Dolutegravir exposure increases when fixed dose combination tablets are crushed

Dolutegravir exposure was higher after crushing the originator fixed dose combination (FDC) tablet and taking with enteral nutrition, compared to taking the whole tablet.

These findings from a pharmacokinetic (PK) evaluation were presented at CROI 2017.

Marieke Roskam-Kwint and colleagues from the Radboud University, Nijmegen, Netherlands conducted a study to investigate whether the dolutegravir/abacavir/lamivudine FDC could be crushed and taken with enteral nutrition without altering PK.

The investigators explained that if people are unconscious or unable to swallow tablets for other reasons, antiretrovirals are sometimes crushed and dissolved before they are given. Crushing can influence PK, possibly leading to treatment failure and development of resistance with low exposure or toxicity if it is too high. They also note that a PK interaction between dolutegravir and enteral nutrition is possible, based on the known interaction between dolutegravir and cations in antacids and supplements.

This was an open-label, 3-period, randomised, cross-over, trial. Participants were randomly assigned to receive: a single dose of the FDC whole tablet fasted (reference); crushed and suspended FDC fasted (intervention 1); crushed and suspended FDC, followed by 250 mL enteral nutrition, taken orally (intervention 2). There was a 7-day washout period between different treatment periods.

A 48-h PK profile was measured for all compounds. Geometric mean ratios (GMR) with 90% confidence interval (CI) for AUC0-inf and Cmax were calculated for intervention 1 and 2 vs reference. The definition of bioequivalence was standard: when the 90% CI was within 80–125% for AUC and Cmax.

The study included 22 HIV negative participants (21 white and 1 mixed-race, 10 female). Participants were a median of 25 years (range 18–54) years and BMI 23 kg/m² (range 20–27).

The investigators found for intervention 1 (crushed tablet fasting) vs reference (whole tablet), the GMR dolutegravir AUC0-inf was 129.5 (90%CI: 119 to 132) and Cmax was 129.5 (95%CI: 123 to 136). The GMRs and 90% CI for AUC0-inf and Cmax for abacavir and lamivudine were within the 80–125% bioequivalence range.

For intervention 2 (crushed tablet, ethereal nutrition) vs reference, the GMR dolutegravir AUC0-inf was 118.4 (90%CI: 112 to 125) and Cmax was 121.7 (95%CI: 115 to 128). Abacavir Cmax decreased by 17%.

As dolutegravir exposure increased by 26% and 30% for AUC0-inf and Cmax with crushed tablets and Cmax increased by 21% with crushed tablets plus ethereal nutrition compared to whole tablets fasted, bioequivalence could not be demonstrated.

The investigators recommended that the dolutegravir FDC can be crushed for people with difficulties swallowing or with an enteral feeding tube and can be combined with enteral nutrition. Although no dose-limiting toxicity of dolutegravir has been observed to date, they advise against crushing dolutegravir if someone needs twice daily dosing and to take it with food.

Comment

These data are also useful to inform possible paediatric administration of dolutegravir as pill crushing is sometimes used in this population.