Ihor Bekersky

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected with Aspergillus Species and Other Filamentous Fungi: Maximum Tolerated Dose Study

ABSTRACT We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (Cmax) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 μg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC24) changed to 692, 1,062, 860, and 554 μg · h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of ≥7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

Tacrolimus oral bioavailability doubles with coadministration of ketoconazole.

To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P‐glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P‐glycoprotein.

Pharmacokinetics, Excretion, and Mass Balance of Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate in Humans

ABSTRACT The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h. The concentrations of AMB were determined by liquid chromatography tandem mass spectrometry (plasma, urine, feces) or high-performance liquid chromatography (HPLC) (plasma). Infusion-related side effects similar to those reported in patients, including nausea and back pain, were observed in both groups. Both formulations had triphasic plasma profiles with long terminal half-lives (liposomal AMB, 152 ± 116 h; AMB-DOC, 127 ± 30 h), but plasma concentrations were higher (P < 0.01) after administration of liposomal AMB (maximum concentration of drug in serum [Cmax], 22.9 ± 10 μg/ml) than those of AMB-DOC (Cmax, 1.4 ± 0.2 μg/ml). Liposomal AMB had a central compartment volume close to that of plasma (50 ± 19 ml/kg) and a volume of distribution at steady state (Vss) (774 ± 550 ml/kg) smaller than the Vss of AMB-DOC (1,807 ± 239 ml/kg) (P < 0.01). Total clearances were similar (approximately 10 ml hr−1 kg−1), but renal and fecal clearances of liposomal AMB were 10-fold lower than those of AMB-DOC (P < 0.01). Two-thirds of the AMB-DOC was excreted unchanged in the urine (20.6%) and feces (42.5%) with >90% accounted for in mass balance calculations at 1 week, suggesting that metabolism plays at most a minor role in AMB elimination. In contrast, <10% of the liposomal AMB was excreted unchanged. No metabolites were observed by HPLC or mass spectrometry. In comparison to AMB-DOC, liposomal AMB produced higher plasma exposures and lower volumes of distribution and markedly decreased the excretion of unchanged drug in urine and feces. Thus, liposomal AMB significantly alters the excretion and mass balance of AMB. The ability of liposomes to sequester drugs in circulating liposomes and within deep tissue compartments may account for these differences.

Comparative Antifungal Activities and Plasma Pharmacokinetics of Micafungin (FK463) against Disseminated Candidiasis and Invasive Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

ABSTRACT Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

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.

The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups.

Our objective was to compare the intravenous and oral pharmacokinetics of tacrolimus among subjects of three different ethnic backgrounds, African American, white, and Latin American.

Pharmacokinetics of Micafungin in Healthy Volunteers, Volunteers With Moderate Liver Disease, and Volunteers With Renal Dysfunction

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol‐O‐methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance <30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single‐dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration‐time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 ± 19 μg•h/mL vs 125.9 ± 26.4 μg•h/mL, P = .03), although there was no difference in micafungin weight‐adjusted clearance (10.9 ± 1.7 mL/h/kg vs 9.8 ± 1.8 mL/h/kg, P = .2). The difference in area under the concentration‐time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Compartmental Pharmacokinetics and Tissue Distribution of the Antifungal Echinocandin Lipopeptide Micafungin (FK463) in Rabbits

ABSTRACT The plasma pharmacokinetics and tissue distribution of the novel antifungal echinocandin-like lipopeptide micafungin (FK463) were investigated in healthy rabbits. Cohorts of three animals each received micafungin at 0.5, 1, and 2 mg/kg of body weight intravenously once daily for a total of 8 days. Serial plasma samples were collected on days 1 and 7, and tissue samples were obtained 30 min after the eighth dose. Drug concentrations were determined by validated high-performance liquid chromatographic methods. Plasma drug concentration data were fit to a two-compartment pharmacokinetic model, and pharmacokinetic parameters were estimated using weighted nonlinear least-square regression analysis. Micafungin demonstrated linear plasma pharmacokinetics without changes in total clearance and dose-normalized area under the concentration-time curve from 0 h to infinity. After administration of single doses to the rabbits, mean peak plasma drug concentrations ranged from 7.62 μg/ml at 0.5 mg/kg to 16.8 μg/ml at 2 mg/kg, the area under the concentration-time curve from 0 to 24 h ranged from 5.66 to 21.79 μg · h/ml, the apparent volume of distribution at steady state ranged from 0.296 to 0.343 liter/kg, and the elimination half-life ranged from 2.97 to 3.20 h, respectively. No significant changes in pharmacokinetic parameters and no accumulation was noted after multiple dosing. Mean tissue micafungin concentrations 30 min after the last of eight daily doses were highest in the lung (2.26 to 11.76 μg/g), liver (2.05 to 8.82 μg/g), spleen (1.87 to 9.05 μg/g), and kidney (1.40 to 6.12 μg/g). While micafungin was not detectable in cerebrospinal fluid, the concentration in brain tissue ranged from 0.08 to 0.18 μg/g. These findings indicate linear disposition of micafungin at dosages of 0.5 to 2 mg/kg and achievement of potentially therapeutic drug concentrations in plasma and tissues that are common sites of invasive fungal infections.

Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A‐mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single‐dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645 ± 236 mL/h/kg, 546 ± 101 mL/h/kg (P = .01), and 540 ± 104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

Concomitant Tacrolimus and Micafungin Pharmacokinetics in Healthy Volunteers

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n = 26). Tacrolimus area under the concentration‐time curve was 298 ± 135 μg•h/L when tacrolimus was administered alone, 305 ± 129 μg•h/L (P = .8; confidence interval 89%, 118%) when tacrolimus was given with single‐dose micafungin, and 282 ± 138 μg•h/L (P = .4; confidence interval 82%, 107%) when tacrolimus was given with steady‐state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single‐dose or steady‐state micafungin administration.