422. Dose Response in HIV Monotherapy Trials Can be Predicted from In-Vitro Data
Session: Poster Abstract Session: HIV - Antiretroviral Therapy
Friday, October 21, 2011
Room: Poster Hall B1

Background: We propose a framework to predict dose-response relationship for a new molecular entity (NME) using in vitro data for the NME and in vitro-in vivo linkage derived for previously studied drugs in the same class.

Methods: Plasma drug concentrations and viral load data from monotherapy trials in HIV-infected patients across four distinct classes of antiretroviral agents (non-nucleoside reverse transcriptase inhibitors (NNRTIs); nucleotide reverse transcriptase inhibitors (NtRTIs); co-receptor inhibitors (CRIs) and integrase inhibitors (INIs)) were obtained. One drug in each class was used as a lead case (e.g., maraviroc for CRIs) to build an in vivo-in vitro linkage. The in vivo IC50 for a lead case was estimated using sequential pharmacokinetic (PK) and pharmacodynamic (PD) analyses in NONMEM. The estimated IC50, in vitro potency (EC50) and associated protein binding correction (PBC) were used to calculate a Scaling Factor (SF). Using the SF obtained from the lead case, in vitro EC50 and PBC, short-term viral load profiles of other drugs (e.g., vicrivoric and CCR5NME for CRIs) were predicted. The simulated viral load-time profiles at various doses were compared to the observed data from clinical trials.

Results: The mechanistic PK-PD disease model well characterized the observed time-course of HIV-1 RNA in the lead case study (Figure 1). For maraviroc, the estimated IC50 was 15.3 ng/mL and the calculated SF was 4.35.  Using the SF derived from maraviroc, in vivo IC50 of 13.0 and 14.9 ng/mL for CCR5NME and vicriviroc were predicted. The simulated viral load-time profiles based on the predicted IC50 matched well with those observed in the monotherapy trials for both application cases (Figure 2). Using the same approach, the SF of 9.47, 1.63 and 0.266 were derived for NNRTIs, INIs and NtRTIs.

Conclusion: For most antiviral drugs, in vitro drug potency (EC50) and in vivo model-based efficacious concentration (IC50) can be linked through a class specific SF. Mechanistic PK-PD disease model offers a great opportunity to assist dose selection for monotherapy trials.




Subject Category: H. HIV/AIDS and other retroviruses

Jing Fang, Pharmaceutical Science, University at Buffalo, Buffalo, NY and Pravin Jadhav, Ph.D, Division of Pharmacometrics, OCP/OTS/CDEA/ FDA, silverspring, MD


J. Fang, None

P. Jadhav, None

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