Sampling and pharmacokinetics of skin interstitial fluid for therapeutically monitored drugs

• Main Author: Schmitt, Veronika
• Language: English
• Published: University of British Columbia 2016
• Online Access: http://hdl.handle.net/2429/56176

To guide therapeutic decision making, the pharmacokinetics (PK) of certain toxic drugs are typically studied in blood. A drug’s blood concentration is thus acting as a surrogate for its target site concentration. However, a drug’s target is often extravascular and measuring tissue concentrations would be more meaningful. Furthermore, blood sampling is painful and can be challenging for some patients such as children, seriously ill, and old patients; it is, however, currently the standard method for drug testing. Current research suggests that a tissue fluid called interstitial fluid (ISF) can be sampled in minimal amounts without pain and can be used to quantify certain drugs. However, to successfully use this fluid for therapeutic drug monitoring, researchers still face three main challenges: sampling ISF, determining the concentrations and PK of drugs in ISF and their relation to blood concentrations, and quantifying drugs in very small volumes. To improve these challenges, we studied all three areas. First, we reviewed and evaluated methods of extracting ISF. Second, we studied ISF and blood concentrations of 13 drugs in a rabbit model to evaluate their PK. And third, we developed a method for quantifying a drug in just 2 µL of serum from rabbits. Currently available methods need larger sample volumes, whereas ISF is only available in small amounts. We found that many of the drugs we tested in a single-dose study were readily detectable in ISF (vancomycin, gentamicin, methotrexate, cisplatin, carboplatin, valproic acid, phenobarbital, mycophenolic acid and theophylline) and their PK parameters were determined using non-compartmental analysis. Furthermore, steady-state concentrations were predicted from the single-dose study for blood and ISF. At equilibrium, ISF drug concentrations were higher (vancomycin and gentamicin) and more stable compared to blood concentrations. For vancomycin these predictions were confirmed in an additional in vivo study. We further found that the concentration vs. time course of some drugs (vancomycin, gentamicin, methotrexate, valproic acid, phenobarbital, mycophenolic acid, digoxin and theophylline) could be well described by compartmental models. This study shows that ISF can be a valuable matrix for therapeutic drug monitoring and merits further studies to ascertain its clinical utility. === Pharmaceutical Sciences, Faculty of === Graduate