No impact on bioavailability of D/C/F/TAF when tablet is split but TAF absorption is reduced if crushed

There was no clinically relevant effect on the bioavailability of darunavir / cobicistat / emtricitabine / tenofovir alafenamide (D/C/F/TAF) components when given as a split tablet compared with a tablet swallowed whole. [1] Crushing the tablet led to a modest decrease in TAF bioavailability.

Whether or not antiretroviral tablets, including fixed dose combinations (FDCs), can be split or crushed for people who are unable to swallow pills and sometimes for paediatric HIV is important to know.

The originator company, Janssen, previously evaluated the stability of D/C/F/TAF in vitro and found that the individual components remained stable: after splitting the tablet in half; and after crushing the tablet and exposing to liquids (water, orange juice, cranberry juice and apple sauce). The components also did not absorb to PVC or silicone feeding tubes.

The company then assessed the relative bioavailabilty of D/C/F/TAF as a spilt or crushed tablet after oral administration compared with a whole tablet. These data were presented at EACS 2018.

This assessment was a phase 1, randomised, open-label, 3-period, 3-treatment, crossover study of a single dose of D/C/F/TAF (800/150/200/10 mg) given as a split or crushed tablet versus a whole tablet.

Thirty HIV negative adults aged 18–55 years were enrolled and the dose was given within 30 minutes of a standard breakfast. Tablets were: swallowed whole (reference); split with a tablet cutter (both halves swallowed); or crushed and mixed with apple sauce.

Full pharmacokinetic (PK) profiles were determined up to 72 hours (darunavir, cobicistat and emtricitabine), and 8 hours for TAF. Primary PK parameters were Cmax and AUC. Treatments were compared using a linear mixed effects model.

The assessment found no relative impact on the bioavailability of D/C/F/TAF components when given as split compared with whole tablet (least squares means ratio confidence intervals all within 80 to 125% boundaries).

There was no relevant impact on the bioavailability of darunavir, cobicistat and emtricitabine when given as a crushed tablet but approximately 20% decrease in the bioavailability of TAF.

The investigators noted that the clinical relevance of the decrease has not been assessed but it is expected to be minimal because of the wide therapeutic window for TAF.

Comment

It is good to have data to inform whether or not tablets can be split in half for people who have difficulties swallowing them whole.

The results for darunavir/cobicistat contrast with those for lopinavir/ritonavir for which crushing significantly reduced exposure of both components with a decrease in AUC by 45% lopinavir and 47% ritonavir in a study in older children. [2]