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Feb 15, 2012 (Vol. 32, No. 4)

Reformulations Must Provide Added Value

Novel Drugs Must Really Improve on the Original; Dosing Convenience Alone Is Not Enough

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    William Polvino, M.D.

    Reformulating currently marketed pharmaceuticals is a common way to both improve drug performance and manage the life cycle of a brand. In the past, it was often sufficient for commercial success to develop only a more convenient dosing regimen, such as once-daily oral dosing from twice-daily oral dosing.

    In today’s environment of constrained resources and rigorous formulary reviews, however, these new drugs must improve on the original beyond only dosing convenience. They should provide a new formulation that can improve bioavailability, pharmacokinetics, and/or route of administration with the goal of improving safety and/or efficacy for its intended use.

    Beyond these hurdles, new formulations must have a clear path to approval. Finally, the new formulation must undergo a detailed analysis of its market position as even with additional product benefits, its market success is not assured.

    There are a number of marketed pharmaceuticals that could benefit from profile improvement. Physicians and patients must deal with one or more challenges with these agents.

    Examples of such challenges include narrow therapeutic indices, altered gastrointestinal absorption caused by the presence of food in the stomach (the so-called “food effect”), administration limited to intravenous or subcutaneous routes due to low or nonexistent oral bioavailability, and poor pharmacokinetics, such as short half-lives requiring multiple daily administrations or wide peak-to-trough blood levels that could put the drug outside of its optimal therapeutic range.

    Attempts have been made to significantly improve pharmaceutical profiles. A recent example has been the efforts to convert administration of short-acting insulin from subcutaneous administration to inhaled administration. It illustrates what appear to be obvious improvements but also highlights regulatory and patient/physician acceptance challenges that can emerge.

    The goal was to improve patient compliance by making the drugs easier to administer. The drug faced regulatory challenges and was eventually approved long after initial projections. Despite the perceived improved dosing convenience, market penetration was minimal. The formulation was withdrawn from the U.S. market a little over one year following its launch.

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    MeltDose modifies active pharmaceutical compounds in a way that can improve bioavailability and modify its pharmacokinetics. (A) Drug solubilized: The drug is dissolved in a “meltable” system of GI-friendly GRAS excipients.
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    (B) Sprayed on carrier particles: In a conventional fluid bed granulator, the drug is sprayed onto an inert carrier particle.
  • Tacrolimus: a Case Study

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    (C) Controlled agglomeration: A well-defined granulate is generated by controlling and optimizing temperature and feed rate. The granulate is then compressed into tablets.

    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.


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