By Ralph Tarantino, PhD
Pharmaceutical Consultant and Principal, SteriTech Solutions, LLCMiddletown, NJ
The FDA’s most recent response to the anti-cancer drug shortage crisis may be a perfect example of “too little, too late.” What follows will not be a rant about offshore outsourcing or the regulatory climate in general. However, the FDA decision (See FDA’s Press Release regarding shortages of anti-cancer drugs here) to allow Sun Pharma’s version of Doxil (doxorubicin HCl liposome injection) into the United States to replace the approved Ben Venue product may be a dangerous one for patients with ovarian cancer.
Significant differences in safety and efficacy are rarely achieved by formulation manipulation alone; however, Doxil is one of the few exceptions. Doxil is liposomally entrapped doxorubicin, truly a drug delivery system. An idealized view of liposomal entrapment in a single layer (unilamellar) liposome can be seen below:
In actuality, liposomes may consist of single or multiple (multilamellar) bilayers and drug maybe entrapped within these layers or within the central core as depicted above. This fact alone can alter the performance of a liposomal formulation. In addition, liposomal entrapment alters drug biodistribution. Drugs entrapped in liposomes preferentially distribute in tissues with relatively porous capillary beds. (Click here to see Working, PK et al. J Liposome Res.1994;4(1):667) In the case of doxorubicin, liposome entrapment favors distribution to tumors rather than cardiac tissue, hence the therapeutic index of the drug is significantly enhanced.
Cardiotoxicity is the key safety issue with doxorubicin. The particle size, the type and qualities of lipids used, the percentage of drug entrapped, and the stability of the liposomes as a function of time are all critical factors in achieving a consistent result. It is a complex system—not your typical isotonic pH 7.4 infusion.
I realize we are dealing with patients with a serious illness and that oncologists must make difficult risk-to-benefit decisions every day, but the FDA seems to be going way out on a limb suggesting replacement of Doxil with Sun Pharma’s product. There is a black box warning in the approved Doxil labeling, and one of the cautions included in the warning is the risk of replacing the product with doxorubicin hydrochloride, which is free or un-entrapped doxorubicin. (See Doxil product information here.) Free doxorubicin is precisely what you would find in formulations in which 100% entrapment was not achieved. Although 100% entrapment is a rarity, the percent-free doxorubicin should remain consistent throughout the shelf life of a liposomal product. If not, then dosing would become a nightmare and in this case, toxicity a real issue.
Do we know that Sun Pharma’s product achieves the same entrapment percentage as Ben Venue’s Doxil? Or that this percentage remains constant throughout its shelf life? Perhaps the FDA has done their due diligence with the Sun Pharma product, and if you have seen comparative data please let me know. But I would also like to hear from the clinicians out there.
Is this an acceptable risk for these patients? Someone may have dropped the ball here. Is this stopgap measure for the shortage of Doxil the correct one for your patients?