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Abstract
Raltegravir and lamivudine have been part of highly active therapy regimens throughout the past years of antiretroviral therapy. A fixed-dose, single-tablet regimen comprising a non-poloxamer formulation of the integrase inhibitor raltegravir and the transcriptase inhibitor lamivudine (raltegravir/lamivudine; Dutrebis®) has been recently licensed for the treatment of HIV-1 infection. In several Phase I pharmacokinetic studies, one Dutrebis (150 mg lamivudine/300 mg raltegravir) fixed-dose combination tablet showed a higher bioavailability but comparable lamivudine and 400 mg raltegravir poloxamer exposures. Thus, the co-administration of raltegravir together with lamivudine created a potent, effective, well-tolerated antiretroviral combination, which could be more convenient for the patient. However, the disadvantage of twice a day administration, and the existence of other fixed-dose combinations limit its widespread clinical use. This article reviews pharmacokinetics data and appraises their potential use in current and future HIV therapy.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
The transcriptase inhibitor lamivudine and the integrase inhibitor raltegravir (RAL) have high tolerability and long-term safety profiles, and their efficacy in combination has been demonstrated in several clinical studies.
Dutrebis®, a fixed-dose, single-tablet regimen comprising a new, non-poloxamer formulation of RAL, and lamivudine (300 mg/150 mg) have been recently evaluated with the objective of developing an immediate release orally available formulation that offers equivalent or better pharmacokinetic properties to the equivalent individual products.
The pharmacokinetic characteristics of Dutrebis fixed-dose combination (FDC) tablet have been evaluated in eight Phase I studies in healthy volunteers (445 subjects; 217 males and 228 females), showing a faster absorption and higher bioavailability of the RAL component of Dutrebis in the fasted state, which permit the reduction of dose. Of note, once absorbed, lamivudine and RAL distribution, metabolism, and excretion are similar to those of the reference components administered individually.
Although there are no clinical Phase II/III studies evaluating the efficacy of Dutrebis FDC in HIV-1 infected patients, a PK/PD viral dynamic model simulating long-term efficacy met the non-inferiority for RAL in the FDC.
Adverse events were rare in Phase I studies: nine subjects discontinued due to an adverse event, but only four were considered to be related to study drug (three rash due to etravirine; one due to vomiting).
The benefits with Dutrebis are the improvement of the dosing regimen by reducing the daily pill burden, with similar efficacy to the individual agents. However, this formulation continues to have the disadvantage of twice a day administration, and once-daily FDC of different antiretroviral drugs are already available.
In hypothesis, Dutrebis could be an option to reinforce dual therapies by adding lamivudine without increasing the number of pills, or it could provide clinicians with a well-tolerated, potent drug for the salvage regimen, avoiding the use of other potentially toxic nucleoside reverse transcriptase inhibitors.