Tacrolimus Formulations

Tacrolimus comes in oral, intravenous and topical formulations. Prograf is the most commonly used oral tacrolimus formulation and is dosed twice daily.

Prograf pharmacokinetics 

Absorption:
Absorption occurs in the small intestine.
Drug levels reach a maximum concentration in 1 to 2 hrs.
Tacrolimus is poorly soluble and oral bioavailability is about 11 to 20%.

Metabolism:
Cytochrome P450 3A4 metabolizes tacrolimus to at least 10 metabolites, some of which retain significant activity. Biliary excretion is the route of elimination for these tacrolimus metabolites. Gastrointestinal tract mucosal cells also contain CYP P450 3A4 activity and contribute significantly to metabolism.

Elimination:
The terminal elimination half-life of tacrolimus is approximately 12 hours. Elimination is prolonged in hepatic dysfunction.

Poor solubility, first pass metabolism, small bowel CYP450 metabolism and p-glycoprotein activity (pumps drug back into the bowel lumen) all cause reduced oral bioavailability of tacrolimus. Low oral bioavailability is a common pharmacological problem and 30% of marketed PO drugs have poor solubility defined as water solubility below 20ug/ml. An oral drug can only be absorbed once dissolved.

LCP-Tacrolimus 
LCP-Tacrolimus was designed to achieve greater bioavailability by increasing the solubility of tacrolimus. LCP is Life Cycle Pharma, a Danish company now trading as Veloxis Pharmaceuticals. This new tacrolimus formulation uses ‘Meltdose’ technology to achieve this goal. LCP Meltdose technology works by decreasing the particle size of the drug to the molecular scale thus increasing particle surface area. Increased surface area increases solubility. Tacrolimus is heated into a ‘liquid like’ state and then atomized and sprayed onto an inert particle carrier. This then solidifies in a state of ‘solid solution’ into granulates and is compressed into tablets. These granulates retain their particle sizes and dissolution characteristics. Thus, once delivered to the small bowel these very small particles of tacrolimus go into solution easily and are better absorbed.

Phase 2 trials of LCP-tacrolimus in de novo kidney transplant patients have shown a more consistent concentration profile, increased bioavailability of about 30% and reduced peak to peak and peak to trough variation compared with bid tacrolimus (Prograf).

This month in AJT
Budde et al report on a phase III study of LCP-Tacrolimus vs bid tacrolimus in de novo kidney transplants.

This was a worldwide, double blind, double-dummy, randomized study in 543 de novo kidney transplants comparing LCP-tacrolimus with Prograf (bid tacrolimus). It was designed as a non-inferiority trial with a primary endpoint of treatment failure at 12 months (death, graft failure, biopsy-proven acute rejection).

More LCPT patients were in ‘target range’ (6-11) after initial doses. Trough/dose ratio increased (reflecting better absorption) over time with LCPT and was statistically higher than Prograf. Trough levels were similar. Total daily doses were lower for LCPT at 1 and 12 months and the cumulative dose over the whole study was 14% lower for LCPT.

The overall incidence of treatment failure was 18.3% for patients in the LCPT group and 19.6% for patients in the tacrolimus twice-daily group. The treatment difference (95% CI) was −1.35% (−7.94% to +5.27%), well below the noninferiority margin of 10%.

There were no significant differences in adverse events between groups. Interestingly 97% of each group had an AE over the 12 months the most common being diarrhea, anemia, UTI, hypertension and constipation. There was a numerical trend towards more NODAT with LCPT that may be explained by higher LCPT exposure in the first 3 weeks. There was a trend towards a smaller rise in lipid abnormalities in the LCPT group.

This was a well-powered and well conducted trial. LCP-Tacrolimus is safe and as efficacious as Prograf. Cumulative doses are lower and therapeutic range was reached earlier and is more likely to remain stable. This is a promising once daily preparation, however, pricing is likely to determine whether this formulation becomes standard of care in kidney transplantation.

What about Advagraf/Astagraf?
Leonardo V Riella and colleagues from Boston posted on Astagraf and LCPT last year. 

Advagraf was approved for the European market in 2007 and the FDA approved Astagraf in 2013. Advagraf contains the same active drug, tacrolimus, as Prograf. Advagraf contains ethylcellulose, which controls water penetration and changes its dissolution properties. The drug also contains a hypromellose protective coat. Both these factors cause the active drug to be released more slowly and further along the GI tract.

In mostly industry sponsored trials Advagraf showed lower peak drug concentrations but equivalent AUC(0-24) and Cmin(trough) concentrations when compared to Prograf. Thus, a 1:1 conversion is suggested in the package insert. However, subsequent experience with Advagraft has demonstrated lower Cmin values and high inter-individual variability leading to the need for higher Advagraft dosing and difficulty with trough interpretation. Furthermore, a phase III study in de novo kidney recipients has shown higher rates of acute rejection with Advagraf, possibly explained by the differing C(max) values achieved with the two preparations. Biopsy-proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%) just outside the prespecified 10% noninferiority margin.

In Europe where this formulation has been approved since 2007 use of the drug is still minimal. It will remain to be seen whether the same trend occurs in the US. Experiences so far make it unlikely that this formulation will become first line therapy in kidney transplantation.