From in vitro EC₅₀ to in vivo dose-response for antiretrovirals using an HIV disease model. Part II: application to drug development.

The purpose of this research was to qualify a previously derived quantitative model-based framework that proposed an in vitro-in vivo linkage to predict the dose-response relationship of an antiretroviral (ARV) new molecular entity (NME) in a monotherapy trial. Human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) data from monotherapy trials in ARV naïve/experienced HIV-infected subjects for eight drugs (i.e. application case, a representative drug for a given class used for external validation) across four distinct classes of ARV agents (co-receptor antagonists; non-nucleoside reverse transcriptase inhibitors; nucleotide reverse transcriptase inhibitors; and integrase strand transfer inhibitors) were obtained. Using the in vitro EC₅₀ (protein binding corrected) and a class-specific scaling factor (SF), the in vivo IC₅₀ was calculated for each drug. The integrated pharmacokinetic (PK)-pharmacodynamic (PD) disease model used the predicted in vivo IC₅₀ to simulate the HIV-1 RNA-time profiles for dosing regimens that were studied in the monotherapy trials for each drug. The simulated HIV-1 RNA time profiles were then compared to the observed data. The simulated HIV-1 RNA-time profiles matched well with those observed in the monotherapy trials except for one drug in the INSTIs class. The derived SF represents a useful in vitro-in vivo linkage to predict the dose-response relationship for a NME using in vitro data. The mechanistic PK-PD disease model-based framework is useful to assist the dose selection for monotherapy trials and comparator modeling approaches.