Oral bioavailability of microdoses and therapeutic doses of midazolam as a 2-dimensionally printed orodispersible film in healthy volunteers.

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).

Gender aspects in clinical presentation and prognostication of chronic heart failure according to NT-proBNP and the Heart Failure Survival Score.

AIMS: We performed a prospective multi-center study to assess gender-specific differences in the predictive value of the measured level of NT-proBNP and the calculated Heart Failure Survival Score (HFSS). METHODS: Baseline characteristics and follow-up data up to 5 years from 2,019 men and 530 women diagnosed with chronic heart failure (CHF) due to ischemic heart disease or dilated cardiomyopathy were prospectively compared. Death from any cause constituted the endpoint of the study. NT-proBNP was measured and HFSS calculated according to standard methods. Survival of men and women according to level of NT-proBNP and HFSS was analyzed in logistic regression models. RESULTS: Median NT-proBNP level in men was 1,394 ng/l (IQR 516-3,406 ng/l) and 1,168 ng/l (IQR 444-2,830 ng/l) in women (p = n.s.). Median HFSS value was 8.4 (IQR 7.7-9.1) and 8.5 (8.0-9.1) in men and women, respectively. NT-proBNP levels and HFSS score correlated well with survival rates in both genders (p for interaction = 0.22 for NT-proBNP and 0.93 for HFSS). The all-cause death rates were similar in men and women. CONCLUSION: Despite a number of gender-specific differences in CHF and the general predominance of men measured levels of NT-proBNP and HFSS score can be utilized for risk stratification with similar informative value in men and women.