Mareile H Breithaupt1, Evelyn Krohmer1, Lenka Taylor2, Eva Koerner2, Torsten Hoppe-Tichy2, Juergen Burhenne1, Kathrin I Foerster1, Markus Dachtler3, Gerald Huber4, Rakesh Venkatesh4, Karin Eggenreich3, David Czock1, Gerd Mikus1, Antje Blank1, Walter E Haefeli5. 1. Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. 2. Hospital Pharmacy, Heidelberg University Hospital, Im Neuenheimer Feld 670, 69120, Heidelberg, Germany. 3. Gen-Plus GmbH & Co KG, Staffelseestrasse 6, 81379, Munich, Germany. 4. DiHeSys, DiHeSys Digital Health Systems GmbH, Marie-Curie-Str. 19, 73529, Schwäbisch Gmünd, Germany. 5. Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. walter.emil.haefeli@med.uni-heidelberg.de.
Abstract
PURPOSE: The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF. METHODS: Midazolam doses of 0.03 and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. RESULTS: The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4-116) compared to oral solution and for 3 mg 101% (86.8-116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2-110) compared to oral solution and 94.3% (78.2-114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2-29.2) and for 3 mg 28.1% (23.4-33.8) (oral solution: 0.03 mg: 24.4% (22.0-27.1); 3 mg: 28.0% (25.0-31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p < 0.0001). CONCLUSION: This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0-∞ in both doses was bioequivalent to the administration of an oral solution. However, Cmax of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration EudraCT: 2020-003984-24, August 10, 2020).
PURPOSE: The use of two-dimensional (2D) printing technologies of drugs on orodispersible films (ODF) can promote dose individualization and facilitate drug delivery in vulnerable patients, including children. We investigated midazolam pharmacokinetics after the administration of 2D-printed ODF. METHODS: Midazolam doses of 0.03 and 3 mg were printed on an ODF using a 2D drug printer. We investigated the bioavailability of the two midazolam doses with ODF swallowed immediately (ODF-IS) or delayed after 2 min (ODF-DS) by comparing their pharmacokinetics with intravenous and oral midazolam solution in 12 healthy volunteers. RESULTS: The relative bioavailability of ODF-IS 0.03 mg was 102% (90% confidence interval: 89.4-116) compared to oral solution and for 3 mg 101% (86.8-116). Cmax of ODF-IS 0.03 mg was 95.5% (83.2-110) compared to oral solution and 94.3% (78.2-114) after 3 mg. Absolute bioavailability of ODF-IS 0.03 mg was 24.9% (21.2-29.2) and for 3 mg 28.1% (23.4-33.8) (oral solution: 0.03 mg: 24.4% (22.0-27.1); 3 mg: 28.0% (25.0-31.2)). Absolute bioavailability of ODF-DS was significantly larger than for ODF-IS (0.03 mg: 61.4%; 3 mg: 44.1%; both p < 0.0001). CONCLUSION: This trial demonstrates the tolerability and unchanged bioavailability of midazolam printed on ODF over a 100-fold dose range, proving the suitability of ODF for dose individualization. Midazolam ODF-IS AUC0-∞ in both doses was bioequivalent to the administration of an oral solution. However, Cmax of the therapeutic dose of ODF-IS missed bioequivalence by a clinically not relevant extent. Prolonged mucosal exposure increased bioavailability. (Trial Registration EudraCT: 2020-003984-24, August 10, 2020).
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