Developing an In Vitro to In Vivo Extrapolation (IVIVE) Model to Predict Human Milk-to-Plasma Drug Concentration Ratios.

Determining the amount of drug transferred into human milk is critical for benefit-risk analysis of taking medication while breastfeeding. In this study, we developed an in vitro and in vivo extrapolation (IVIVE) model to predict human milk/plasma (M/P) drug concentration ratios. Drug unionized fractions at pH 7.0 (Fni,7.0) and 7.4 (Fni,7.4), drug fractions unbound in human plasma (fup) and milk (fum), and in vitro cell permeability in both directions (efflux ratio, ER) were incorporated into the IVIVE model. A multiple regression Emax model was chosen to predict fum from fup and polar surface area (PSA). A total of 97 drugs with experimental ER from Caco-2 cells were used to test the IVIVE model. The M/P ratios predicted by the IVIVE model had a 1.93-fold geometric mean fold error (GMFE) and 72% of predictions were within two-fold error (Pw2FE), which were superior to the performance of previously reported five models. The IVIVE model showed a reasonable prediction accuracy for passive diffusion drugs (GMFE = 1.71-fold, Pw2FE = 82%, N = 50), BCRP substrates (BCRP: GMFE = 1.91-fold, Pw2FE = 60%, N = 5), and substrates of P-gp and BCRP (GMFE = 1.74-fold, Pw2FE = 75%, N = 8) and a lower prediction performance for P-gp substrates (GMFE = 2.51-fold, Pw2FE = 55%, N = 22). By fitting the observed M/P ratios of 39 P-gp substrates, an optimized ER (1.61) was generated to predict the M/P ratio of P-gp substrates using the developed IVIVE model. Compared with currently available in vitro models, the developed IVIVE model provides a more accurate prediction of the drug M/P ratio, especially for passive diffusion drugs. The model performance is expected to be further improved when more experimental fum and ER data are available.

Nanoparticle Delivery in Prostate Tumors Implanted in Mice Facilitated by Either Local or Whole-Body Heating.

This work discusses in vivo experiments that were performed to evaluate whether local or whole-body heating to 40 °C reduced interstitial fluid pressures (IFPs) and enhanced nanoparticle delivery to subcutaneous PC3 human prostate cancer xenograft tumors in mice. After heating, 0.2 mL of a previously developed nanofluid containing gold nanoparticles (10 mg Au/mL) was injected via the tail vein. The induced whole-body hyperthermia led to increases in tumor and mouse body blood perfusion rates of more than 50% and 25%, respectively, while the increases were much smaller in the local heating group. In the whole-body hyperthermia groups, the IFP reduction from the baseline at the tumor center immediately after heating was found to be statistically significant when compared to the control group. The 1 h of local heating group showed IFP reductions at the tumor center, while the IFPs increased in the periphery of the tumor. The intratumoral gold nanoparticle accumulation was quantified using inductively coupled plasma mass spectrometry (ICP-MS). Compared to the control group, 1 h or 4 h of experiencing whole-body hyperthermia resulted in an average increase of 51% or 67% in the gold deposition in tumors, respectively. In the 1 h of local heating group, the increase in the gold deposition was 34%. Our results suggest that 1 h of mild whole-body hyperthermia may be a cost-effective and readily implementable strategy for facilitating nanoparticle delivery to PC3 tumors in mice.