Effects of Liver Disease on Pharmacokinetics

Transcription

1 Effects of Liver Disease on Pharmacokinetics Jan J.L. Lertora, M.D., Ph.D. Director Clinical Pharmacology Program October 29, 2015 National Instittes of ealth Clinical Center GOALS of Effects of Liver Disease Lectre Estimation of epatic Clearance Effect of Liver Disease on Elimination: - RESTRICTIVELY Eliminated Drgs - NON-RESTRICTIVELY Eliminated Drgs Other Effects of Liver Disease: - Renal Fnction - Drg Distribtion - Drg Response Modification of Drg Therapy in Patients with Liver Disease Correlation of Lab Test Reslts with Impaired CYP Enzyme Fnction The Central Problem: There is no laboratory test of liver fnction that is as sefl for giding drg dose adjstment in patients with liver disease as is the estimation of creatinine clearance in patients with impaired renal fnction. 1

2 FDA-approved Drg Labels: Dosing Gidance in Liver Disease Evalation of hepatic impairment dosing recommendations in FDA-approved * prodct labels. Chang Y, Brckart GJ, Lesko LJ, Dowling TC J Clin Pharmacol. 2013;53:962-6 * Janary 2004-December 2011 (67/157 NMEs) ADDITIVITY of Clearances E R NR ESTIMATED FROM PLASMA LEVEL- VS.-TIME CURVE ESTIMATED FROM RECOVERY OF DRUG IN URINE ESTIMATED AS E - R CALCULATION OF Cl Cl E Cl R ASSUMES = NR 2

3 FICK EQUATION A - V Cl Q A A - V E A So Cl Q E A = CONCENTRATION ENTERING LIVER V = CONCENTRATION LEAVING LIVER Q = EPATIC BLOOD FLOW Derivation of ROWLAND EQUATION (I) Blood Flow (Q) C a WELL- STIRRED COMPART- V, MENT V, CC v v C v f f = FRACTION OF DRUG TAT IS UNBOUND = EPATIC EARANCE IN ABSENCE OF BINDING RESTRICTION Derivation of ROWLAND EQUATION (II) Blood Flow (Q) C a C v V, C v f MASS BALANCE EQUATION : dc V ν QC QC f C dt a v v 3

4 Derivation of ROWLAND EQUATION (III) Blood Flow (Q) C a C v V, C v f atsteady state: QC a QC v f C v 0 so : Q C a C v f C v QC a Q f C v therefore: C a C v f ER C a Q f ROWLAND EQUATION WELL-STIRRED COMPARTMENT f Q E Q Q f TWO LIMITING CASES: RESTRICTIVELY METABOLIZED DRUGS (Q >> fu): f NON-RESTRICTIVELY METABOLIZED DRUGS (fu >> Q): Q RESTRICTIVELY and NON-RESTRICTIVELY Eliminated Drgs (examples) RESTRICTIVELY METABOLIZED DRUGS: Phenytoin Warfarin Theophylline NON-RESTRICTIVELY METABOLIZED DRUGS: Lidocaine Propranolol Morphine 4

5 EPATIC FIRST-PASS METABOLISM A V E A IF E = 1: V = 0 IF E = 0: V = A V A PORTAL VEIN EPATIC VEIN NON-RESTRICTIVELY Eliminated Drgs Cl Q Q ER A - V FOR : ER V A 1, 0 BUT : F 1- ER, So F 0 TESE DRUGS AVE EXTENSIVE FIRST-PASS METABOLISM ACUTE VIRAL EPATITIS Acte inflammatory condition Mild and transient changes related to extent of disease in most cases. Infreqently severe and flminant May become chronic and severe Changes in drg disposition less than in chronic disease epatic elimination retrns to normal as disease resolves 5

6 CRONIC LIVER DISEASE Usally related to chronic alcohol se or viral hepatitis Irreversible hepatocyte damage Decrease in SERUM ALBUMIN concentration Decrease in INTRINSIC EARANCE of drgs Intrahepatic and extrahepatic shnting of blood from fnctioning hepatocytes FIBROSIS disrpts normal hepatic architectre NODULES of regenerated hepatocytes form RESTRICTIVELY Metabolized Drgs: Effects of LIVER DISEASE f FREE CONC. ALBUMIN NO CANGE PORTOSYSTEMIC SUNTING RESTRICTIVELY Metabolized Drgs: Effect of PROTEIN BINDING Changes C SS DOSE / FOR RESTRICTIV ELY ELIMINATED DRUGS : f FREE CONC. C SS f DOSE / f f 6

7 [PENYTOIN] μg/ml FREE and TOTAL PENYTOIN Levels (DOSE = 300 MG/DAY) INT = BOUND [PENYTOIN] FREE [PENYTOIN] 2 0 NORMAL RENAL FUNCTION FUNCTIONALLY ANEPRIC RESTRICTIVELY Metabolized Drgs : Effect of PROTEIN BINDING Changes RESTRICTIVELY Metabolized Drgs: Effects of LIVER DISEASE f FREE CONC. ALBUMIN NO CANGE PORTOSYSTEMIC SUNTING 7

8 % NORMAL INTRINSIC EARANCE- Role of CYP ENZYMES in epatic Drg Metabolism RELATIVE EPATIC CONTENT OF CYP ENZYMES CYP2D6 2% CYP2E1 7% % DRUGS METABOLIZED BY CYP ENZYMES CYP 2C19 11% CYP 2C9 CYP 2C 17% CYP 1A2 OTER 36% 14% CYP 1A2 14% CYP2D6 23% 12% CYP 3A4-5 26% CYP 3A4-5 33% CYP2E1 5% RESTRICTIVELY Metabolized Drgs: Effect of CIRROSIS on CYP2D GLUCURONIDATION CYP3A CYP2C19 CYP1A2 NORMAL MILD MODERATE SEVERE PUG-CILD ASSIFICATION Of Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SCORE 1 POINT 2 POINTS 3 POINTS ENCEPALOPATY GRADE 0 1 or 2 3 or 4 ASCITES ABSENT SLIGT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTROMBIN TIME (seconds > control) > 10 ASSIFICATION OF INICAL SEVERITY INICAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 8

9 % NORMAL FUNCTION - Correlation of SPECIAL TESTS of Liver Fnction with CILD-PUG SCORES* INDOCYANINE GREEN EARANCE GALACTOSE ELIMINATION CAPACTY SORBITOL EARANCE 20 ANITPYRINE BREAT TEST 0 NORMAL MILD MODERATE SEVERE * Data from erold C, et al. Liver 2001;21: PITTSBURG COCKTAIL Approach* DRUG CAFFEINE CLORZOXAZONE DAPSONE DEBRISOQUIN MEPENYTOIN ENZYME CYP 1A2 CYP 2E1 CYP 3A + NAT2 CYP 2D6 CYP 2C19 * From: Frye RF, et al. Clin Pharmacol Ther 1997;62: RESTRICTIVELY Metabolized Drgs: Effects of Liver Disease f FREE CONC. ALBUMIN NO CANGE PORTOSYSTEMIC SUNTING 9

10 Effects of EPATIC SUNTING on ROWLAND EQUATION* Q Q P T QT f QT f Q T = TOTAL BLOOD FLOW TO LIVER Q P = BLOOD FLOW PERFUSING LIVER Q T Q P = SUNT BLOOD FLOW FOR RESTRICTIVELY ELIMINATED DRUGS: Q T >> f, = (Q P /Q T ) f * From: McLean A, et al. Clin Pharmacol Ther 1979;25: RESTRICTIVELY Metabolized Drgs: Effects of epatic Shnting* SEVERITY Q T Q P Q P /Q T ANTIPYRINE (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. Clin Pharmacol Ther 1979;25: NON-RESTRICTIVELY Metabolized Drgs: Effects of Liver Disease Q F ALBUMIN NO CANGE* NO CANGE NO CANGE NO CANGE EPATIC PERFUSION * OWEVER, NOTE TAT FREE CONCENTRATION IS 10

11 NON-RESTRICTIVELY Metabolized Drgs: Effects of Liver Disease Q F ALBUMIN NO CANGE* NO CANGE NO CANGE NO CANGE EPATIC PERFUSION OWEVER, f MAY NO LONGER BE >> Q NON-RESTRICTIVELY Metabolized Drgs: Effects of Liver Disease Q F ALBUMIN NO CANGE* NO CANGE NO CANGE NO CANGE EPATIC PERFUSION Effects of epatic Shnting on Rowland Eqation* Q Q P T QT f QT f Q T = TOTAL BLOOD FLOW TO LIVER Q P = BLOOD FLOW PERFUSING LIVER Q T Q P = SUNT BLOOD FLOW FOR NON-RESTRICTIVELY ELIMINATED DRUGS: f Cl >> Q T, = (Q P /Q T ) Q T = Q P * From: McLean A, et al. Clin Pharmacol Ther 1979;25:

12 NON-RESTRICTIVELY Metabolized Drgs: Effects of Decreased Liver Perfsion* SEVERITY Q T Q P Q P /Q T ICG (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. Clin Pharmacol Ther 1979;25: Inflence of PORTOSYSTEMIC SUNTING on Oral Bioavailability (F) RESTRICTIVELY Eliminated Drgs: Little change NON-RESTRICTIVELY Eliminated Drgs: SUNTING may markedly increase oral bioavailability (F) de to redced first-pass metabolism (drg bypasses hepatocytes) CIRROSIS Affects Exposre to Some NON-RESTRICTIVELY Metabolized Drgs ABSOLUTE BIOAVAILABILITY CONTROLS (%) CIRROTICS (%) RELATIVE EXPOSURE CIRROTICS/CONTROL IV ORAL MEPERIDINE PENTAZOCINE PROPRANOLOL * 2.0* * TIS ALSO INCORPORATES 55% INCREASE IN PROPRANOLOL f 12

13 CIRROSIS Affects Renal Fnction: The epatorenal Syndrome Risk in Patients with Cirrhosis, Ascitis, and GFR > 50 ml/min: - 18% within 1 year - 39% within 5 years Predictors of Risk: - Small liver - Low serm albmin - igh plasma renin Cockcroft and Galt Eqation may overestimate renal fnction CIRROSIS Affects Renal Fnction: The epatorenal Syndrome The Syndrome has a FUNCTIONAL rather than an Anatomical Basis. EPATORENAL SYNDROME ANTEMORTEM Arteriogram 13

14 EPATORENAL SYNDROME POSTMORTEM Arteriogram CIRROSIS Affects Renal Fnction: The epatorenal Syndrome Therapy with some drgs may precipitate epatorenal Syndrome ACE Inhibitors NSAIDs Frosemide (igh Total Doses) CIRROSIS May Affect Drg Distribtion Increased Free Concentration of NON-RESTRICTIVELY Eliminated Drgs (e.g. PROPRANOLOL) Increased Permeability of Blood:CNS Barrier (e.g. CIMETIDINE) 14

15 CIMETIDINE CSF/SERUM RATIO CIRROSIS Affects Drg Distribtion: Increased CNS Penetration of Cimetidine* NONE RENAL + LIVER DISEASE LIVER DISEASE * From Schentag JJ, et al. Clin Pharmacol Ther 1981;29: CIRROSIS may affect PARMACODYNAMICS Sedative response to BENZODIAZEPINES is exaggerated Response to LOOP DIURETICS is redced Drgs CONTRAINDICATED in Patients with Severe Liver Disease May precipitate renal failre: - NSAIDs - ACE Inhibitors Predispose to bleeding: - β-lactams with N-Methylthiotetrazole Side Chain (e.g. CEFOTETAN) 15

16 Drg Reqiring 50% Dose Redction in Patients with MODERATE CIRROSIS CANGE IN CIRROSIS F E ANALGESIC DRUGS Morphine 213% 59% Meperidine 94% 46% Pentazocine 318% 50% Drgs Reqiring 50% Dose Redction in Patients with MODERATE CIRROSIS CARDIOVASC. DRUGS CANGE IN CIRROSIS F E Propafenone 257% 24% Verapamil 136% 51% Nifedipine 78% 60% Losartan 100% 50% Drgs Reqiring 50% Dose Redction in Patients with MODERATE CIRROSIS CANGE IN CIRROSIS F E OTER DRUGS Omeprazole 75% 89% Tacrolims 33% 72% 16

17 PUG-CILD ASSIFICATION of Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SCORE 1 POINT 2 POINTS 3 POINTS ENCEPALOPATY GRADE 0 1 or 2 3 or 4 ASCITES ABSENT SLIGT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTROMBIN TIME (seconds > control) > 10 ASSIFICATION OF INICAL SEVERITY INICAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 Recommended Evalation of Pharmacokinetics in Liver Disease Patients* REDUCED Stdy Design: - Stdy Control Patients and Patients with Child-Pgh Moderate Impairment - Findings in Moderate Category Applied to Mild Category; Dosing Prohibited in Severe Category FULL Stdy Design: - Stdy Control Patients and Patients in All Child-Pgh Categories - Poplation PK Approach * FDA Clinical Pharmacology Gidance, May