Bioequivalence Study of CRushed TriUMeq With or Without Drip Feed Compared to the Whole Tablet
Condition: HIV
MeSH terms: Crush Injuries
Study type: Interventional
Phase: Phase 1

Summary: 
      Dolutegravir is an HIV-1 integrase inhibitor which is marketed as a single tablet (Tivicay®)
      and in a fixed dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as
      TRI). For patients with swallowing difficulties, administration of whole tablets can be
      problematic and tablets are cut or crushed to ease administration.

      Currently there is no information about crushing TRI tablets. Therefore this study will be
      conducted to investigate whether crushed and suspended TRI and crushed and suspended TRI with
      drip feed are bioequivalent to taking TRI as a whole.
    

Detailed description: 
      Dolutegravir is an HIV-1 integrase inhibitor which is marketed as a single tablet (Tivicay®)
      and in a fixed dose combination tablet with abacavir and lamivudine (Triumeq®, referred to as
      TRI). 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 opportunistic 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 TRI through a different route,
      like a feeding tube. If TRI 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 TRI tablets. 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 crushing of tablets as low
      concentrations are associated with virologic failure. Therefore higher doses or switching to
      other HIV-drugs 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 DTG plasma concentration is influenced by food, with higher AUC en
      Cmax after a high-fat meal compared to administration in a fasted state. During clinical
      development, however, dolutegravir intake was studied without regard to food intake.
      Therefore, it is recommended that dolutegravir can be taken with or without food.

      In addition, it has been shown that simultaneous oral ingestion of antacids and dolutegravir
      gives a decrease in Cmax and AUC of dolutegravir. This interaction is not shown for
      co-ingestion with omeprazole, which makes it unlikely that this interaction is caused by a
      pH-lowering effect influencing the absorption of dolutegravir. It is probably a local
      gastrointestinal complexation phenomenon, similar to what has been observed with other HIV
      integrase inhibitors. A possible pharmacokinetic interaction between dolutegravir and
      complexation formers may be expected. Especially considering the active binding sites of
      dolutegravir which bind magnesium metal ion cofactors. It is currently unclear if certain
      foods or liquids containing high amounts of magnesium or other cations, like drip feed, can
      cause this same interaction.

      Therefore this study will be conducted to investigate whether crushed and suspended TRI and
      crushed and suspended TRI with drip feed are bioequivalent to taking TRI as a whole.
    

Intervention name(s): Triumeq; Triumeq crushed + breakfast; Triumeq crushed + drip feed
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Single-dose Triumeq as a whole tablet; Single-dose crushed and suspended tablet of Triumeq; Drip feed followed by single-dose crushed and suspended tablet of Triumeq
Intervention MeSH terms: Abacavir, dolutegravir, and lamivudine drug combination; Lamivudine; Abacavir; Dolutegravir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Triumeq; Pharmacokinetics; Crushing; Drip feed