1. Eur J Clin Pharmacol. 2009 Aug;65(8):757-73. Epub 2009 Jun 20.

Pharmacokinetics and dosage adjustment in patients with renal dysfunction.

Verbeeck RK, Musuamba FT.

Faculty of Pharmacy, Rhodes University, Grahamstown, Eastern Cape, South Africa. 
roger.verbeeck@uclouvain.be

INTRODUCTION: Chronic kidney disease is a common, progressive illness that is
becoming a global public health problem. In patients with kidney dysfunction, the
renal excretion of parent drug and/or its metabolites will be impaired, leading
to their excessive accumulation in the body. In addition, the plasma protein
binding of drugs may be significantly reduced, which in turn could influence the 
pharmacokinetic processes of distribution and elimination. The activity of
several drug-metabolizing enzymes and drug transporters has been shown to be
impaired in chronic renal failure. In patients with end-stage renal disease,
dialysis techniques such as hemodialysis and continuous ambulatory peritoneal
dialysis may remove drugs from the body, necessitating dosage adjustment.
METHODS: Inappropriate dosing in patients with renal dysfunction can cause
toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug
may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is
based on the remaining kidney function, most often estimated on the basis of the 
patient's glomerular filtration rate (GFR) estimated by the Cockroft-Gault
formula. Net renal excretion of drug is a combination of three processes:
glomerular filtration, tubular secretion and tubular reabsorption. Therefore,
dosage adjustment based on GFR may not always be appropriate and a re-evaluation 
of markers of renal function may be required. DISCUSSION: According to EMEA and
FDA guidelines, a pharmacokinetic study should be carried out during the
development phase of a new drug that is likely to be used in patients with renal 
dysfunction and whose pharmacokinetics are likely to be significantly altered in 
these patients. This study should be carried out in carefully selected subjects
with varying degrees of renal dysfunction. In addition to this two-stage
pharmacokinetic approach, a population PK/PD study in patients participating in
phase II/phase III clinical trials can also be used to assess the impact of renal
dysfunction on the drug's pharmacokinetics and pharmacodynamics. CONCLUSION: In
conclusion, renal dysfunction affects more that just the renal handling of drugs 
and/or active drug metabolites. Even when the dosage adjustment recommended for
patients with renal dysfunction are carefully followed, adverse drug reactions
remain common.

PMID: 19543887 [PubMed - indexed for MEDLINE]