| Abstract: | Estimating early exposure of drugs used for the treatment of emergent conditions is challenging because blood sampling to measure concentrations is difficult. The objective of this work was to evaluate predictive performance of two early concentrations and prior pharmacokinetic (PK) information for estimating early exposure. The performance of a modeling approach was compared with a noncompartmental analysis (NCA). A simulation study was performed using literature‐based models for phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA). These models were used to simulate rich concentration‐time profiles from 0 to 2 h. Profiles without residual unexplained variability (RUV) were used to obtain the true partial area under the curve (pAUC) until 2 h after the start of drug infusion. From the profiles with the RUV, two concentrations per patient were randomly selected. These concentrations were analyzed under a population model to obtain individual population PK (PopPK) pAUCs. The NCA pAUCs were calculated using a linear trapezoidal rule. Percent prediction errors (PPEs) for the PopPK pAUCs and NCA pAUCs were calculated. A PPE within ±20% of the true value was considered a success and the number of successes was obtained for 100 simulated datasets. For PHT, LEV, and VPA, respectively, the median value of the success statistics obtained using the PopPK approach of 81%, 92%, and 88% were significantly higher than the 72%, 80%, and 67% using the NCA approach (p < 0.05; Mann–Whitney U test). This study provides a means by which early exposure can be estimated with good precision from two concentrations and a PopPK approach. It can be applied to other settings in which early exposures are of interest. Study Highlights - WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Conducting pharmacokinetic (PK) studies with intensive sampling in emergent conditions like status epilepticus is challenging. Hence, getting a reliable estimate of early drug exposure to correlate with treatment response in order to develop exposure‐response relationships is difficult. - WHAT QUESTION DID THIS STUDY ADDRESS?
The results obtained in this simulation study support the notion that a two‐sample approach can be used to estimate early drug exposure. The population PK (PopPK) approach was found to be superior in estimating early exposure as compared with the standard noncompartmental analysis (NCA) approach. - WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This PK simulation study shows that using prior information based on the PopPKs of the drug and just two plasma concentration measures per patient in the first 2 h post drug administration, it is possible to adequately estimate early drug exposure. The study not only provides an alternative method to estimate early exposure but also demonstrates that it is superior to the standard NCA approach. - HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study provides a means by which early exposure can be estimated with good precision using limited sampling. This approach can be applied to any setting in which early exposures are of interest and these exposures can be related to outcomes of interest in clinical and translational pharmacology. |
