Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Department of Pharmacy, Elisabeth-TweeSteden Hospital, Tilburg, The Netherlands.
J Antimicrob Chemother. 2018 Sep 1;73(9):2430-2434. doi: 10.1093/jac/dky191.
If HIV patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is crushed and dissolved prior to administration. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq®, referred to as TRI); therefore, crushing of TRI is not recommended.
To investigate whether the TRI fixed-dose combination tablet can be crushed and combined with enteral nutrition without influencing pharmacokinetics (PK).
We carried out an open-label, three-period, randomized, single-dose, crossover trial in 22 healthy adult volunteers. Subjects randomly received whole-tablet TRI with fasting (reference), crushed and suspended TRI with fasting or crushed and suspended TRI with oral intake of enteral nutrition. Bioequivalence criteria (80%-125% acceptance range) of AUC0-∞ and Cmax were used. ClinicalTrials.gov: NCT02569346.
Crushing TRI leads to higher dolutegravir exposure (AUC0-∞: +26% and Cmax: +30%) and, if crushed TRI is combined with enteral nutrition, to a decrease in abacavir Cmax (-17%). Lamivudine concentrations were not affected as geometric mean ratios with 90% CIs fell within the 80%-125% range.
Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition.
如果 HIV 患者无意识或因其他原因无法吞服片剂，在给药前会将抗逆转录病毒药物压碎并溶解。压碎会改变药物暴露，可能导致治疗失败、耐药性发展或毒性。目前，尚无关于多替拉韦/阿巴卡韦/拉米夫定固定剂量复方制剂（Triumeq ® ，简称 TRI）压碎的信息；因此，不建议压碎 TRI。
研究 TRI 固定剂量复方片剂在不影响药代动力学（PK）的情况下是否可以压碎并与肠内营养联合使用。
我们在 22 名健康成年志愿者中开展了一项开放标签、三周期、随机、单剂量、交叉试验。受试者随机接受空腹时整片 TRI（参比）、空腹时压碎并混悬 TRI 或压碎并混悬 TRI 与口服肠内营养联合使用。采用 AUC0-∞和 Cmax 的生物等效性标准（80%-125%接受范围）。ClinicalTrials.gov：NCT02569346。
TRI 压碎后多替拉韦暴露增加（AUC0-∞：+26%，Cmax：+30%），如果将压碎的 TRI 与肠内营养联合使用，则阿巴卡韦 Cmax 降低（-17%）。拉米夫定浓度不受影响，其几何均数比值的 90%CI 落在 80%-125%范围内。
与空腹时整片 TRI 相比，压碎并混悬片剂或压碎并混悬片剂与口服肠内营养联合使用时，均不能证明生物等效。两种情况均导致多替拉韦暴露增加，但未超过随餐或每日两次给药后的暴露。在我们看来，TRI 可以压碎用于吞咽困难的患者，并且可以与肠内营养同时使用。
