Background: A lack of substantial pharmacokinetic analysis in overdose exists, because of uncertainty in dose and time of ingestion, and limited sampling in the absorption phase. Population pharmacokinetic analyses with uncertainty models have been used in overdose to understand dose-concentration relationships. This study uses concentration-time data in a single patient with multiple occasions of paracetamol overdose to investigate the pharmacokinetics of paracetamol in overdose and factors that affect uncertainty in dose and dose-time.
Methods: Reported time and dose of ingestion, first and last possible ingestion times, therapeutic use of carbamazepine, year of ingestion and timed paracetamol concentrations were obtained from a single patient. The data set included 80 concentration-time points from 44 paracetamol overdose events (median dose, 15g [5 – 26g]). A population pharmacokinetic analysis was undertaken using Monolix 3.1R2. Initial estimates for pharmacokinetic parameters were taken from Anderson et al (2009). Veracity scores were included for time of ingestion and reported dose, utilising information obtained from the medical chart.
Results: A one-compartment model with first-order input and lagtime with first-order elimination described the data. Uncertainty in dose-time was included as a between occasion variability (BOV) on lagtime and uncertainty in dose as BOV on relative fraction absorbed (F) — both improved the model. The model was further improved by including veracity scores for reported dose (verified objectively or patient history alone) and time of ingestion (utilising the last possible time of ingestion). The population mean estimates of clearance (CL) and volume of distribution (Vd) were 11.7L/h and 48.4L respectively. Between occasion variability of CL was 0.22L/h and BOV of Vd was assumed to be zero. Including the absorption constant (Ka) did not improve the model and was fixed to the published population mean. 1.03 h-1.. Median half-life for individual events was 2.8 hours. Therapeutic carbamazapine use was not a significant covariate of clearance.
Discussion: The pharmacokinetics of paracetamol overdose in this patient are similar to the that of therapeutic paracetamol. The analysis provides another method for including uncertainty in dose and dose-time, as well as means of including veracity, in modeling the pharmacokinetics in overdose.
- Anderson, BJ & Holford, NH (2009) Drug metabolism and pharmacokinetics, 24: 25-36