February 28, 2017
The boosted integrase inhibitor-based fixed dose combination (FDC) Stribild (STB) can be safely crushed without affecting pharmacokinetics.1
Mieke Jongbloed-de Hoon et al from Radboud University Medical Center, Nijmegen carried out this open-label, three-period, single dose, randomised, cross-over, trial in 24 HIV-negative volunteers to asses the safety and absorbance of the four constituent drugs in the FDC, when taken with a standard breakfast meal or with enteral nutrition.
Stribild is an FDC of elvitegravir (EVG), cobicistat (COBI) booster, emtricitabine (FTC) and tenofovir-DF (TDF).
For people who are severely ill or have difficulty swallowing, taking whole tablets can be difficult. While crushing tablets helps with administration in such cases, it can also adversely affect the pharmokinetics (PK) of the drug, leading to decreased or increased drug levels, and in turn drug resistance or toxicity. In addition, the integrase inhibitor elvitegravir can form complexes with cations contained in enteral nutrition, reducing its absorbance. As no information is currently available about crushing STB, this study aimed to determine the bio-equivalence of crushed STB taken with a standardised breakfast or with enteral nutrition, in comparison to administration of the whole tablet.
The study consisted of three treatment regimens:
Volunteers were randomised to one of the six possible sequences: ABC, ACB, BCA, BAC, CAB, or CBA, with each treatment period followed by a seven-day wash out. The standardised 350 kcal breakfast contained two slices of buttered wheat bread (one slice with 40+ cheese and one with luncheon meat or cervelat) and one cup of tea; 350 mL of enteral nutrition, Nutrison (Nutricia), contained also 350 kcal and was orally ingested.
Three standard PK curves were produced for each participant with frequent blood samples taken over a 32-hour period following observed intake. Liquid chromatography was used to measure plasma concentrations of EVG, COBI, TFV and FTC.
Half the participants were women, median age was 37 and all were Caucasian except one who was mixed race. Intervention 1 (crushed STB with standardised breakfast) versus reference treatment (whole tablet) for time 0 to 32 hours AUC was bio-equivalent. All the 90% confidence intervals for EVG, COBI, TFV and FTC fell between 80-125%. In contrast, bio-equivalence for Cmax of EVG, COBI and TFV could not be shown between intervention 1 and the reference treatment (whole tablet). For EVG the 90% CI was above the required limit of 80-125% at 105-127%. For COBI and TFV the 90% CI was under the required limits, at 76-91% and 71-92% respectively. For intervention 2 (crushed STB with enteral nutrition) versus reference treatment, all 90% CIs were within the required limits, meaning that the AUC and Cmax of crushed STB with enteral nutrition was bio-equivalent with reference treatment.
While crushed STB with breakfast had no influence on the total AUC, (compared with a whole tablet with breakfast), it did have a small influence on the Cmax. The Cmax of EVG was increased by 16% and the Cmax of TFV was decreased by 19%. The authors state that these differences between Cmax of crushed STB and a whole STB are small and considered to be less relevant in clinical practice, as inter-patient variation is much larger.
Jongbloed-de Hoon M et al. Pharmacokinetics of crushed elvitegravir combination tablet given with or without enteral nutrition. JAIDS. 2017. Epub ahead of print DOI: 10.1097/Q AI.0000000000001296
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