Tacrolimus: a Case Study
Tacrolimus is an immunosuppressant drug that could benefit from improving and stabilizing its bioavailability and pharmacokinetics. The medication is used after organ transplant to prevent organ rejection, and it has been shown to provide a more favorable short-term clinical outcome and a lower incidence of rejection when compared to cyclosporine. Tacrolimus is the most commonly prescribed branded immunosuppressant on the market, with a 90% patient share.
Tacrolimus does, however, present several challenges. It is difficult to control the amount of drug present in the blood. Patients must frequently check their blood levels and have their dose adjusted accordingly. If the levels are too high, there is a higher probability of side effects occurring, including high blood pressure, diabetes, nephrotoxicity, and neuropsychiatric symptoms. If the levels are too low, there is an increased risk of organ rejection.
Tacrolimus is dosed twice daily. There is a wide peak-to-trough range in blood levels with particularly high levels after the morning dose. The morning peak blood levels rise above the therapeutic range, and these blood levels may be associated with side effects.
Tacrolimus is a multisource drug, and current regulations dictate that blood concentrations of generic versions can range from 80% to 125% of the brand (Prograf®). Maintaining patients in the therapeutic range is already a challenge; drugs from multiple manufacturers can add to that burden, both for the patient and for their physicians when the patient is switched between differently sourced products.
Physician concern over this issue is significant and is demonstrated by a brand market share of 45% despite generic availability for several years. Therefore, tacrolimus is a drug that could benefit by improving its performance.
A once-daily formulation of tacrolimus, called LCP-Tacro™, is in Phase III development in the U.S. and Europe. It may offer a potential solution to the challenges of managing patients on tacrolimus. The formulation technology, called controlled agglomeration (MeltDose®), modifies active pharmaceutical compounds in a way that can improve bioavailability and modify its pharmacokinetics.
The process takes a drug with low water-solubility, such as tacrolimus, and incorporates it into a “meltable” vehicle by using fluid bed equipment to spray it on an inert particulate carrier. This solidifies the melt, and the result is an active drug captured in a solid dispersion, either in a nanocrystalline state or as a solid solution.
The particle size can then be increased by controlling and optimizing the product temperature and feed rate of the melt. The granulate can then be compressed into tablets for oral administration.
The most evident improvement in performance is that the bioavailability of LCP-Tacro remains more stable throughout the day from time of dosing, particularly when compared to twice-daily dosing of tacrolimus.
The pharmacokinetic profile of LCP-Tacro remains relatively flat with a peak-to-trough range that remains in the therapeutic window of ~6 to ~11 ng/mL.
Improving old drug formulas holds promise as a business model, but it is vital to improve them in a fashion that adds value to the new drug. Incremental changes may no longer be enough to pass muster with payors and health professionals. An ideal improvement will incorporate meaningful beneficial changes, resulting in a drug that is needed and differentiated in the market.