Dear editor
The review by Posadas Salas and Srinivas of the clinical utility of once-daily tacrolimus
formulations in the management of transplant patients1 was timely and relevant. It
is worth noting, however, the data were presented in a way that overlooked several
key differences between two distinct once-daily tacrolimus formulations. These formulations
differ in bioavailability, Cmax, Tmax, dose required to achieve target trough levels,
and time to reach target trough. The specific formulation and dosing information of
one product was detailed in this review (described as modified release 4 [MR-4]; Astagraf®,
Astellas Pharma Inc., Tokyo, Japan), but no formulation or dosing details were provided
for a very different once-daily tacrolimus formulation (LCP-Tacro™; Veloxis Pharmaceuticals
A/S, Hørsholm, Denmark) for which a thorough review was recently published.2 The latter
product is currently approved in Europe and under review by the US Food and Drug Administration
in the US. In presenting data in this review, the authors did not identify which product
was investigated in each of the studies discussed. This could easily lead to misinterpretation
of results or erroneous conclusions, ie, that both once-daily formulations are the
same. In fact, a careful parsing of the data clearly demonstrates that they are not
equivalent. Misunderstanding of this point could have a potentially serious impact
on appropriate dosing, safety, and patient management in the post-transplant setting.
Differentiation between the two products is needed to clarify what appear to be conflicting
results of the studies presented in this review.
LCP-Tacro
To date, two Phase III non-inferiority studies have been published evaluating the
efficacy of LCP-Tacro in kidney transplant recipients.3,4 The first was an open-label,
randomized trial evaluating conversion from twice-daily to once-daily LCP-Tacro in
stable kidney transplant recipients and was detailed thoroughly by Posadas Salas and
Srinivas.3 The second, a double-blind, double-dummy, randomized, non-inferiority trial
of LCP-Tacro versus twice-daily tacrolimus in 543 de novo kidney transplant recipients,
was not included in this review.4 The results of the 324-patient conversion trial
and 543-patient de novo trial each individually demonstrated non-inferiority of once-daily
LCP-Tacro to twice-daily tacrolimus with identical or lower rates of treatment failure.3,4
These trial results stand in direct opposition to data from trials that evaluated
the alternative once-daily formulation (MR-4) in which rates of biopsy-proven acute
rejection (BPAR), or treated rejection, were increased, in some cases significantly
so.5–7 In one of these studies, the MR-4 formulation of once-daily tacrolimus failed
to demonstrate non-inferiority.5
Posadas Salas and Srinivas report results of a study that demonstrated rejection episodes
requiring anti-lymphocyte therapy were more commonly seen among de novo kidney transplant
patients treated with the MR-4 once-daily formulation of tacrolimus compared to twice-daily
tacrolimus. They go on to note that about one-third of patients who received MR-4
had trough levels below target during the early post-transplant period (day 3 post-transplant).
While the difference in rejection rate did not reach statistical significance, the
authors note a trend toward higher mean tacrolimus levels in the twice-daily tacrolimus
group who did not experience BPAR compared to those who developed BPAR. These data
stand in contrast to data not presented by Posadas Salas and Srinivas, which demonstrate
that in de novo kidney transplant patients treated with the LCP-Tacro once-daily formulation,
therapeutic tacrolimus concentrations were achieved rapidly – with 66.5% of patients
having a serum tacrolimus trough concentration of at least 6 ng/mL 24 hours after
their first dose of LCP-Tacro.8 LCP-Tacro-treated patients in this study experienced
similar, though numerically lower, rates of BPAR compared to twice-daily tacrolimus
at both 1 year and 2 years post-transplant.
Furthermore, pharmacokinetic (PK) differences are noteworthy between the two once-daily
tacrolimus formulations. In contrast to data demonstrating the need for potentially
higher total daily doses of tacrolimus when the MR-4 formulation is used,5,9 LCP-Tacro
has consistently demonstrated greater bioavailability and significantly lower total
daily dose requirements compared with twice-daily tacrolimus (Prograf®, Astellas Pharma
Inc.) in kidney and liver recipients and in both the de novo and conversion settings.8,10–12
The Phase II study of 47 stable kidney transplant patients cited by Posadas Salas
and Srinivas, reporting a 30% lower daily dosing requirement, evaluated the PK of
LCP-Tacro after conversion from twice-daily tacrolimus,11 and cannot be extrapolated
to the MR-4 formulation.10 Results of this study, as summarized in the review, were
that patients taking LCP-Tacro had similar overall tacrolimus exposure (area under
the curve) but with significantly lower Cmax (P,0.0001), delayed Tmax (1.8 hours for
twice-daily versus 6 hours for LCP-Tacro, P=0.0001), lower peak-trough ratios (P<0.0001
on day 14, P=0.0004 on day 21), and less fluctuation (P<0.0001) compared with twice-daily
tacrolimus.10
Based on the PK data presented in this response, the greater bioavailability and lower
dose requirement are clinically relevant PK differences of the LCP-Tacro formulation
compared with MR-4. The authors put forth the message that the PK profiles of once-
and twice-daily tacrolimus suggest bioequivalence, yet available data for LCP-Tacro
do not support this claim versus twice-daily or the MR-4 once-daily tacrolimus formulations.
While no direct Phase III data comparing the two once-daily formulations have been
published, Phase I data in healthy volunteers demonstrate that LCP-Tacro was 50% more
orally bioavailable compared to the MR-4 once-daily formulation.13 This difference
could result in significantly different dose requirements and conversion factors,
and it is vital for clinicians to understand these important differences to ensure
safe use of these unique once-daily formulations of tacrolimus.
Conclusion
Without clarity on the specific once-daily tacrolimus formulation evaluated in each
of the trials discussed in the review by Posadas Salas and Srinivas, it is difficult
to reconcile potentially conflicting data.
A more complete review of the data regarding once-daily formulations clearly shows
important differences between the MR-4 and LCP-Tacro once-daily tacrolimus formulations.
These differences may have important clinical implications when selecting a once-daily
tacrolimus to manage immunosuppression in transplant recipients.