Claire Johnston (1,2), Andrew J McLachlan (3,4), Carl M Kirkpatrick (5) and Sarah N Hilmer (1,2)
1. Sydney Medical School, University of Sydney, Sydney, Australia; 2. Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney, Australia; 3. Centre for Education and Research on Ageing, Concord RG Hospital, Sydney, Australia; 4. Faculty of Pharmacy, University of Sydney, Sydney, Australia; 5. Centre for Medicine Use and Safety, Monash University, Melbourne, Australia.
Objectives: The aims of this study were to investigate the pharmacokinetics of paracetamol and its sulfide and glucuronide metabolites in older people. Paracetamol can be used as a marker of hepatic intrinsic clearance and Phase 2 metabolism. This is due to its capacity limited clearance and low protein binding [1]. There is large variability in drug response in older people that is often not explained by chronological age. The investigation of important covariates to pharmacokinetic and pharmacodynamic responses in this population is vital as they are frequently excluded from clinical trials and dosing recommendations may not be appropriate. The concept of frailty as a determining factor of health outcomes in older people is an increasing trend in geriatric medicine [2]. There are only a handful of papers that have investigated the use of frailty in explaining pharmacokinetic changes in old age. To our knowledge this is one of the only studies to use frailty as a covariate in population modeling. We aim to determine the important covariates that can describe the variability seen in paracetamol pharmacokinetics in pain patients aged over 70 years.
Methods: Data from two studies of oral paracetamol were pooled. The first was a study of steady state paracetamol in healthy volunteers with intensive plasma sampling over 6 hours post dose [3]. The second was a large observational study of inpatients over 70 years old, admitted for pain. These patients had residual blood taken from routine blood tests, with 1-25 samples per patient. Frailty was measured using the Reported Edmonton Frailty Scale (REFS), with a score of more then or equal to 8 out of a possible 18 being considered frail [4]. Both the categorical and continuous frailty score will be included in the model. The paracetamol glucuronide and sulfide metabolites were measured for each sample along with the parent drug concentration using HPLC. Population pharmacokinetic analysis was undertaken using NONMEM (version 7.2) and Pirana software. Missing data for weight and height was imputed [5].
Results: The total study population was 219; 20 healthy volunteers and 199 inpatients. The average age of the volunteers was 35.7 years and the inpatients was 84.7 years. There were 139 frail patients and 61 non-frail. The best model was a one-compartment linear model for parent drug and one compartment models for each of the metabolites. There was high variability in both populations.
Conclusions: Decreasing variability in the model will allow for more predictable therapeutic outcomes in older people. Frailty may be an important measure for predicting drug responses in older people.
References:
[1]. Bannwarth et al., Drugs 63(2): 5-13 (2003)
[2]. Clegg et al., Lancet 381: 752-762 (2013)
[3]. Rittau et al., JPP 64(5):705-711 (2012)
[4]. Hilmer et al., AJA 28(4):182-188 (2009)
[5]. Jackson et al., Biostatistics 10:335-351 (2009)
Reference: PAGE 22 (2013) Abstr 2822 [www.page-meeting.org/?abstract=2822]
Poster: Other Drug/Disease Modelling