Effects of Liver Disease on Pharmacokinetics

Transcription

1 Effects of Liver Disease on Pharmacokinetics Juan J.L. Lertora, M.D., Ph.D. Director Clinical Pharmacology Program October 31, 2013 National Institutes of Health Clinical Center 1

2 GOALS of Effects of Liver Disease Lecture Estimation of Hepatic Clearance Effect of Liver Disease on Elimination: - RESTRICTIVELY Eliminated Drugs - NON-RESTRICTIVELY Eliminated Drugs Other Effects of Liver Disease: - Renal Function - Drug Distribution - Drug Response Modification of Drug Therapy in Patients with Liver Disease 2

3 ADDITIVITY of Clearances CL E CL R CL NR ESTIMATED FROM PLASMA LEVEL- VS.-TIME CURVE ESTIMATED FROM RECOVERY OF DRUG IN URINE ESTIMATED AS CL E - CL R 3

4 CALCULATION OF CL H Cl H Cl E Cl R ASSUMES CL H = CL NR 4

5 FICK EQUATION Cl E So Q Cl A - V A A - V A Q E A = CONCENTRATION ENTERING LIVER V = CONCENTRATION LEAVING LIVER Q = HEPATIC BLOOD FLOW 5

6 Derivation of ROWLAND EQUATION (I) Blood Flow (Q) C a WELL- STIRRED COMPART- V, MENT V, CC v v C v f u CL int f u = FRACTION OF DRUG THAT IS UNBOUND CL int = HEPATIC CLEARANCE IN ABSENCE OF BINDING RESTRICTION 6

7 Derivation of ROWLAND EQUATION (II) Blood Flow (Q) C a C v V, C v f u CL int MASS BALANCE EQUATION : dc V ν dt QC a QC v f CL C u int v 7

8 Derivation of ROWLAND EQUATION (III) Blood Flow (Q) C a C v at steady state: QC a QC v so : V, C v Q C a C v QC a Q therefore: C a C ER v C a f u CL int f u CL int C v f u CL int C v f u CL int Q C v 0 f u CL int f u CL int 8

9 ROWLAND EQUATION WELL-STIRRED COMPARTMENT CL H Q E Q Q f CL u int f CL u int TWO LIMITING CASES: RESTRICTIVELY METABOLIZED DRUGS (Q >> f U CL int ): CL H f ucl int NON-RESTRICTIVELY METABOLIZED DRUGS (f U CL int >> Q): CL H Q 9

10 RESTRICTIVELY and NON-RESTRICTIVELY Eliminated Drugs RESTRICTIVELY METABOLIZED DRUGS: Phenytoin Warfarin Theophylline NON-RESTRICTIVELY METABOLIZED DRUGS: Lidocaine Propranolol Morphine 10

11 HEPATIC FIRST-PASS METABOLISM A V E A IF E = 1: V = 0 IF E = 0: V = A V A PORTAL VEIN HEPATIC VEIN 11

12 NON-RESTRICTIVELY Eliminated Drugs Cl H Q Q ER FOR : ER A - V A 1, V 0 BUT : F 1- ER, So F 0 THESE DRUGS HAVE EXTENSIVE FIRST-PASS METABOLISM 12

13 ACUTE VIRAL HEPATITIS Acute inflammatory condition Mild and transient changes related to extent of disease in most cases. Infrequently severe and fulminant May become chronic and severe Changes in drug disposition less than in chronic disease Hepatic elimination returns to normal as disease resolves 13

14 CHRONIC LIVER DISEASE Usually related to chronic alcohol use or viral hepatitis Irreversible hepatocyte damage Decrease in SERUM ALBUMIN concentration Decrease in INTRINSIC CLEARANCE of drugs Intrahepatic and extrahepatic shunting of blood from functioning hepatocytes FIBROSIS disrupts normal hepatic architecture NODULES of regenerated hepatocytes form 14

15 RESTRICTIVELY Metabolized Drugs: Effects of LIVER DISEASE CL H f u CL int CL H FREE CONC. ALBUMIN NO CHANGE CL int PORTOSYSTEMIC SHUNTING 15

16 RESTRICTIVELY Metabolized Drugs: Effect of PROTEIN BINDING Changes C SS DOSE / CL H FOR RESTRICTIVELY ELIMINATED DRUGS : CL H FREE f u CL int CONC. C SS f u f u DOSE / f u CL int 16

17 [PHENYTOIN] μg/ml FREE and TOTAL PHENYTOIN Levels (DOSE = 300 MG/DAY) CL H CL INT = 8 6 BOUND [PHENYTOIN] FREE [PHENYTOIN] NORMAL RENAL FUNCTION FUNCTIONALLY ANEPHRIC 17

18 RESTRICTIVELY Metabolized Drugs : Effect of PROTEIN BINDING Changes 18

19 RESTRICTIVELY Metabolized Drugs: Effects of LIVER DISEASE CL H f u CL int CL H FREE CONC. ALBUMIN NO CHANGE CL int PORTOSYSTEMIC SHUNTING 19

20 Role of CYP ENZYMES in Hepatic Drug Metabolism RELATIVE HEPATIC CONTENT OF CYP ENZYMES CYP2D6 2% CYP2E1 7% % DRUGS METABOLIZED BY CYP ENZYMES CYP 2C 17% CYP 1A2 12% CYP 3A4-5 26% OTHER 36% CYP 2C9 14% CYP 1A2 14% CYP 2C19 11% CYP 3A4-5 33% CYP2D6 23% CYP2E1 5% 20

21 % NORMAL INTRINSIC CLEARANCE- RESTRICTIVELY Metabolized Drugs: Effect of CIRRHOSIS on CL int CYP2D6 GLUCURONIDATION CYP3A CYP2C19 CYP1A2 NORMAL MILD MODERATE SEVERE 21

22 PUGH-CHILD CLASSIFICATION Of Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SCORE 1 POINT 2 POINTS 3 POINTS ENCEPHALOPATHY GRADE 0 1 or 2 3 or 4 ASCITES ABSENT SLIGHT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTHROMBIN TIME (seconds > control) > 10 CLASSIFICATION OF CLINICAL SEVERITY CLINICAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 22

23 Correlation of Lab Test Results with Impaired CYP Enzyme Function The Central Problem: There is no laboratory test of liver function that is as useful for guiding drug dose adjustment in patients with liver disease as is the estimation of creatinine clearance in patients with impaired renal function. 23

24 % NORMAL FUNCTION - Correlation of SPECIAL TESTS of Liver Function with CHILD-PUGH SCORES* INDOCYANINE GREEN CLEARANCE GALACTOSE ELIMINATION CAPACTY SORBITOL CLEARANCE 20 ANITPYRINE BREATH TEST 0 NORMAL MILD MODERATE SEVERE * Data from Herold C, et al. Liver 2001;21:

25 PITTSBURGH COCKTAIL Approach* DRUG CAFFEINE CHLORZOXAZONE DAPSONE DEBRISOQUIN MEPHENYTOIN ENZYME CYP 1A2 CYP 2E1 CYP 3A + NAT2 CYP 2D6 CYP 2C19 * From: Frye RF, et al. Clin Pharmacol Ther 1997;62:

26 RESTRICTIVELY Metabolized Drugs: Effects of Liver Disease CL H f u CL int CL H FREE CONC. ALBUMIN NO CHANGE CL int PORTOSYSTEMIC SHUNTING 26

27 Effects of HEPATIC SHUNTING on ROWLAND EQUATION* CL H Q Q P T Q Q T T fu CLint f CL u int Q T = TOTAL BLOOD FLOW TO LIVER Q P = BLOOD FLOW PERFUSING LIVER Q T Q P = SHUNT BLOOD FLOW FOR RESTRICTIVELY ELIMINATED DRUGS: Q T >> f u CL int, CL H = (Q P /Q T ) f u CL int * From: McLean A, et al. Clin Pharmacol Ther 1979;25:

28 RESTRICTIVELY Metabolized Drugs: Effects of Hepatic Shunting* SEVERITY Q T Q P Q P /Q T ANTIPYRINE CL H (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. Clin Pharmacol Ther 1979;25:

29 NON-RESTRICTIVELY Metabolized Drugs: Effects of Liver Disease CL H Q CL H F ALBUMIN NO CHANGE* NO CHANGE CL int NO CHANGE NO CHANGE HEPATIC PERFUSION * HOWEVER, NOTE THAT FREE CONCENTRATION IS 29

30 NON-RESTRICTIVELY Metabolized Drugs: Effects of Liver Disease CL H Q CL H F ALBUMIN NO CHANGE* NO CHANGE CL int NO CHANGE NO CHANGE HEPATIC PERFUSION HOWEVER, f u CL int MAY NO LONGER BE >> Q 30

31 NON-RESTRICTIVELY Metabolized Drugs: Effects of Liver Disease CL H Q CL H F ALBUMIN NO CHANGE* NO CHANGE CL int NO CHANGE NO CHANGE HEPATIC PERFUSION 31

32 Effects of Hepatic Shunting on Rowland Equation* CL H Q Q P T Q Q T T fu CLint f CL u int Q T = TOTAL BLOOD FLOW TO LIVER Q P = BLOOD FLOW PERFUSING LIVER Q T Q P = SHUNT BLOOD FLOW FOR NON-RESTRICTIVELY ELIMINATED DRUGS: f u Cl int >> Q T, CL H = (Q P /Q T ) Q T = Q P * From: McLean A, et al. Clin Pharmacol Ther 1979;25:

33 NON-RESTRICTIVELY Metabolized Drugs: Effects of Decreased Liver Perfusion* SEVERITY Q T Q P Q P /Q T ICG CL H (ml/min) (ml/min) (%) (ml/min) MODERATE SEVERE SEVERE/ MODERATE * From: McLean A, et al. Clin Pharmacol Ther 1979;25:

34 Influence of PORTOSYSTEMIC SHUNTING on Oral Bioavailability (F) RESTRICTIVELY Eliminated Drugs: Little change NON-RESTRICTIVELY Eliminated Drugs: SHUNTING may markedly increase extent of drug absorption (F) 34

35 CIRRHOSIS Affects Exposure to Some NON-RESTRICTIVELY Metabolized Drugs ABSOLUTE BIOAVAILABILITY CONTROLS (%) CIRRHOTICS (%) RELATIVE EXPOSURE CIRRHOTICS/CONTROL IV ORAL MEPERIDINE PENTAZOCINE PROPRANOLOL * 2.0* * THIS ALSO INCORPORATES 55% INCREASE IN PROPRANOLOL f u 35

36 CIRRHOSIS Affects Renal Function: The Hepatorenal 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 serum albumin - High plasma renin Cockcroft and Gault Equation may overestimate renal function 36

37 CIRRHOSIS Affects Renal Function: The Hepatorenal Syndrome The Syndrome has a FUNCTIONAL rather than an Anatomical Basis. 37

38 HEPATORENAL SYNDROME ANTEMORTEM Arteriogram 38

39 HEPATORENAL SYNDROME POSTMORTEM Arteriogram 39

40 CIRRHOSIS Affects Renal Function: The Hepatorenal Syndrome Therapy with some drugs may precipitate Hepatorenal Syndrome ACE Inhibitors NSAIDs Furosemide (High Total Doses) 40

41 CIRRHOSIS May Affect Drug Distribution Increased Free Concentration of NON-RESTRICTIVELY Eliminated Drugs (e.g. PROPRANOLOL) Increased Permeability of Blood:CNS Barrier (e.g. CIMETIDINE) 41

42 CIMETIDINE CSF/SERUM RATIO CIRRHOSIS Affects Drug Distribution: Increased CNS Penetration of Cimetidine* NONE RENAL + LIVER DISEASE LIVER DISEASE * From Schentag JJ, et al. Clin Pharmacol Ther 1981;29:

43 CIRRHOSIS may affect PHARMACODYNAMICS Sedative response to BENZODIAZEPINES is exaggerated Response to LOOP DIURETICS is reduced 43

44 Drug Dosing in Patients with LIVER DISEASE The Central Problem: There is no laboratory test of liver function that is as useful for guiding drug dose adjustment in patients with liver disease as is the estimation of creatinine clearance in patients with impaired renal function. 44

45 PUGH-CHILD CLASSIFICATION of Liver Disease Severity ASSESSMENT PARAMETERS ASSIGNED SCORE 1 POINT 2 POINTS 3 POINTS ENCEPHALOPATHY GRADE 0 1 or 2 3 or 4 ASCITES ABSENT SLIGHT MODERATE BILIRUBIN (mg/dl) > 3 ALBUMIN (gm/dl) > < 2.8 PROTHROMBIN TIME (seconds > control) > 10 CLASSIFICATION OF CLINICAL SEVERITY CLINICAL SEVERITY MILD MODERATE SEVERE TOTAL POINTS > 9 45

46 Drugs CONTRAINDICATED in Patients with Severe Liver Disease May precipitate renal failure: - NSAIDs - ACE Inhibitors Predispose to bleeding: - β-lactams with N-Methylthiotetrazole Side Chain (e.g. CEFOTETAN) 46

47 Drug Requiring 50% Dose Reduction in Patients with MODERATE CIRRHOSIS CHANGE IN CIRRHOSIS F CL E ANALGESIC DRUGS Morphine 213% 59% Meperidine 94% 46% Pentazocine 318% 50% 47

48 Drugs Requiring 50% Dose Reduction in Patients with MODERATE CIRRHOSIS CARDIOVASC. DRUGS CHANGE IN CIRRHOSIS F CL E Propafenone 257% 24% Verapamil 136% 51% Nifedipine 78% 60% Losartan 100% 50% 48

49 Drugs Requiring 50% Dose Reduction in Patients with MODERATE CIRRHOSIS CHANGE IN CIRRHOSIS F CL E OTHER DRUGS Omeprazole 75% 89% Tacrolimus 33% 72% 49

50 Recommended Evaluation of Pharmacokinetics in Liver Disease Patients* REDUCED Study Design: - Study Control Patients and Patients with Child-Pugh Moderate Impairment - Findings in Moderate Category Applied to Mild Category; Dosing Prohibited in Severe Category FULL Study Design: - Study Control Patients and Patients in All Child-Pugh Categories - Population PK Approach * FDA Clinical Pharmacology Guidance, May