Kaminskas, Lisa; Landersdorfer, Cornelia; Bischof, Robert; Leong, Nathania; Ibrahim, Jibriil; Davies, Andrew; Pham, Stephen; Beck, Steven; Montgomery, A.; Surber, Mark
doi: 10.1007/s11095-019-2732-2pmid: 31823096
Hussaarts, Koen; Berger, Florine; Binkhorst, Lisette; Oomen - de Hoop, Esther; van Leeuwen, Roelof; van Alphen, Robbert; Mathijssen - van Stein, Daniëlle; Groot, Natasja; Mathijssen, Ron; van Gelder, Teun
doi: 10.1007/s11095-019-2746-9pmid: 31845095
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose</jats:title> <jats:p>Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; <jats:italic>P</jats:italic> = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; <jats:italic>P</jats:italic> = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; <jats:italic>P</jats:italic> < 0.01) and citalopram (20.7 ms; 95%CI:0.7–40.7 ms; <jats:italic>P</jats:italic> = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.</jats:p> </jats:sec>
Govender, Rydvikha; Abrahmsén-Alami, Susanna; Folestad, Staffan; Larsson, Anette
doi: 10.1007/s11095-019-2720-6pmid: 31848730
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose</jats:title> <jats:p>This study uses high drug content solid dispersions for dose window extension beyond current demonstrations using fused deposition modelling (FDM) to; i) accommodate pharmaceutically relevant doses of drugs of varying potencies at acceptable dosage form sizes and ii) enable enhanced dose flexibility via modular dosage form design concepts.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>FDM was used to generate ~0.5 mm thick discs of varying diameter (2–10 mm) from melt-extruded feedstocks based on 10% to 50% w/w felodipine in ethyl cellulose. Drug content was determined by UV spectroscopy and dispensing precision from printed disc mass.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Mean felodipine content was within ±5% of target values for all print volumes and compositions including contents as high as ~50% w/w. However, poor dispensing precision was evident at all print volumes.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In pursuit of dose flexibility, this successful demonstration of dose window extension using high content solid dispersions preserves FDM design flexibility by maintaining applicability to drugs of varying potencies. The achieved uniformity of content supports the application of varying content solid dispersions to modular dosage form concepts to enhance dose flexibility. However, poor dispensing precision impedes its utilisation until appropriate compatibility between FDM hardware and materials at varying drug contents can be attained.</jats:p> </jats:sec>
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