Bioequivalence of Crushed Stribild with a normal breakfast or with drip feed compared to the whole tablet.

Elvitegravir is an HIV-1 integrase inhibitor which is marketed in a fixed dose
combination tablet with cobicistat, tenofovir and emtricitabine (Stribild®,
referred to as STB). For patients with swallowing difficulties, administration
of whole tablets can be problematic and tablets are cut or crushed to ease
administration. In addition if HIV patients develop oppor-tunistic infections,
patients can become severely ill and may end up on the intensive care. Patients
at the intensive care might not be able to swallow medication. Therefore it is
useful to know if it is possible to administer STB through a different route,
like a feeding tube. If STB can be crushed or dissolved and given through a
catheter it is also useful to know if it can be given with drip feed.

Currently there is no information about crushing STB tablets. *Crushing STB
tablets into a liquid medium has not been studied and is not recom-mended*
according to the SPC text. Depending on the biopharmaceutical characteristics
of a drug formulation, crushing tablets can lead to altered pharmacokinetics of
drugs. This has been shown for some of the antiretroviral drugs, such as
ritonavir, lopinavir, efavirenz and tenofovir.

It is important to know whether pharmacokinetics are influenced by crush-ing of
tablets as low concentrations are associated with virologic failure. Therefore
higher doses might be needed. In addition, higher Cmax and/or exposure can lead
to toxicity. As a result therapeutic drug monitoring is advised, or crushing
the drug is a contra-indication based on the available data.
It has been shown that simultaneous oral ingestion of antacids and
elvitegravir gives a decrease in Cmax and AUC of elvitegravir. This
interac-tion is not shown for co-ingestion with omeprazole. Which makes it
un-likely that this interaction is caused by a pH-lowering effect influencing
the absorption of elvitegravir. It is probably a local gastrointestinal
complexation phenomenon, similar to what has been observed with other HIV
integrase inhibitors. A possible pharmacokinetic interaction between
elvitegravir and complexation formers may be expected. Especially con-sidering
the active binding sites of elvitegravir which bind magnesium metal ion
cofactors. Although there is data that STB can be ingested with a protein rich
drink, it is unclear if certain foods or liquids containing high amounts of
magnesium or other cations can cause this same interaction. [1, 2]

Therefore this study will be conducted to investigate whether crushed and
suspended STB and crushed and suspended STB with drip feed are bioe-quivalent
to taking STB as a whole.

Primary objective:
To assess the bioequivalence of single dose STB after administration of
standardized breakfast followed by a whole tablet (reference) and a crushed and
suspended tablet (intervention I).
To assess the bioequivalence of single dose STB after administration of a
standardized breakfast followed by a whole tablet (reference) and a
standardized dose of drip feed followed by a crushed and suspended tablet
(intervention II).
• To assess bioequivalence of the different administrations, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T¬1/2) of elvitegravir, cobicistat,
emtricitabine and tenofovir disoproxyl will be obtained and the geometric mean
ratios of the AUC0-* and Cmax of the test versus reference treatment.

Secondary objective:
To assess the bioequivalence of single dose STB after administration of
standardized breakfast followed by a crushed and suspended tablet (intervention
I) versus administration of a standardized amount of drip feed followed by a
crushed and suspended tablet (intervention II).
• To assess bioequivalence of the different ways of administration, the
pharmacokinetics (AUC0-*, Cmax, Tmax, T¬1/2) of elvitegravir, cobicistat,
emtricitabine and tenofovir disoproxyl will be determined and the geometric
mean ratios of the AUC0-* and Cmax of intervention I vs intervention II.

Tertiary objective:
To evaluate the safety and tolerability of co administration of elvitegravir,
cobicistat, emtricitabine and tenofovir disoproxil in healthy subjects, after
administration of whole and crushed STB.

Open-label, 3-period, randomized, cross-over, single-centre, phase-I, sin-gle
dose trial in 24 healthy volunteers.

The 24 subjects will be divided into one of the following treatment
se-quences: ABC; ACB; BCA; BAC; CAB; CBA

Treatment period:
A Standardized breakfast followed by STB (whole tablet).
B Standardized breakfast followed by crushed and suspended STB.
C 350 mL of drip feed (type) followed by crushed and suspended STB.

Between the different treatment periods a wash-out period of 7 days is
scheduled.
On the day of administration, day 1, 7 and 14, a pharmacokinetic curve is
recorded.

See study design;
3 different administrations of one tablet of Stribild.

- breakfast + whole tablet
- breakfast + crushed and suspended tablet
- drip feed + crushed and suspended tablet

This study will be performed in healthy volunteers instead of HIV-infected
patients. The study participants will not benefit from the participation in
this clinical trial.
The most common adverse events are generally transient, self-limiting and
mild-to moderate in severity. The most frequently reported adverse reactions
were nausea (16%) and diarrhea (12%) [3].
Common adverse events of STB (>= 1 to <10% of the users): neutropenia, allergic
reaction, hypophosphataemia, hyperglycaemia, hypertriglyceridaemia, decreased
appetite, insomnia, abnormal dreams, headache, dizziness, diarrhea, vomiting,
nausea, elevated amylase including elevated pancreatic amylase, elevated serum
lipase, abdominal pain, dyspepsia, constipation, abdominal distension,
flatulence, increased transaminases, hyperbilirubinaemia1,rash,vesiculobullous
rash, pustular rash, maculopapular rash, pruritus, urticaria, skin
discolouration (increased pigmentation), elevated creatine kinase, increased
blood creatinine, asthenia, pain and fatigue. See the Summary of Product
Characteristics for complete information on all adverse reactions.
Participants will visit the clinical research centre for a screening visit , 6
short visits (10 minutes) and 3 full days (13 hours). The duration of the
entire trial is 15 days. Duration of treatment with study medication is 3 days.
For pharmacokinetic purposes 45 blood samples will be taken in total. For
safety assessment (haematology and clinical chemistry), hCG bloodtest and blood
glucose a total of 12 blood samples will be collected. The total bloodvolume
taken will be approximately 423 mL. During the days that blood samples will be
collected for a pharmacokinetic curve an intravenous cannula will be inserted
to facilitate blood sampling and limit the amount of venous punctions.