Deciding on Success Criteria for Predictability of Pharmacokinetic Parameters from In Vitro Studies: An Analysis Based on In Vivo Observations

Abstract

Prediction accuracy of pharmacokinetic parameters is often assessed using prediction fold error, i.e., being within 2-, 3-, or n-fold of observed values. However, published studies disagree on which fold error represents an accurate prediction. In addition, "observed data" from only one clinical study are often used as the gold standard for in vitro to in vivo extrapolation (IVIVE) studies, despite data being subject to significant interstudy variability and subjective selection from various available reports. The current study involved analysis of published systemic clearance (CL) and volume of distribution at steady state (V ss ) values taken from over 200 clinical studies. These parameters were obtained for 17 different drugs after intravenous administration. Data were analyzed with emphasis on the appropriateness to use a parameter value from one particular clinical study to judge the performance of IVIVE and the ability of CL and V ss values obtained from one clinical study to "predict" the same values obtained in a different clinical study using the n-fold criteria for prediction accuracy. The twofold criteria method was of interest because it is widely used in IVIVE predictions. The analysis shows that in some cases the twofold criteria method is an unreasonable expectation when the observed data are obtained from studies with small sample size. A more reasonable approach would allow prediction criteria to include clinical study information such as sample size and the variance of the parameter of interest. A method is proposed that allows the "success" criteria to be linked to the measure of variation in the observed value.

Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children

“…The PBPK modeling approach could predict clearance for all nine drugs in the studies from infants to adolescents (1 month to 18 years old). The twofold range of the prediction accuracy is a commonly used standard in pediatric PK modeling, and in vitro‐in vivo extrapolation prediction . Although twofold boundaries are wide for drugs with PK parameters that have low variability and have been accurately characterized with large sample size, such boundaries are considered reasonable when the observed data are obtained from studies with small sample size .…”

Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

“…The exposure was defined as maximum plasma concentration (C max ) or AUC. Several success criteria (1.25‐fold or 2‐fold range) have been used in the literature . Here, a 1.5‐fold range was chosen on the basis of the intrinsic PK variability of efavirenz, as well as the moderate‐to‐mild extent of efavirenz perpetrated DDIs …”

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

“…More careful reporting of the simulated and observed study populations would also be critically important when model performance is assessed. As has been highlighted in the literature (Abduljalil et al, 2014), PBPK simulations are often compared to clinical studies with small study populations, and the true inter-and intraindividual variability of the observed PK parameters of the compound of interest are not known. This can lead to a situation in which one clinical study does not accurately predict the PK parameters observed in another study with the same compound (Abduljalil et al, 2014).…”