Browsing by Subject "pharmacokinetic modeling"
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(2012)Elucidation of transporter- and/or metabolic enzyme-mediated drug interactions is important part of early drug development. However the knowledge about clinical consequences of transporter-mediated drug-drug interactions is still limited and more investigation is needed to improve our understanding. MDR1 transporter, widely distributed on the pharmacokinetic barriers in the body (e.g. intestine) and has been shown no limit the bioavailability of drugs. Substrates of MDR1 are exposed to limited intestinal drug absorption and intestinal drug-drug interactions due to inhibition of the transporter. In predicting the clinical significance of an interaction, the principal obstacle has been the limited ability to appropriately scale the preclinical data into in vivo situation. In vitro-in vivo correlations on the extent of MDR1's influence on absorption and standardized predicting methods for drug-drug interactions using the inhibitory constants (IC50 and Ki) would greatly increase the value of in vitro studies. Current in vitro and in silico methods for prediction of the influence of MDR1 on intestinal absorption and related drug-drug interactions are discussed in the literature review. In addition, the latest regulatory draft guidances (FDA, EMA) are reviewed. Aliskiren has been shown to be a sensitive MDR1 substrate in vivo and high affinity substrate for the transporter in vitro. The objective of the experimental work was to study the MDR1-mediated transport of aliskiren and the related drug-drug interactions in vitro and in silico. Vesicular transport assay was used to obtain kinetic parameters for aliskiren (Km and Vmax) and inhibitor potencies (IC50) for ketoconazole, verapamil, itraconazole and its metabolite hydroxyitraconazole. Ki was further calculated for itraconazole and hydroxyitraconazole. Aliskiren showed high affinity to MDR1 transporter with a Km value 5 µM, consistent to what was reported previously in different assay systems. The interactions between aliskiren and the inhibitors in vitro correlated to the observed interactions in vivo in humans. In addition, hydroxyitraconazole was shown to be a potent inhibitor of MDR1-mediated transport of aliskiren in vitro. This suggests that hydroxyitraconazole may contribute to the pronounced interaction observed between aliskiren and itraconazole in a clinical interaction study. A compartmental absorption and transit (CAT) model with added enterocyte compartments and MDR1 efflux was used to describe the influence of MDR1 on intestinal absorption of aliskiren in humans. The integration of kinetic parameters (Km) from in vitro studies requires further optimization on how to describe the intracellular drug concentrations in the model. Aliskiren is however suitable MDR1 probe substrate to be used in in vitro and in vivo trials in humans and therefore gives a good basis for developing vitro-in vivo predictive models.
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Nanofibrillaarinen selluloosa-hydrogeelilääkeformulaatio ja kirurginen lanka Crohnin taudin hoidossa (2016)Crohn's disease is a type of inflammatory bowel disease. There are no treatment procedures that can cure Crohn's disease, but it is usually controllable with medicinal options. However 70 - 80 % of patients will require surgery and most undergo several during their life, due to weak local potency of drugs and disrupted recovery from surgical treatment. A better method of combined treatment, such as a drug releasing surgical suture, could improve the disease recovery process. One approach would be to coat a surgical suture with nanofibrillar cellulose (NFC) hydrogel containing the active drug ingredient within. NFC is biocompatible, biostable and it can be easily chemically modified. It displays pseudoplastic and thixotropic gel-like behavior in aqueous suspension in addition to high shear thinning properties under low and high shear rates. The shear-thinning behavior is particularly useful in a range of different coating applications. Furthermore, recent studies have shown the potential of NFC in controlled drug release. The aim of this Master's thesis was to investigate the suitability of anionic NFC hydrogel for surgical suture coatings and controlled release applications. The structure of NFC hydrogel was modified with crosslinking cations (Fe3+, Al3+, Ca2+) and alginate. The diffusion studies were performed with two antibiotics, metronidazole and rifaximin together with FITC-dextrans (10 and 250 kDa). The surgical suture was coated with each type of hydrogels (n = 16). Furthermore, the suitability of suture drug formulation for controlled drug release was simulated with STELLA® modeling software. It was shown that the NFC hydrogel structure was stiffened with the use of crosslinking cations; however similar results were not observed with the addition of alginate. Release profiles of model compounds were similar before and after NFC hydrogel crosslinking. At 6 days, 50 - 60 % of 10 kDa dextran (6 µg) was released. For 250 kDa dextran (6 µg) the released amount was 25 - 35 %. During the first 3 days of the diffusion study, all of metronidazole (20 µg) was released. Rifaximin samples were not obtained due to high adsorption to the container surfaces. The release profiles of metronidazole and 10 kDa dextran had linear correlation with square-root diffusion process. 250 kDa dextran followed a near zero-order kinetics after a few hours from the start. The coating was performed successfully with NFC hydrogels except for hydrogels with dextrans or without crosslinking. Metronidazole was predicted to release from the surgical suture almost instantly with STELLA® modeling software. NFC hydrogel shows potential as a matrix for controlled drug release and the coating of surgical sutures. However, the manufacturing method of the NFC hydrogel could be improved with surface modifications of nanofibrils or with the choice of a drug or of its derivatives. With pharmacokinetic simulation models it is possible to predict and estimate different factors which affect drug release from the surgical suture. Furthermore, the simulation models can be used to estimate an effect in the treatment of Crohn's disease.
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(2014)Certain drugs accumulate into pigmented tissues due to their binding to melanin, a macromolecule inside pigmented cells. Melanin can affect the drug's pharmacokinetics by acting as a drug reservoir. Binding can also cause toxic effects by accumulating compounds to pigmented cells. This thesis focuses on ocular melanin. The literature review covers the most common methods used in the study of ocular melanin binding and concentrates on in vitro methods and the analysis and usability of the results in pharmacokinetic modeling. The aim of the experimental part was to study melanin binding of a set of compounds in vitro with melanin isolated from the retinal pigment epithelium (RPE) and choroid of porcine eyes and with primary porcine RPE cells and then construct a pharmacokinetic model of melanin binding with STELLA® software and simulate it with the in vitro results. The compounds chosen for the study; nadolol, timolol, chloroquine, methotrexate, carboxydichlorofluorescein (CDCF) and dexamethasone, are small molecules with diverse physicochemical properties (octanol/water partitioning coefficient (logP), pKa, acid/base status). Some are also efflux substrates. The in vitro binding with melanin was studied at pH 7.4 and in addition at pH 5 for the acidic compounds, since the pH inside melanosomes where melanin is located is acidic. Porcine RPE cells were used to study the amount of uptake and rate of elimination of the set of compounds. The effect of efflux was also evaluated with a general efflux inhibitor probenecid. All the basic compounds bound to melanin in vitro. The acidic compounds did not seem to bind at pH 7.4 but bound at pH 5. Chloroquine, as expected, had the highest binding. In the cell studies, the uptake of chloroquine was significant, at least partly due to melanin binding. The other compounds were taken into the cells to a much smaller extent. The efflux inhibitor did not seem to affect the results. The results of the binding study were used in the models constructed of melanin binding and cellular pharmacokinetics. The constructed model was a very simple one not taking into account many factors affecting cellular pharmacokinetics. The results of both the in vitro studies and the model give a good idea of the importance of melanin binding in ocular drug delivery. The model can be used in the future as a base for more comprehensive models of the effect of melanin binding on ocular pharmacokinetics.
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