© 2008 Universitair Ziekenhuis Gent PHARMACOKINETICS IN CKD R Vanholder University Hospital, Gent, Belgium

2 2 © 2008 Universitair Ziekenhuis Gent MECHANISMS Naud et al, J Clin Pharmacol, 52: 10S-22S; 2012 OAT: organic acid transporter P-gp: p-glycoprotein CYP: cytochrome P MRP: multidrugresistance associated protein BSEP: bile salt export pump

3 3 © 2008 Universitair Ziekenhuis Gent CONTRIBUTORS TO PHARMACOKINETICS IN CKD Renal clearance Glomerulus Tubulus Metabolism Enterocyte Hepatocyte Excretion in intestine Direct Biliary Protein binding Distribution volume Disturbed gastro-intestinal motility and uptake

4 4 © 2008 Universitair Ziekenhuis Gent CONTRIBUTORS TO PHARMACOKINETICS IN CKD Renal clearance Glomerulus Tubulus Metabolism Enterocyte Hepatocyte Excretion in intestine Direct Biliary Protein binding Distribution volume Disturbed gastro-intestinal motility VIRTUALLY ALL THESE FACTORS INCREASE BIOAVAILABILITY

© 2008 Universitair Ziekenhuis Gent RENAL CLEARANCE

6 6 © 2008 Universitair Ziekenhuis Gent

7 7 drug

8 8 © 2008 Universitair Ziekenhuis Gent

9 9 ORGANIC ANION TRANSPORTERS

10 © 2008 Universitair Ziekenhuis Gent OAT ACTIVITY IS DEPRESSED IN KIDNEY FAILURE Takeuchi, KI, 60: ; 2001

11 © 2008 Universitair Ziekenhuis Gent UREMIC TOXINS INHIBIT OATs Wang and Sweet, Biochem Pharmacol, 84: ; 2012

© 2008 Universitair Ziekenhuis Gent NON-RENAL CLEARANCE

13 © 2008 Universitair Ziekenhuis Gent METABOLIC ACTIVITY CYPs IS DECREASED IN CKD Leblond at al, JASN, 13: 1579–1585; 2002

© 2008 Universitair Ziekenhuis Gent PROTEIN BINDING

15 © 2008 Universitair Ziekenhuis Gent PROTEIN BINDING CKD patients have low serum albumin due to inflammation, fluid overload, malnutrition and urinary protein losses In CKD the structure of albumin is modified In CKD many drugs and protein bound toxins compete for protein binding sites All these elements tend to decrease drug protein binding, to increase their free fraction, and to increase their activity (toxicity) This effect is partly compensated: increased metabolism and redistribution

16 © 2008 Universitair Ziekenhuis Gent IMPORTANCE OF PROTEIN BINDING Vanholder et al, KI, 33: ; 1989

17 © 2008 Universitair Ziekenhuis Gent Vanholder et al, KI, 33: ; 1989 IMPORTANCE OF PROTEIN BINDING

18 © 2008 Universitair Ziekenhuis Gent OTHER COMPETITORS Indoxyl sulfate Indole-acetic acid P-cresylsulfate …

19 © 2008 Universitair Ziekenhuis Gent PRACTICAL CONSEQUENCES

20 © 2008 Universitair Ziekenhuis Gent PRACTICAL CONSEQUENCES

21 © 2008 Universitair Ziekenhuis Gent PRACTICAL CONSEQUENCES

© 2008 Universitair Ziekenhuis Gent DISTRIBUTION VOLUME

23 © 2008 Universitair Ziekenhuis Gent V d C 0 Dose X 0 IV DISTRIBUTION VOLUME

24 © 2008 Universitair Ziekenhuis Gent DECREASE DITRIBUTION VOLUME IN AKI INCREASES DIGOXIN CONCENTRATION Nephron.Nephron. 1984;37(3): Rising serum digoxin without further dosage in acute renal failure. Gault MHGault MH, Gallway B, Fine A, Vasdev S.Gallway BFine AVasdev S Abstract A 73-year-old man was given a total of 1 mg of digoxin intravenously over 3 days, close to the time that he developed acute renal failure with oligo-anuria. He received no cardiac glycosides before or after this 3-day period. 2 days after the last dose, the serum digoxin concentration (SDC) was 2.9 ng/ml, yet a peak value of 4.2 ng/ml was reached only 11 days later. The SDC remained above 2 ng/ml for another week, until urine output began to increase appreciably. As renal function improved, the SDC gradually fell to become undetectable 32 days after the last dose. Values for apparent volume of distribution calculated from the total dose, and also determined after injection of tritiated digoxin, suggest that the rise in SDC in the absence of additional doses was due in large part to a decrease in the apparent volume of distribution. Dosage and parameters of toxicity should be carefully monitored in patients receiving digoxin who develop acute renal failure.

© 2008 Universitair Ziekenhuis Gent INTESTINAL ABSORPTION

26 © 2008 Universitair Ziekenhuis Gent INTESTINAL MOBILITY IS DECREASED IN DIABETES Rana et al, Diab Tech Ther, 13: ; 2011

27 © 2008 Universitair Ziekenhuis Gent INTESTINAL MOBILITY IS DECREASED IN CKD Strid et al, Digestion, 13: ; 2003

28 © 2008 Universitair Ziekenhuis Gent MANY DIFFERENT EFFECTS Decreased intestinal motility Slowing down peak concntration, no change in bioavailability Decreased gastric acidity Due to uremia (ammonia), drugs (antacids, H2-antagonists) Reduction bioavailability GI edema Cirrhosis Cardiac failure Reduction absorption: bioavailability furosemide from 50  10% Sorbents Sevelamer All together, most elements reduce bioavailability

29 © 2008 Universitair Ziekenhuis Gent ABSORPTION OF MYCOPHENOLATE MOFETYL BY SEVELAMER Pieper et al, NDT, 19: ; 2004

© 2008 Universitair Ziekenhuis Gent THE EFFECT OF DIALYSIS

31 © 2008 Universitair Ziekenhuis Gent EFFECTS OF DIALYSIS ON DRUG KINETICS One may accept that dialysis almost always decreases drug bioavailability and at best keeps it unmodified Drug administration best occurs after the dialysis session The only exception are drugs that are difficult to remove by dialysis and of which peak concentration is more important than trough (e.g. aminoglycosides)

32 © 2008 Universitair Ziekenhuis Gent EXAMPLE: MEROPENEM

33 © 2008 Universitair Ziekenhuis Gent HEMODIALYSIS RESTORES ACTIVITY OF CYP3A4 Michaud et al, J Pharmacol Sci, 108: ; 2008

34 © 2008 Universitair Ziekenhuis Gent CONCLUSIONS The impact of renal failure on the many aspects of drug pharmacokinetics is hard to predict in detail The net effect of all influening factors is to increase bioavailability If possible, drug treatment should be monitored by considering plasma concentrations