Browsing by Subject "317 Pharmacy"

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  • Fallarero, Adyary; Skogman, Malena; Kujala, Janni; Rajaratnam, M; Moreira, Vânia M.; Yli-Kauhaluoma, Jari; Vuorela, Pia (2013)
  • Virjamo, Virpi; Fyhrquist, Pia; Koskinen, Akseli; Lavola, Anu; Nissinen, Katri; Julkunen-Tiitto, Riitta (2020)
    Knowledge about the defensive chemistry of coniferous trees has increased in recent years regarding a number of alkaloid compounds; in addition to phenolics and terpenes. Here, we show that Norway spruce (Picea abies (L.) H. Karst.), an important boreal zone tree species; accumulates 1,6-dehydropinidine (2-methyl-6-(2-propenyl)-1,6-piperideine) in its needles and bark. We reanalyzed previously published GC-MS data to obtain a full picture of 1,6-dehydropinidine in P. abies. 1,6-dehydropinidine appeared to especially accumulate in developing spring shoots. We used solid-phase partitioning to collect the alkaloid fraction of the sprouts and thin-layer chromatography to purify 1,6-dehydropinidine. The antibacterial properties of the 1,6-dehydropinidine fraction were tested using a broth microdilution method; with Streptococcus equi subsp. equi as a model organism. Based on our results 1,6-dehydropinidine is common in alkaloid extractions from P. abies (0.4 +/- 0.03 mg g(-1) dw in mature needles) and it is especially abundant in young spruce shoots (2.7 +/- 0.5 mg g(-1) dw). Moreover; 1,6-dehydropinidine extracted from P. abies sprouts showed mild antibacterial potential against Streptococcus equi subsp. equi (MIC 55 mu g mL(-1)). The antibacterial activity of a plant compound thought of as an intermediate rather than an end-product of biosynthesis calls for more detailed studies regarding the biological function of these coniferous alkaloids
  • McVey, Alyssa; Bartlett, Sean; Kajbaf, Mahmoud; Pellacani, Annalisa; Gatta, Viviana; Tammela, Päivi; Spring, David R.; Welch, Martin (2020)
    Pseudomonas aeruginosa is an opportunistic pathogen responsible for many hospital-acquired infections. P. aeruginosa can thrive in diverse infection scenarios by rewiring its central metabolism. An example of this is the production of biomass from C-2 nutrient sources such as acetate via the glyoxylate shunt when glucose is not available. The glyoxylate shunt is comprised of two enzymes, isocitrate lyase (ICL) and malate synthase G (MS), and flux through the shunt is essential for the survival of the organism in mammalian systems. In this study, we characterized the mode of action and cytotoxicity of structural analogs of 2-aminopyridines, which have been identified by earlier work as being inhibitory to both shunt enzymes. Two of these analogs were able to inhibit ICL and MS in vitro and prevented growth of P. aeruginosa on acetate (indicating cell permeability). Moreover, the compounds exerted negligible cytotoxicity against three human cell lines and showed promising in vitro drug metabolism and safety profiles. Isothermal titration calorimetry was used to confirm binding of one of the analogs to ICL and MS, and the mode of enzyme inhibition was determined. Our data suggest that these 2-aminopyridine analogs have potential as anti-pseudomonal agents.
  • Lou, Yan-Ru; Toh, Tai Chong; Tee, Yee Han; Yu, Hanry (2017)
    25-Hydroxyvitamin D-3 [25(OH)D-3] has recently been found to be an active hormone. Its biological actions are demonstrated in various cell types. 25(OH)D-3 deficiency results in failure in bone formation and skeletal deformation. Here, we investigated the effect of 25(OH)D-3 on osteogenic differentiation of human mesenchymal stem cells (hMSCs). We also studied the effect of 1 alpha, 25-dihydroxyvitamin D-3[1 alpha,25-(OH)(2)D-3], a metabolite of 25(OH)D-3. One of the vitamin D responsive genes, 25(OH)D-3-24-hydroxylase (cytochrome P450 family 24 subfamily A member 1) mRNA expression is up-regulated by 25(OH)D-3 at 250-500 nM and by 1 alpha, 25-(OH)(2)D-3 at 1-10 nM. 25(OH)D-3 and 1 alpha, 25-(OH)(2)D-3 at a time-dependent manner alter cell morphology towards osteoblast-associated characteristics. The osteogenic markers, alkaline phosphatase, secreted phosphoprotein 1 (osteopontin), and bone gamma-carboxyglutamate protein (osteocalcin) are increased by 25(OH)D-3 and 1 alpha,25-(OH)(2)D-3 in a dose-dependent manner. Finally, mineralisation is significantly increased by 25(OH)D-3 but not by 1 alpha, 25-(OH)(2)D-3. Moreover, we found that hMSCs express very low level of 25(OH)D-3-1 alpha-hydroxylase (cytochrome P450 family 27 subfamily B member 1), and there is no detectable 1 alpha, 25-(OH)(2)D-3 product. Taken together, our findings provide evidence that 25(OH)D-3 at 250-500 nM can induce osteogenic differentiation and that 25(OH)D-3 has great potential for cell-based bone tissue engineering.
  • Germini, Giorgia; Peltonen, Leena (2021)
    The aim of the study was to prepare indomethacin nanocrystal-loaded, 3D-printed, fast-dissolving oral polymeric film formulations. Nanocrystals were produced by the wet pearl milling technique, and 3D printing was performed by the semi-solid extrusion method. Hydroxypropyl methyl cellulose (HPMC) was the film-forming polymer, and glycerol the plasticizer. In-depth physicochemical characterization was made, including solid-state determination, particle size and size deviation analysis, film appearance evaluation, determination of weight variation, thickness, folding endurance, drug content uniformity, and disintegration time, and drug release testing. In drug nanocrystal studies, three different stabilizers were tested. Poloxamer F68 produced the smallest and most homogeneous particles, with particle size values of 230 nm and PI values below 0.20, and was selected as a stabilizer for the drug-loaded film studies. In printing studies, the polymer concentration was first optimized with drug-free formulations. The best mechanical film properties were achieved for the films with HPMC concentrations of 2.85% (w/w) and 3.5% (w/w), and these two HPMC levels were selected for further drug-loaded film studies. Besides, in the drug-loaded film printing studies, three different drug levels were tested. With the optimum concentration, films were flexible and homogeneous, disintegrated in 1 to 2.5 min, and released the drug in 2-3 min. Drug nanocrystals remained in the nano size range in the polymer films, particle sizes being in all film formulations from 300 to 500 nm. When the 3D-printed polymer films were compared to traditional film-casted polymer films, the physicochemical behavior and pharmaceutical performance of the films were very similar. As a conclusion, 3D printing of drug nanocrystals in oral polymeric film formulations is a very promising option for the production of immediate-release improved- solubility formulations.
  • Viidik, Laura; Seera, Dagmar; Antikainen, Osmo; Kogermann, Karin; Heinämäki, Jyrki; Laidmäe, Ivo (2019)
    Printing technologies combined with a computer-aided design (CAD) have found an increasing number of uses in pharmaceutical applications. In extrusion-based printing, the material is forced through a nozzle to form a three-dimensional (3D) structure pre-designed by CAD. The aim of this study was to evaluate the 3D-printability of biocompatible aqueous poly(ethylene oxide) (PEO) gels and to investigate the effects of three formulation parameters on the 3D printing process. The impact of PEO concentration (gel viscosity), printing head speed and printing plate temperature was investigated at three different levels using a full factorial experimental design. The aqueous PEO gels were printed with a bench-top extrusion-based 3D printing system at an ambient room temperature. The viscosity measurements confirmed that the aqueous PEO gels follow a shear-thinning behaviour suitable for extrusion-based printing. Heating the printing plate allowed the gel to dry faster resulting in more precise printing outcome. With the non-heated plate, the gel formed a dumbbell-shaped grid instead of straight lines. Higher concentration and more viscous PEO gels formed the best structured 3D-printed lattices. In conclusion, the accuracy and precision of extrusion-based 3D printing of aqueous PEO gels is highly dependent on the formulation (PEO concentration) and printing parameters (printing head speed, plate temperature). By optimizing these critical process parameters, PEO may be suitable for printing novel drug delivery systems.
  • Shaqour, Bahaa; Reigada, Ines; Gorecka, Zaneta; Choinska, Emilia; Verleije, Bart; Beyers, Koen; Swieszkowski, Wojciech; Fallarero, Adyary; Cos, Paul (2020)
    Additive manufacturing technologies have been widely used in the medical field. More specifically, fused filament fabrication (FFF) 3D-printing technology has been thoroughly investigated to produce drug delivery systems. Recently, few researchers have explored the possibility of directly 3D printing such systems without the need for producing a filament which is usually the feedstock material for the printer. This was possible via direct feeding of a mixture consisting of the carrier polymer and the required drug. However, as this direct feeding approach shows limited homogenizing abilities, it is vital to investigate the effect of the pre-mixing step on the quality of the 3D printed products. Our study investigates the two commonly used mixing approaches-solvent casting and powder mixing. For this purpose, polycaprolactone (PCL) was used as the main polymer under investigation and gentamicin sulfate (GS) was selected as a reference. The produced systems' efficacy was investigated for bacterial and biofilm prevention. Our data show that the solvent casting approach offers improved drug distribution within the polymeric matrix, as was observed from micro-computed topography and scanning electron microscopy visualization. Moreover, this approach shows a higher drug release rate and thus improved antibacterial efficacy. However, there were no differences among the tested approaches in terms of thermal and mechanical properties.
  • Zhang, Liucheng; Xiang, Yi; Zhang, Hongbo; Cheng, Liying; Mao, Xiyuan; An, Ning; Zhang, Lu; Zhou, Jinxiong; Deng, Lianfu; Zhang, Yuguang; Sun, Xiaoming; Santos, Hélder A.; Cui, Wenguo (2020)
    The development of science and technology often drew lessons from natural phenomena. Herein, inspired by drying-driven curling of apple peels, hydrogel-based micro-scaled hollow tubules (MHTs) are proposed for biomimicking microvessels, which promote microcirculation and improve the survival of random skin flaps. MHTs with various pipeline structures are fabricated using hydrogel in corresponding shapes, such as Y-branches, anastomosis rings, and triangle loops. Adjustable diameters can be achieved by altering the concentration and cross-linking time of the hydrogel. Based on this rationale, biomimetic microvessels with diameters of 50-500 mu m are cultivated in vitro by coculture of MHTs and human umbilical vein endothelial cells. In vivo studies show their excellent performance to promote microcirculation and improve the survival of random skin flaps. In conclusion, the present work proposes and validifies a biomimetic 3D self-forming method for the fabrication of biomimetic vessels and microvascular scaffolds with high biocompatibility and stability based on hydrogel materials, such as gelatin and hyaluronic acid.
  • Pallares, Jordi; Senan, Oriol; Guimera, Roger; Vernet, Anton; Aguilar-Mogas, Antoni; Vilahur, Gemma; Badimon, Lina; Sales-Pardo, Marta; Cito, Salvatore (2015)
    Thrombus formation is a multiscale phenomenon triggered by platelet deposition over a protrombotic surface (eg. a ruptured atherosclerotic plaque). Despite the medical urgency for computational tools that aid in the early diagnosis of thrombotic events, the integration of computational models of thrombus formation at different scales requires a comprehensive understanding of the role and limitation of each modelling approach. We propose three different modelling approaches to predict platelet deposition. Specifically, we consider measurements of platelet deposition under blood flow conditions in a perfusion chamber for different time periods (3, 5, 10, 20 and 30 minutes) at shear rates of 212 s(-1), 1390 s(-1) and 1690 s(-1). Our modelling approaches are: i) a model based on the mass-transfer boundary layer theory; ii) a machine-learning approach; and iii) a phenomenological model. The results indicate that the three approaches on average have median errors of 21%, 20.7% and 14.2%, respectively. Our study demonstrates the feasibility of using an empirical data set as a proxy for a real-patient scenario in which practitioners have accumulated data on a given number of patients and want to obtain a diagnosis for a new patient about whom they only have the current observation of a certain number of variables.
  • Okutachi, Sunday; Manoharan, Ganesh Babu; Kiriazis, Alexandros; Laurini, Christina; Catillon, Marie; McCormick, Frank; Yli-Kauhaluoma, Jari; Abankwa, Daniel (2021)
    Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. Here we identified a less toxic, functional analog of OphA that can efficiently inactivate CaM by covalent inhibition. We analyzed a small series of benzazulenones, which bear some structural similarity to OphA and can be synthesized in only six steps. We identified the formyl aminobenzazulenone 1, here named Calmirasone1, as a novel and potent covalent CaM inhibitor. Calmirasone1 has a 4-fold increased affinity for CaM as compared to OphA and was active against K-Ras in cells within minutes, as compared to hours required by OphA. Calmirasone1 displayed a 2.5-4.5-fold higher selectivity for KRAS over BRAF mutant 3D spheroid growth than OphA, suggesting improved relative on-target activity. Importantly, Calmirasone1 has a 40-260-fold lower unspecific toxic effect on HRAS mutant cells, while it reaches almost 50% of the activity of novel K-RasG12C specific inhibitors in 3D spheroid assays. Our results suggest that Calmirasone1 can serve as a new tool compound to further investigate the cancer cell biology of the K-Ras and CaM associated stemness activities.
  • Hemilä, Harri (1985)
    The Orthomolecular approach to medicine has been under constant criticism ever since its origin. One cause for this may be the somewhat conflicting experimental results, but I suggest that an even more important reason for the lack of acceptance results from the traditional conceptual approach towards nutrition. Understanding the nature of this conceptual hindrance may be relevant for the Orthomolecular school in arguing for the general acceptance of the "optimal intake" approach.
  • Sathyanarayanan, Gowtham; Haapala, Markus; Dixon, Christopher; Wheeler, Aaron R.; Sikanen, Tiina M. (2020)
    Microfluidic sample manipulation is a key enabler in modern chemical biology research. Both discrete droplet-based digital microfluidic (DMF) assays and continuous flow in-channel assays are well established, each featuring unique advantages from the viewpoint of automation and parallelization. However, there are marked differences in the applicable microfabrication materials and methods, which limit the interfacing of DMF sample preparation with in-channel separation systems, such as the gold standard microchip electrophoresis. Simultaneously, there is an increasing demand for low-cost and user-friendly manufacturing techniques to foster the adaptation of microfluidic technology in routine laboratory analyses. This work demonstrates integration of DMF with in-channel separation systems using only low-cost and accessible (non-cleanroom) manufacturing techniques, i.e., inkjet printing of silver for patterning of the driving electrodes and UV curing of off-stoichiometric thiol-ene (OSTE) polymers both for dielectric coating of the electrode arrays and replica molding of the microchannel network. As a dielectric, OSTE performs similar to Parylene C (a gold standard dielectric in electrowetting), whereas its tunable surface and bulk properties facilitate straightforward bonding of the microchannel with the dielectric layer. In addition, a new chip design that facilitates efficient droplet transfer from the DMF part to the microchannel inlet solely by electrowetting is showcased.
  • Rautamo, Maria M; Kvarnström, Kirsi; Siven, Mia; Airaksinen, Marja; Lahdenne, Pekka Olavi; Sandler, Niklas (2020)
    Oral drug administration to pediatric patients is characterized by a lack of age-appropriate drug products and the off-label use of medicines. However, drug administration practices at hospital wards is a scarcely studied subject. The aim of this study was to explore the oral drug administration practices at pediatric hospital wards, with a focus on experiences and challenges faced, methods used to mitigate existing problems, drug manipulation habits, perceptions about oral dosage forms and future needs of oral dosage forms for children. This was a qualitative study consisting of focus group discussions with physicians, nurses and clinical pharmacists in a tertiary university hospital with the objective of bringing forward a holistic view on this research topic. These healthcare professionals recognized different administration challenges that were classified as either dosage form-related or patient-related ones. A lack of depot formulations developed especially for children as well as oral pediatric dosage forms of drug substances currently available as intravenous dosage forms was recognized. The preferred oral dosage forms were oral liquids and orodispersible tablets. Patient-centered drug administration practices including factors facilitating drug administration both at hospital wards and at home after patient discharge were identified. Among all healthcare professionals, the efficient cooperation in drug prescribing and administration as well as in educating the child's caregivers in correct administration techniques before discharge and improving the overall discharge process of patients was emphasized. This study complements the prevalent understanding that new dosage forms for children of varying ages and stages of development are still needed. It also brings a holistic view on different aspects of oral drug administration to pediatric patients and overall patient-centered drug administration practices.
  • Lippert, J; Brosch, M; von Kampen, O; Meyer, M; Siegmund, H.-U; Schafmayer, C; Becker, T; Laffert, B; Görlitz, L; Schreiber, S; Neuvonen, PJ; Niemi, M; Hampe, J; Kuepfer, L (2012)
  • Poller, Bettina; Strachan, Clare; Broadbent, Roland; Walker, Greg F. (2017)
    The purpose of this study was to evaluate electrospun drug loaded nanofibers as a new matrix for mini tablets. Prednisone, a poorly water-soluble drug, was loaded into povidone (polyvinylpyrrolidone, PVP) nanofibers using the process of electrospinning. The drug-loaded nanofiber mat was compressed into minitablets with a 2 mm diameter and a height of 2.63 0.04 mm. SEM analysis of the minitablet identified a nano-web structure with a nanofiber diameter in the range of 400-500 nm. The minitablets met the requirements of the US Pharmacopeia with respect to content uniformity and friability. DSC and XRPD analysis of the minitablet indicated that the drug-polymer mixture was a one-phase amorphous system. XRPD analysis of the drug loaded nanofiber mat after 10-months of storage at ambient temperature showed no evidence of recrystallization of the drug. Solubility and dissolution properties of the drug formulated into a nanofiber mat and minitablet were evaluated. These results show that electrospun nanofibers may provide a useful matrix for the further development of minitablets. (C) 2017 Elsevier B.V. All rights reserved.
  • Leigh, Robert S.; Ruskoaho, Heikki J.; Kaynak, Bogac L. (2020)
    Reliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse embryonic stem cells (mESCs) to predict in vivo developmental toxicity, but does not take into account the stage-specific patterning of progenitor populations into anterior (ventricular) and posterior (atrial) compartments. In this study, we generated a novel dual reporter mESC line with fluorescent reporters under the control of anterior and posterior cardiac promoters. Reporter expression was observed in nascent compartments in transgenic mouse embryos, and mESCs were used to develop differentiation assays in which chemical modulators of Wnt (XAV939: 3, 10 mu M), retinoic acid (all-trans retinoic acid: 0.1, 1, 10 mu M; 9-cis retinoic acid: 0.1, 1, 10 mu M; bexarotene 0.1, 1, 10 mu M), and Tgf-beta (SB431542: 3, 10 mu M) pathways were tested for stage- and dose-dependent effects on in vitro anterior-posterior patterning. Our results suggest that with further development, the inclusion of anterior-posterior reporter expression could be part of a battery of high-throughput tests used to identify and characterize teratogens.
  • Sidorova, Yulia A.; Bespalov, Maxim M.; Wong, Agnes W.; Kambur, Oleg; Jokinen, Viljami; Lilius, Tuomas O.; Suleymanova, Ilida; Karelson, Gunnar; Rauhala, Pekka V.; Karelson, Mati; Osborne, Peregrine B.; Keast, Janet R.; Kalso, Eija A.; Saarma, Mart (2017)
    Neuropathic pain caused by nerve damage is a common and severe class of chronic pain. Disease-modifying clinical therapies are needed as current treatments typically provide only symptomatic relief; show varying clinical efficacy; and most have significant adverse effects. One approach is targeting either neurotrophic factors or their receptors that normalize sensory neuron function and stimulate regeneration after nerve damage. Two candidate targets are glial cell line-derived neurotrophic factor (GDNF) and artemin (ARTN), as these GDNF family ligands (GFLs) show efficacy in animal models of neuropathic pain (Boucher et al., 2000; Gardell et al., 2003: Wang et al., 2008, 2014). As these protein ligands have poor drug-like properties and are expensive to produce for clinical use, we screened 18,400 drug-like compounds to develop small molecules that act similarly to GFLs (GDNF mimetics). This screening identified BT13 as a compound that selectively targeted GFL receptor RET to activate downstream signaling cascades. BT13 was similar to NGF and ARTN in selectively promoting neurite outgrowth from the peptidergic class of adult sensory neurons in culture, but was opposite to ARTN in causing neurite elongation without affecting initiation. When administered after spinal nerve ligation in a rat model of neuropathic pain, 20 and 25 mg/kg of BT13 decreased mechanical hypersensitivity and normalized expression of sensory neuron markers in dorsal root ganglia. In control rats, BT13 had no effect on baseline mechanical or thermal sensitivity, motor coordination, or weight gain. Thus, small molecule BT13 selectively activates RET and offers opportunities for developing novel disease-modifying medications to treat neuropathic pain.
  • Fewer, David P.; Metsä-Ketelä, Mikko (2020)
    Abstract Microbes are talented chemists with the ability to generate tremendously complex and diverse natural products which harbor potent biological activities. Natural products are produced using sets of specialized biosynthetic enzymes encoded by secondary metabolism pathways. Here, we present a two-step evolutionary model to explain the diversification of biosynthetic pathways that account for the proliferation of these molecules. We argue that the appearance of natural product families has been a slow and infrequent process. The first step led to the original emergence of bioactive molecules and different classes of natural products. However, much of the chemical diversity observed today has resulted from the endless modification of the ancestral biosynthetic pathways. The second step rapidly modulates the pre-existing biological activities to increase their potency and to adapt to changing environmental conditions. We highlight the importance of enzyme promiscuity in this process, as it facilitates both the incorporation of horizontally transferred genes into secondary metabolic pathways and the functional differentiation of proteins to catalyze novel chemistry. We provide examples where single point mutations or recombination events have been sufficient for new enzymatic activities to emerge. A unique feature in the evolution of microbial secondary metabolism is that gene duplication is not essential but offers opportunities to synthesize more complex metabolites. Microbial natural products are highly important for the pharmaceutical industry due to their unique bioactivities. Therefore, understanding the natural mechanisms leading to the formation of diverse metabolic pathways is vital for future attempts to utilize synthetic biology for the generation of novel molecules.
  • Li, Xia; Frechen, Sebastian; Moj, Daniel; Lehr, Thorsten; Taubert, Max; Hsin, Shih-hsuan; Mikus, Gerd; Neuvonen, Pertti J; Olkkola, Klaus; Saari, Teijo; Fuhr, Uwe (2020)
    Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to <5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.
  • Lautala, S.; Koivuniemi, A.; Kulig, W.; Rog, T.; Talman, V.; Tuominen, R.; Bunker, A. (2019)