Pharmacokinetics and dosage adjustment in patients with renal dysfunction |
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Authors: | Roger K Verbeeck Flora T Musuamba |
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Institution: | (1) Faculty of Pharmacy, Rhodes University, Grahamstown, Eastern Cape, South Africa;(2) School of Pharmacy, Catholic University of Louvain, Louvain, Belgium |
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Abstract: | 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. |
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Keywords: | Dosage adjustment Non-renal drug clearance Pharmacokinetic/pharmacodynamic processes Renal dysfunction Renal drug clearance |
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