De Toni Luca, De Rocco Ponce Maurizio, Franceschinis Erica, Dall'Acqua Stefano, Padrini Roberto, Realdon Nicola, Garolla Andrea, Foresta Carlo
Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy.
PharmaTeG - Pharmaceutical Technology Group, Department of Pharmaceutical and Pharmacological Sciences, School of Medicine, University of Padova, Padova, Italy.
Front Pharmacol. 2018 Feb 6;9:59. doi: 10.3389/fphar.2018.00059. eCollection 2018.
Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original formulation. disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared. , ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT ( = 0.017 and = 0.008, respectively). , compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF; < 0.01 and < 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%; < 0.05) and improved pattern of flushing and nasal congestion. Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects.
5型磷酸二酯酶抑制剂（PDE5i）是用于治疗勃起功能障碍（ED）的有效药物；然而，据报道因主要副作用导致的停药率很高。本研究的目的是评估与新型口腔崩解膜（ODF）舌下给药相关的西地那非（Sild）药代动力学的可能改善情况，与作为原始剂型的口腔分散片（ODT）和薄膜包衣片（FCT）进行比较。在特定装置中进行崩解试验、溶出试验和渗透试验，以估计经粘膜吸收情况。通过高效液相色谱-串联质谱法（HPLC-MS/MS）对20例心因性ED患者进行血清Sild水平分析，这些患者交替接受FCT或舌下ODT或ODF，剂量相同（50mg）。比较了每种制剂给药后Sild的药代动力学参数和药物不良反应。结果显示，与ODT和FCT相比，ODF的崩解时间最长，渗透速率增加（分别为P = 0.017和P = 0.008）。此外，与FCT和ODT相比，ODF的血清Sild水平升高更快（给药后15分钟时的血清水平分别为：FCT为2.24±1.4ng/ml，ODT为0.5±0.3ng/ml，ODF为13.5±9.1ng/ml；与ODF相比，P<0.01和P<0.05），给药后60分钟内药物生物利用度更高（相对AUC与FCT相比分别为：FCT为100.0±44.9%，ODT为183.8±75.4%，ODF为304.2±156.0%）。观察到ODF的血清峰值水平有降低趋势。最后，与FCT相比，ODF的头痛发生率较低（1%对35%；P<0.05），潮红和鼻充血模式有所改善。舌下含服Sild ODF可能通过改变药代动力学提高药物耐受性，这也提示其在临床疗效方面可能有潜在影响。口腔崩解制剂的舌下给药可能是一种改善PDE5i治疗依从性的策略，尤其是对于因副作用而气馁的患者。
