Population pharmacokinetics and renal function-sparing effects of amphotericin B colloidal dispersion in patients receiving bone marrow transplants

Abstract

The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventyfive patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had >30% increases in creatinine clearance, whereas 13 had >30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.Patients undergoing bone marrow transplant procedures receive a plethora of immunosuppressive agents. These patients are vulnerable to infections with a number of opportunistic organisms, including fungi. In a recent review of over 1,500 patients undergoing bone marrow transplants, the incidence of invasive candidiasis was 11% and that of invasive aspergillosis was 4.5%, with mortalities of 73 and 84%, respectively (22).Amphotericin B (AmB), a polyene antibiotic that is available as a deoxycholate micellar dispersion (DAmB), has been the mainstay of systemic antifungal therapy for almost 4 decades. Its antifungal activity is due to its affinity for sterols (ergosterols) found in the membranes of fungal cells. However, its undesirable binding to host cell sterols is believed to account for its various toxicities, which include nausea, vomiting, chills, fever, anemia, and thrombophlebitis (14,21,27). The primary dose-limiting toxicity of AmB is nephrotoxicity, which occurs in up to 80% of patients receiving cumulative doses of 4 to 5 g. Consequently, the cumulative amount of AmB that can be administered to patients and the duration of treatment are limited (12, 15). The potential for nephrotoxicity poses a therapeutic challenge for bone marrow transplant recipients, for whom long-term therapy with DAmB for the treatment of systemic suspected or documented fungal disease is generally required. Furthermore, many of these patients are receiving other nephrotoxic drugs...

Update on antifungal agents for paediatric patients

“…The available pharmacokinetic and safety data for the lipid formulations of amphotericin B in paediatric age groups indicate no fundamental differences relative to the adult population [4,[10][11][12][13][14][15][16][17][18][19][20][21] (48th ICAAC, Abstract A-005, Walsh T, 2008) ( Table 1). Taken together, the lipid formulations have less renal toxicity as defined by development of azotaemia than conventional amphotericin B; distal tubular toxicity also may be somewhat reduced.…”

Antifungal Therapy in Pediatric Patients

“…There were no fundamental differences in the plasma pharmacokinetics of immunocompromised children less than 13 years of age who received the compound at 7.0 and 7.5 mg/kg per day relative to a dose-matched cohort of adult patients [6]. In the safety summary of five open-label phase II trials with pediatric enrollment, 80% of patients receiving ABCD reported some adverse symptoms; most of them were infusion-related, whereas nephrotoxicity was reported in only 12%, significantly less often than with DAMB [7].…”

“…Explorative pharmacokinetic studies of ABLC in pediatric cancer patients (mean age, 10 years; range, 4-17 years) who received the compound at 2.5 mg/kg over 6 weeks for hepatosplenic candidiasis have demonstrated no differences versus adults [6,8,9]. Similarly, a population pharmacokinetic study in 28 mostly immature infants (median weight, 1.06 kg; range, 0.48-4.9 kg; median gestational age, 27 weeks; range, 24-41 weeks) with invasive Candida infections revealed that the disposition of ABLC in this population is similar to that in older age groups, and weight was the only factor that influenced clearance [10].…”

Pediatric pharmacology of antifungal agents

“…Compartmental pharmacokinetic analyses of a few immunocompromised children younger than age 13 years who received the compound at 7.0 and 7.5 mg/kg/d revealed no fundamental differences in plasma pharmacokinetics as compared with a dose-matched cohort of adult patients [10]. Safety data of approximately 100 pediatric patients enrolled in a prospective, randomized trial comparing ABCD with DAMB showed significantly less renal toxicity in children receiving ABCD than in those receiving DAMB (12.0% vs 52.4%; P = 0.003); other adverse symptoms were not significantly different.…”