Pharmacokinetic similarity demonstrated after crushing of the elbasvir/grazoprevir fixed-dose combination tablet for HCV infection

Abstract

Background Finding a suitable treatment for HCV patients with swallowing disorders is still a major challenge. In practice, direct-acting antivirals are crushed without knowledge of adequate absorption. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the fixed-dose combination tablet of elbasvir/grazoprevir; therefore, crushing of this tablet is not recommended. Objectives To investigate the influence of crushing on the pharmacokinetics of the elbasvir/grazoprevir fixed-dose combination tablet. Methods We conducted an open-label, two-period, randomized, cross-over, Phase I, single-dose trial in 11 healthy adult volunteers. Subjects randomly received whole-tablet elbasvir/grazoprevir or crushed and suspended elbasvir/grazoprevir in a fasted state. Pharmacokinetic similarity criteria (90% CIs lie within 70%–143% acceptance range) were used for AUC0–∞ and AUC0–72. Results Mean plasma concentration–time curves of elbasvir and grazoprevir showed similar pharmacokinetic profiles. The primary pharmacokinetic parameters AUC0–∞ and AUC0–72 of elbasvir and grazoprevir after intake of a crushed tablet were on average 12%–16% higher compared with the whole tablet, but 90% CIs were all within the predefined boundaries of pharmacokinetic similarity. Crushing leads to a higher Cmax of grazoprevir (42%); no significant difference was found between treatments with regard to the Cmax of elbasvir. No serious adverse events were reported during the trial. Conclusions Pharmacokinetic similarity could be demonstrated for a crushed and suspended tablet compared with a whole tablet, without impacting drug safety or efficacy. Crushed and suspended administration of elbasvir/grazoprevir can be used in patients with swallowing disorders.

Crushing and Splitting Direct-Acting Antivirals for Hepatitis C Virus Treatment: A Case Series and Literature Review

“…However, stability and pharmacokinetic data of crushed or split tablets are not readily available. Reports of DAA tablet manipulation are limited to 2 small phase 1 pharmacokinetic studies [ 12 , 13 ] and case reports ( Table 2 ) [ 14–23 ]. Pijnenburg et al [ 12 ] conducted a phase 1, single-dose trial evaluating pharmacokinetic data of elbasvir/grazoprevir in 11 healthy adult volunteers.…”

“…Reports of DAA tablet manipulation are limited to 2 small phase 1 pharmacokinetic studies [ 12 , 13 ] and case reports ( Table 2 ) [ 14–23 ]. Pijnenburg et al [ 12 ] conducted a phase 1, single-dose trial evaluating pharmacokinetic data of elbasvir/grazoprevir in 11 healthy adult volunteers. Pharmacokinetic similarities were demonstrated between crushed and suspended elbasvir/grazoprevir tablets compared with whole tablets; thus, crushed tablets can be an administration option for patients with swallowing disorders.…”

Review of Renal Transplantation of Hepatitis C Viremic Donor Organs into Aviremic Recipients

“…Antiviral treatment regimens that are initiated early after transplantation may be started while patients are still intubated and unable to swallow pills. There is limited pharmacokinetic data on delivery of DAAs in crushed form via enteral access tube [22][23][24]. In addition, there are several drug-drug interactions to be aware of as well including immunosuppressants, amiodarone, proton pump inhibitors, azole family drugs [25][26][27].…”

Elbasvir/grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response: A case report and a review of the literature

“…Pijnenburg et al reported the pharmacokinetic parameters of crushed EBR/GZR resulting from an open-label, randomized, cross-over study. 9 Healthy adults received a single dose of the reference (whole) tablet and crushed tablet given with 250 ml of water under fasted conditions with a 14-day washout period between each dosage form. There was no significant difference in pharmacokinetic parameters of crushed versus whole EBR.…”