Garry W. Boswell

AmBisome (liposomal amphotericin B): a comparative review.

AmBisome (NeXstar Pharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid‐complexed amphotericin B formulations, with greatly increased area under the plasma concentration—time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs

AbstractPurpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisomes non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18−94 µg/mL.

Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome®): A 91-day study in rats

AbstractPurpose. Amphotericin B in small, unilamellar liposomes (AmBisome) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures, the potential for drug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods. Rats (174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg), dextrose, or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] ≤51 mg/dl; creatinine unchanged). Liposome-related changes (vacuolated macrophages and hypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma; kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation, AmBisome revealed predictable hepatic and renal toxicities after 91 days, with no new or delayed effects after prolonged treatment at high doses that resulted in plasma levels >200 μg/ml and tissue levels >3000 μg/g.

Coadministration of Tacrolimus and Mycophenolate Mofetil in Stable Kidney Transplant Patients: Pharmacokinetics and Tolerability

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long‐term tacrolimus‐based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12‐hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12‐hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra‐ and intergroup PK of T were variable. The mean AUC0–12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.

Pharmacokinetics of cefoxitin in patients at term gestation: Lavage versus intravenous administration

Despite the increasing popularity of antibiotic prophylaxis to reduce febrile morbidity in patients who undergo cesarean delivery, little is known of the pharmacokinetics of antibiotics in the patient at term gestation. This study was designed to elucidate the pharmacokinetics of cefoxitin when administered intravenously or by uterine and peritoneal lavage at cesarean section. Significant differences were found in the values for total body clearance area under the serum concentration-time curve (AUC), and K21 of cefoxitin administered intravenously to pregnant patients at term gestation compared to values for these parameters observed in nonpregnant patients. The concentration of cefoxitin in decidual tissue after uterine and peritoneal lavage with the antibiotic was 92.5 +/- 10.1 micrograms/gm (mean +/- SEM), whereas the concentration of cefoxitin in decidual tissue after intravenous administration of the antibiotic was 36.9 +/- 10.5 micrograms/gm (mean +/- SEM). This difference is statistically significant (p less than 0.05). We conclude that the pharmacokinetics of cefoxitin are altered in the pregnant patient as evidenced by the increased rapidity of clearance of the antibiotic (total body clearance for cefoxitin in pregnant patients, 20.41 L/hr). Moreover, uterine and peritoneal lavage results in significant tissue concentrations of antibiotic, which is of potential importance since the decidua is a presumed site of initiation of bacterial infection after cesarean section.

Topical Application of Tacrolimus Ointment Did Not Alter the Cutaneous Pigmentation of Yucatan Micropigs

Tacrolimus is a potent immunosuppressant marketed for the prevention of rejection in liver and kidney transplantation. Topical tacrolimus has been shown to be effective in the treatment of atopic dermatitis, a disease with an immunologic basis, and is currently being developed for this indication. The objective of the current study was to determine whether repeated topical application of tacrolimus ointment could result in hypopigmentation at the application site(s). Each of 10 Yucatan miniature pigs received topical application of 0.03%, 0.1%, and 0.3% tacrolimus ointment, positive control (a combination of 2% 4-hydroxyanisole and 0.01% all-trans-retinoic acid, 4-HAArRA), and a negative control (vehicle placebo) to five test sites (approximately 12.5 cm2) along either side of the dorsal midline (10 sites per animal). Tacrolimus and controls were randomly assigned to the test site on each animal and were applied unoccluded twice daily for 8 weeks at a dose volume of 0.1 ml per site for tacrolimus and vehicle control and 0.025 ml per site for the positive control. Topical application of tacrolimus ointment in concentrations of up to 0.3% for 8 weeks had no effect on the cutaneous pigmentation of Yucatan miniature swine. In contrast, the application of 4-HAArRA produced a statistically significant (P<.05) induction of hypopigmentation from week 4 through the end of the study application.

Exogenous Methemoglobin as a Cyanide Antidote in Rats

The effects of the administration of methemoglobin (MetHb) prepared in vitro were evaluated in Sprague–Dawley rats given increasing doses of potassium cyanide (KCN). Median lethal dose (LD50) studies were conducted by giving intraperitoneal injections of KCN (in 0.3- to 0.5-ml volumes), then 2 min later administering intravenous (iv) doses of 1000, 1500, or 2500 mg/kg of MetHb through the tail vein. Control rats received an equivalent volume of saline. The resulting LD50 values for KCN were 7.4 ± 1.1, 11.7 ± 1.1, 13.9 ± 1.0, and 14.2 ± 1.0 mg/kg (mean ± SD) for the control (no MetHb) and 1000-, 1500-, and 2500-mg/kg dose groups, respectively. Additional groups of rats were given 1000, 1500, or 2500 mg/kg MetHb and submitted for necropsy. The gross finding of darkened kidneys was present in both dose groups, but became consistent and more prominent in the 2500-mg/kg dose group. Evidence of pathologic changes was not present in other organs. Single-dose pharmacokinetic studies were conducted using iv doses of 1600 and 2500 mg/kg MetHb. The elimination half-life was similar in both doses (62.6 min), but the volume of distribution (95.3 ± 7.2 and 126.3 ± 5.2 ml/kg, mean ± SE) and clearance (1.1 ± 0.1 and 1.5 ± 0.1 ml/min/kg) were significantly different (P < 0.05) for the 1600-and 2500-mg/kg dose groups, respectively. From these data we conclude that although MetHb is cleared from the vascular system rapidly, it may be an effective and nontoxic antidote for doses of cyanide up to twice that of the control LD50.