Zazo. H1,2, MartÃn-Suárez. A1,2, Lanao. JM1,2
1-Dep. Farmacia y TecnologÃa Farmaceútica. Facultad de Farmacia. Universidad de Salmanca.2-Institute of Biomedical Research of Salamanca (IBSAL), Spain
Objectives: To develop a PK/PD model to simulate, using Monte Carlo simulation, the antiviral activity of stavudine at intra-and extracellular levels, by administering stavudine nanoparticles with different schedules of administration.
Methods: The PK model describes plasma and intracellular levels of free stavudine and stavudine bond nanoparticles.The PD model based on the Hill equation predicts the inhibition of virus replication versus the stavudine concentrations[2]. This model describes the number of total CD4+T cells (Tc) and infected cells, total macrophages and infected (reservoir),and virus load in macrophages and in Tc [1]. The PK and PD parameters of stavudine were derived from the literature [3, 4].The simulation has been performed based on different modes of administration of stavudine in HIV patients: conventional tablets (Oral) (40mg / 12 hours); nanoparticles system (NP)(1mg / 12 hours by i.v.) and a combination of both (O+NP). The Monte Carlo simulations were performed to generate data of 1000 individuals during 4000 days of treatment. The software package of probabilistic simulation GoldSim Pro version 10.1 (Goldsim Technology Group, Issaquah, WA, USA) was used.
Results: Stavudine administration, by Oral regimen, achieves therapeutic steady-state plasma levels, although the intracellular levels of drug are negligible. By contrast, the administration of stavudineNP provides high intracellular levels but with very low plasma levels. The viral load–time profile shows that at the beginning of treatment most virus load is from Tc infected. Oral administration allows reducing this viral load with similar probability to O+NP. However, over the course of the disease the number of Tc decreased (around 2000 days) and the reservoir viral load began to be relevant in the total virus load. At this time, the NP lets the viral growth inhibit inside macrophages, unlike the Oral treatment. Therefore, the probability of Oral treatment efficacy is lower than O+NP treatment (probability: 30% and 70% respectively of exceeding the critical Tc value, and 20% and 7% of exceeding viral load).
Conclusions: A PK/PD model has been develop to simulate intra and extracellular stavudine concentration and their antiviral activity when administered stavudine by Oral or by NP. The administration of O+NP dosage regimens, when the number of Tc is below critical values, lets the viral load and the number of Tc control with high probability.
References:
[1] Duffin RP, Richard HT. Mathematical Models of the Complete Course of HIV Infection and AIDS. J Theor Med. (2002) 4(4): 215-221[2] Rosario MC, Jacqmin P, Dorr P, van der Ryst E, Hitchcock Cl. A pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc.ClinPharmacolTher. (2005) 78(5):508-19[3] Schaad HJ, Petty BG, Grasela DM, Christofalo B, Raymond R, Stewart M. Antimicrob. Agents Chemother.(1997)41(12):2793-2796 [4] Garg M, Asthana A, Agashe HB, Agrawal GP, Jain NK. J Pharm Pharmaco. (2006)58:605-616
Reference: PAGE 23 () Abstr 3220 [www.page-meeting.org/?abstract=3220]
Poster: Drug/Disease modeling - Infection