Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs

Abstract

What is already known about this subject: • Renal impairment may affect the pharmacokinetics of peptide and protein drugs. • Molecular size is a predictor. Small molecules are eliminated by the kidneys, whereas large molecules (>67 kDa) are not. • Urinary recovery of peptide and protein drugs in healthy volunteers is not predictive for pharmacokinetic changes in patients with renal impairment.

What this study adds: • An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations as observed in patients with severe renal impairment or end-stage renal disease is described. • Potentially relevant pharmacokinetic changes were found for drugs with a molecular weight below 50 kDa. • Analysis of observed pharmacokinetics in patients with severe renal impairment may be a useful approach, especially when urinary recovery in healthy volunteers is not predictive.

Aim: Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived.

Methods: Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid E(max) model was applied and fitted to the data and the prediction error was analyzed.

Results: Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life).

Conclusion: An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients.

Figure 1

Pharmacokinetic changes in severe renal impairment or end-stage renal disease. For example, a fractional clearance (f_CL) of 0.4 indicates that the observed total body clearance of a drug was 40% of the observed clearance in healthy subjects or patients with normal renal function. Similarly, a half-life factor () of 3 indicates a three-fold prolongation of half-life in renal failure. The continuous lines represent the fitted sigmoid E_max model (equation 4). The broken lines represent the hypothetical condition of no change