The developed repository for aging subjects provides a singular specific source for key system parameters needed for physiologically based pharmacokinetic modeling and can in turn be used to investigate drug kinetics and drug-drug interaction magnitudes in the elderly.
Tenofovir (TFV) is a nucleotide analogue active against HIV and hepatitis B virus. Although TFV rarely affects the glomerular function, abnormalities in the kidney tubular function appear to be quite common. The relationship between TFV exposure and kidney tubular dysfunction (KTD) was examined prospectively in 92 HIV-infected individuals. Median TFV plasma trough concentration was higher in patients with KTD than in the rest (182 vs. 106 ng/ml; P = 0.001). This dose-dependent effect further supports an involvement of TFV in KTD.
Physiologically‐based pharmacokinetic (PBPK) models are useful tools to predict clinical scenarios for special populations for whom there are high hurdles to conduct clinical trials such as children or the elderly. However, the coding of a
PBPK
model in a mathematical programming language can be challenging. This tutorial illustrates how to build a whole‐body
PBPK
model in Matlab to answer specific pharmacological questions involving drug disposition and magnitudes of drug–drug interactions in different patient populations.
Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion-templated freeze-drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non-nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z-average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four-fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible.
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