Influence of adult age on the total and free clearance and protein binding of (R)‐ and (S)‐warfarin

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Hepatic drug clearance is thought to be reduced with age. However for highly protein bound drugs, which are cleared by capacity-limited metabolism, studies on total clearance have been conflicting. The hypothesis that protein binding decreases with age has been used to explain this.• Warfarin is a highly protein bound drug, which is cleared by capacity-limited metabolism. There are conflicting or little data on the relationship between adult age and total and free clearance and protein binding of (R)-and (S)-warfarin. WHAT THIS STUDY ADDS• In a clinical study of 72 patients (18-89 years) on warfarin therapy, both total and free clearance of (R)-warfarin decreased with age. For (S)-warfarin there was a stronger signal of a decrease in free than total clearance. Protein binding was found not to correlate with age for (R)-and (S)-warfarin.• In an ex vivo study, in which warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years), no correlation between protein binding and age was found.• These data support the hypothesis that hepatic drug clearance decreases with age. This should be taken into consideration when individualizing dosing, particularly in the elderly. AIMSTo test the hypothesis that the clearance (CL) of warfarin, a very highly protein bound drug with capacity-limited metabolism, decreases with age. METHODSIn a clinical study, a steady-state blood sample was taken from 72 patients (18-89 years) on routine treatment with warfarin. Concentrations of (R)-and (S)-warfarin were determined in plasma (total) and ultrafiltrate (free) by LC-MS/MS. Total and free CL and protein binding were determined and regressed against age and other covariates. In an ex vivo study, warfarin was spiked to plasma samples from 60 healthy subjects (19-87 years) and protein binding was regressed against age and other covariates. RESULTSFor (R)-warfarin a significant decrease with age was found for both total and free CL (P < 0.001). For (S)-warfarin there was a stronger signal of a decrease with age in free CL (P = 0.005) vs. total CL (P = 0.045). The decrease in CL of (R)-and (S)-warfarin was 0.3-0.5% per year. Other covariates influencing CL were lean body weight for both (R)-and (S)-warfarin and CYP2C9 genotype and blood sampling time for (S)-warfarin. Protein binding of (R)-and (S)-warfarin was not found to change significantly with age in either the clinical or the spiked samples, despite a slight decrease in albumin concentration with age. CONCLUSIONSThese data support the hypothesis that the CL of (R)-and (S)-warfarin decreases with age. More accurate information was gained when measuring free CL for (S)-warfarin. Warfarin protein binding did not change significantly with age.

Predicted metabolic drug clearance with increasing adult age

“…The decrease in CL PT shown here (39%) is consistent with lower recovery of 4‐hydroxymephenytoin (35%) and a decreased S : R enantiomeric ratio (25%) in the urine of patients ≥50 years , although the effect of changes in renal function may contribute to this result. In the eight studies that report changes in total S‐warfarin clearance with ageing, most found a significant decrease with age, although in two of the studies this was only a trend . The majority of these studies were not designed to investigate specifically changes in clearance with age and data are not available to allow for a direct comparison with the Simcyp® data generated here.…”

“…The majority of these studies were not designed to investigate specifically changes in clearance with age and data are not available to allow for a direct comparison with the Simcyp® data generated here. However, for the studies in which multiple regression analysis or population pharmacokinetic modelling was used on populations of 39–306 patients, the decline in S‐warfarin clearance with age was reported to be 0.3‐1% per year , which roughly translates to a 14–45% decline between the young and elderly age groups used in the Simcyp® simulations. For one recent study that specifically investigated the influence of adult age on warfarin clearances , it was possible to stratify the results as shown in Table .…”

Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage

“…Thus older patients are more sensitive to warfarin compared with younger patients. Age‐related changes in drug response are multifactorial with a decline in clearance, albumin binding, or renal excretion contributing to pharmacokinetic changes . Moreover, the increase in comorbid conditions and concomitant medication use in the elderly may influence warfarin response in complex ways through drug‐drug and drug‐disease interactions.…”

Analysis of the first therapeutic-target-achieving time of warfarin therapy and associated factors in patients with pulmonary embolism

“…However, Jensen et al (27) have previously demonstrated that the TTA time increases with age. The metabolic clearance rate of warfarin would decrease, whereas its protein-binding rate would not increase; thus, Jensen et al (27) considered that age may affect an individual's sensitivity to warfarin and first TTA time. Therefore, further studies are required to investigate this phenomenon.…”