**7. References**

692 Non-Viral Gene Therapy

linear output compartment interpreted as the urine compartment (Fig. 13). The 50th percentiles of the model-based prediction for plasma concentrations and cumulative urinary excretions are presented together with the observed value. To obtain 50th percentiles of the model estimations, 10000 simulations were performed using the estimated model parameters, variability in the estimated parameters, and residual variability of the data.

Fig. 13. Plasma concentration–time profile (A) and cumulative urinary excretion (B) of PI polyamide B after intravenous administration at 2.0 mg/kg to rats. Each data point

percentiles from model estimations of 10000 simulations.

**5. Conclusion** 

polyamide B did not accumulate following multiple-dose administration.

represents observed data from three rats (for plasma and urine). The solid line indicates 50th

To predict the effective dose of PI polyamide B in Dahl-S rats administered at 1 mg every 2 or 3 days for 4 weeks, pharmacokinetic simulations of PI polyamide B were performed using a slightly modified pharmacokinetic model (Nagashima et al., 2009b) by NONMEM program. The average plasma concentrations of PI polyamide B after the administration at 1 mg every 3 and 2 days were 0.18 and 0.28 µg/mL, respectively, which were calculated by the area under the concentration-time curves between 0 and 27 days, divided by 27 days. PI

PI polyamides show a remarkable potential for use in non viral gene therapy as many attractive results were obtained. The novel compounds could provide a promising impact on gene therapy for diseases not treatable by current remedies. To obtain the maximum therapeutic effect of the PI polyamide, it is crucial to evaluate the pharmacokinetics of the compounds for designing appropriate dosage regimens. Bioanalytical procedures for PI polyamides A and B were successfully developed and validated by HPLC or LC-MS/MS, and applied to sample assay. The pharmacokinetic profiles of PI polyamides show interesting results, which are thought to be related to their molecular weights (Brown et al.,


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