Discrepancy between in vitro potency and in vivo efficacy in human - Implications in PK-PD modeling
Dong-Seok Yim
The Catholic University of Korea
Objectives: Reliability of a PK-PD model is dependent on its assumptions on which the model was build up as well as the robustness in the model building process. The in vitro potency parameters such as IC50 have been routinely used to predict human efficacious exposures (AUC, Cmin etc) in PK-PD modeling. However, its fundamental assumption that the in vitro potency is well correlated with the in vivo efficacy has never been verified extensively. Thus, we tried to look into this assumption by comparing a wide range of published PK and PD data.
Methods: If the in vitro potency and in vivo effects are well correlated, patients’ exposure to unbound drugs at steady state (Cu-ssavg= fu·F·Dose/(CL·τ) = fu·AUCss/τ) by approved dosage regimens should be higher than or, at least, comparable to the in vitro potency parameters such as IC50. We reviewed the ratios of Cu-ssavg / potency for drugs of major therapeutic categories using the dosage, PK and in vitro potency information published to journals. As for potency, only those of at least two moieties in a class reported in a single original research article by a single laboratory were included so that inter-laboratory or inter-method variation may be avoided.
Results: A total of 49 drug moieties (13 categories) were reviewed. The ratios were extremely varied (about 100 to 100,000 fold differences in the same category drugs) despite trends by categories. Average ratios (unbound) of statins and CCBs were lower than 0.1. In the 49 moieties, the Cu-ssavg / potency ratios were <1 in 32 (65%) and <0.1 in 15 (31%) moieties. Even in the case of Ctot-ssavg (total concentration), the ratios of 15 (31%) moieties were <1. When the ratios were plotted against fu (unbound fraction), the ‘ratio<1’ phenomena were more prevalent at drugs with higher protein binding (88% of drugs with fu ≤ 0.05: 22 out of 25). This finding implies that there still remains room for improvement in protein binding assays, especially at the higher extreme.
Conclusions: Efficacious unbound exposure levels (Cu-ssavg) were lower than in vitro potency values in 65% of drugs. Our results raise a question on the widely-used assumption of in vitro-in vivo correlation. Thus, PK-PD modeling approaches using in vitro potency values without in vivo PD data does not seem to be appropriate.
