 |
The dose-dependent toxicity of conventional AmB is the rationale for the development of lipid-based formulations [71]. By encapsulating AmB into liposomal vesicles or binding it to other lipid carriers, it is hoped that a significant reduction of toxicity and possibly an increased therapeutic index of the drug will be achieved. These new agents aim to improve the therapeutic ratio with a higher concentration of drug reaching target tissue, such as lung, liver, and spleen, and with lower concentrations of the drug in the kidney.
Three lipid formulations of amphotericin B (LFAB) are now licensed and marketed in the US:
- Amphotericin B lipid complex — ABLC
- Amphotericin B colloidal dispersion
— ABCD
- Liposomal amphotericin B
These 3 formulations differ significantly in composition and pharmacokinetics. Amphotericin B serum levels, after administration of ABLC and ABCD, are relatively low when compared with liposomal amphotericin B. A much higher dose (3 to 6 mg/kg/day) of all the lipid formulations must be administered for therapeutic efficacy, although there are limited data on optimal therapeutic dosages. The therapeutic index is much wider than that of AmB and toxicity is less likely even at these higher doses administered for prolonged periods. All of the preparations appear to be preferentially accumulated in organs of the reticuloendothelial system, as opposed to the kidney, and have considerably reduced nephrotoxicity.
Approved indications are for patients who have systemic mycoses, primarily invasive aspergillosis, and who are intolerant of, or their disease is refractory to, conventional AmB. In addition, liposomal amphotericin B is approved as empiric therapy for the neutropenic patient who has persistent fever despite broad-spectrum antibiotic therapy.
Clinical Experience
All 3 agents have been used to treat adult and pediatric patients with confirmed or presumed fungal infections intolerant of or refractory to conventional amphotericin B deoxycholate [72 -79]. Liposomal amphotericin B has also been used as empirical antifungal therapy in febrile neutropenic patients [80-84].
The lipid-based products have demonstrated equivalent efficacy when prospectively compared with conventional AmB in the treatment of presumed or documented infections [76, 77, 79] and empirical treatment of febrile neutropenia [73, 80-82, 85]. In preventing proven emergent fungal infections, liposomal amphotericin B was superior to AmB; however, the short-term survival rate was not improved [83]. The impact of prior fluconazole prophylaxis on the results of empirical antifungal therapy was not assessed in this and similar published studies and remains an important need.
Published reports to date support the contention that lipid formulations are better tolerated than conventional amphotericin B. Nephrotoxicity is less common with all 3 lipid formulations of amphotericin B than with conventional AmB. However, the degree of tolerance varies among the 3 formulations [80, 82-84]. All 3 have been evaluated in clinical trials, usually at doses 1-5 mg/kg of body weight per day. A recent randomized controlled trial compared efficacy and toxicity between liposomal amphotericin B and amphotericin B lipid complex [84]. Febrile neutropenic patients were randomized to receive either liposomal amphotericin B 3 mg/kg/day or 5 mg/kg/day, or ABLC 5 mg/kg/day for the empiric treatment of suspected fungal infection. The incidence of nephrotoxicity defined as a doubling of serum creatinine level over baseline was significantly lower in both liposomal amphotericin groups than in the amphotericin B lipid complex group (liposomal AmB 3 mg/kg/day 14%; 5 mg/kg/day 15%; ABLC 42%) [84].
The incidence of infusion-related adverse events (IRAEs) varies among the 3 lipid formulations [74]. Estimates are imprecise due to lack of comparability of dosing, variability in administration of premedications prior to dosing, and little standardization of definitions of adverse events. However, infusion-related reactions with amphotericin B colloidal dispersion and amphotericin B lipid complex appear to be considerably more common than those associated with liposomal amphotericin B, and similar in frequency to infusion-related events associated with conventional AmB [72, 76, 77, 80, 83, 84, 86]. One prospective randomized trial reported a higher incidence of IRAEs with ABCD compared to conventional AmB [80]. In 2 randomized controlled trials in febrile neutropenic patients, liposomal amphotericin B-treated patients experienced significantly fewer infusion-related reactions compared to those treated with conventional amphotericin B (chills, 18% versus 54% of patients; fever 17% versus 44%) [83] or those treated with ABLC (chills, 21% versus 79% of patients; and fever, 22% versus 58%) [84].
The lipid formulations are considerably more expensive than conventional AmB, ranging from 10- to 20-fold higher costs per dose; the pharmacoeconomics of liposomal versus conventional therapy in febrile neutropenic cancer patients was recently reported [87].
Course Number: V035B.043001
This CME Expires on July 1, 2003; no tests will be accepted after this date.
This course is accredited by
The University of Pittsburgh School of Medicine, Center for Continuing Education
|
|
