PROPRANOLOL * 2.0* * THIS ALSO INORPORATES 55% INREASE IN PROPRANOLOL IRRHOSIS Aects Renal Fnction: The Hepatorenal Syndrome Risk in Patients with irrhosis, Ascitis, and GFR > 50 ml/min: - 18% within 1 year - 39% within 5 years Predictors o Risk: - Small liver - Low serm albmin - High plasma renin ockcrot and Galt Eqation may overestimate renal nction 12

13 IRRHOSIS Aects Renal Fnction: The Hepatorenal Syndrome The Syndrome has a FUNTIONAL rather than an Anatomical Basis. HEPATORENAL SYNDROME ANTEMORTEM Arteriogram HEPATORENAL SYNDROME POSTMORTEM Arteriogram 13

14 IMETIDINE SF/SERUM RATIO IRRHOSIS Aects Renal Fnction: The Hepatorenal Syndrome Therapy with some drgs may precipitate Hepatorenal Syndrome AE Inhibitors NSAIDs Frosemide (High Total Doses) IRRHOSIS May Aect Drg Distribtion Increased Free oncentration o NON-RESTRITIVELY Eliminated Drgs (e.g. PROPRANOLOL) Increased Permeability o Blood:NS Barrier (e.g. IMETIDINE) IRRHOSIS Aects Drg Distribtion: Increased NS Penetration o imetidine* NONE RENAL + LIVER DISEASE LIVER DISEASE * From Schentag JJ, et al. lin Pharmacol Ther 1981;29:

15 IRRHOSIS may aect PHARMAODYNAMIS Sedative response to BENZODIAZEPINES is exaggerated Response to LOOP DIURETIS is redced Drg Dosing in Patients with LIVER DISEASE The entral Problem: There is no laboratory test o liver nction that is as sel or giding drg dose adjstment in patients with liver disease as is the estimation o creatinine clearance in patients with impaired renal nction. PUGH-HILD ASSIFIATION o Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SORE 1 POINT 2 POINTS 3 POINTS ENEPHALOPATHY GRADE 0 1 or 2 3 or 4 ASITES ABSENT SLIGHT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTHROMBIN TIME (seconds > control) > 10 ASSIFIATION OF INIAL SEVERITY INIAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 15

16 Drgs ONTRAINDIATED in Patients with Severe Liver Disease May precipitate renal ailre: - NSAIDs - AE Inhibitors Predispose to bleeding: - β-latams with N-Methylthiotetrazole Side hain (e.g. EFOTETAN) Drg Reqiring 50% Dose Redction in Patients with MODERATE IRRHOSIS HANGE IN IRRHOSIS F E ANALGESI DRUGS Morphine 213% 59% Meperidine 94% 46% Pentazocine 318% 50% Drgs Reqiring 50% Dose Redction in Patients with MODERATE IRRHOSIS ARDIOVAS. DRUGS HANGE IN IRRHOSIS F E Propaenone 257% 24% Verapamil 136% 51% Niedipine 78% 60% Losartan 100% 50% 16

17 Drgs Reqiring 50% Dose Redction in Patients with MODERATE IRRHOSIS HANGE IN IRRHOSIS F E OTHER DRUGS Omeprazole 75% 89% Tacrolims 33% 72% Recommended Evalation o Pharmacokinetics in Liver Disease Patients* REDUED Stdy Design: - Stdy ontrol Patients and Patients with hild-pgh Moderate Impairment - Findings in Moderate ategory Applied to Mild ategory; Dosing Prohibited in Severe ategory FULL Stdy Design: - Stdy ontrol Patients and Patients in All hild-pgh ategories - Poplation PK Approach * FDA linical Pharmacology Gidance, May