H. Zazo (1, 2), A. MartÃn-Suárez (1, 2) and J.M. Lanao (1, 2)
(1) Department of Pharmacy and Pharmaceutical Technology. University of Salamanca, Spain. (2) Institute of Biomedical Research of Salamanca (IBSAL), Spain
Objectives: Evaluation of a dosage regimen of antiretroviral gold nanoparticles based on the PK/PD parameters estimated by Monte Carlo Simulation. An improved PK/PD model of antiretroviral gold nanoparticles previously developed has been used.
Methods: PK model describes serum nanoparticles and free stavudine released concentrations. PD model describes number of T cells (HIV target cells), number of macrophages (HIV reservoir) and virus load (from T cells, macrophages and total) . A priori information of PK and PD parameters were obtained from the literature . Both models are linked by Hill equation to predict the inhibition of virus replication by the antiretroviral drug inside the cell. The dosage regimens have been designed taking into account the toxic gold nanoparticles concentration (0.5 mM) and the serum stavudine concentrations achieve with the conventional drug formulations . The schedules evaluated have been: 1 mg/kg/day; 2 mg/kg/day; 2 mg/kg/2days; 4 mg/kg/2days and 3 mg/kg/3days. Monte Carlo simulations were performed to generate data of 1000 individuals during 10 years of treatment. The software package of probabilistic simulation GoldSim Pro version 10.1 (Goldsim Technology Group, Issaquah, WA, USA) has been used.
Results: PK model simulates multiple i.v administrations of antiretroviral gold nanoparticles. The nanoparticles serum concentration achieved is lower than the toxic in all dosage regimens evaluated. The serum stavudine levels achieved with the 6 mg/kg/3 days regimen are too high during more than 1 day. The others dosage regimens evaluated have therapeutic serum drug levels. According to this model, there is a high probability to have total viral load values lower than the target value (100 virions/µL) during a long time in all dosage regimens simulated. About the virus from the reservoir, the 3mg/kg/3 days regimen has the highest probability of exceeding the reservoir virus load target value (10 virions/µL). According to the number of T cells simulated, the 2 mg/kg/day regimen keeps healthy T cells/µL values (8 106cells/µL) with the highest probability.
Conclusions: According to the Monte Carlo simulation with the PK/PD antiretroviral gold nanoparticles model developed, the best dosage regimen evaluated is 2 mg/kg/day. This dosage regimen lets to control the viral load and the T cells number with a high probability (>70 %) during more than seven years with low drug and gold nanoparticles serum concentrations.
References:
[1] Duffin RP, Richard HT. J Theor Med. (2002) 4(4): 215-21
[2] Chitriani BD, Chan WCW. Nano Lett. (2007) 7 (6): 1542-50 [3] Basu S et al. Int J Nanomedicine. (2012) 7:6049–61 [4] European public assessment report for Zerit. Update 08/08/2014 [5] Alkilany AM, Murphy CJ. J Nanopart Res. 2010 Sep; 12(7): 2313–2333
Reference: PAGE 24 () Abstr 3674 [www.page-meeting.org/?abstract=3674]
Poster: Drug/Disease modeling - Infection