Martin Stogniew

Anidulafungin Does Not Require Dosage Adjustment in Subjects With Varying Degrees of Hepatic or Renal Impairment

Two open‐label studies assessed the effects of hepatic and renal impairment on anidulafungin pharmacokinetics. A single 50‐mg dose was administered intravenously to subjects with varying degrees of hepatic or renal insufficiency or with end‐stage renal disease; all were matched to normal healthy controls. Anidulafungin was well tolerated. AUC, CL, Cmax, tmax, t1/2, and Vss between renally impaired subjects and controls were not significantly different (P .05), and no measurable amounts of drug were found in dialysate. The same pharmacokinetic parameters were also not affected (P .05) by mild or moderate hepatic insufficiency, with respective mean AUCs of 50.6 ± 11.7 μg·h/mL and 68.6 ± 14.5 μg·h/mL, compared to 70.0 ± 13.4 μg·h/mL in controls. Statistically significant decreases (P < 05) of AUC (33% change) and Cmax (36% change) in severely hepatically impaired subjects compared to controls—most likely secondary to ascites and edema—were not clinically relevant. Anidulafungin can be safely administered to patients with any degree of hepatic or renal impairment without dosage adjustment and without regard to hemodialysis schedules.

Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H‐cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple‐dose, open‐label clinical study of 12 healthy volunteers. Subjects received a 200‐mg intravenous loading dose of anidulafungin, followed by a daily 100‐mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose‐limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

Lack of Pharmacokinetic Interaction Between Anidulafungin and Tacrolimus

The safety and pharmacokinetics of anidulafungin coadministered with tacrolimus were investigated using a single‐sequence, open‐label design. Healthy volunteers received 5 mg tacrolimus orally on days 1 and 13 of the study. Anidulafungin (200 mg) was administered intravenously on day 4, followed by 100‐mg doses on days 5 through 13. Key pharmacokinetic parameters, including Cmax, AUC, t½, CL, and Vss, were derived from concentration‐time data. The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of anidulafungin plus tacrolimus to each drug alone were well within the 80% to 125% bioequivalence range, indicating no pharmacokinetic interaction. This ratio was 101.6 (90% CI: 92.77–111.22) for tacrolimus AUC0‐∞ and 107.2 (90% CI: 105.1–109.4) for anidulafungin AUCss. The 2 drugs were well tolerated, and no drug‐related serious adverse events were reported. Because of its lack of pharmacokinetic interaction with key immunosuppressive agents, anidulafungin is an important option for the prevention and treatment of invasive fungal infections in transplant recipients.

In Vitro and In Vivo Studies To Characterize the Clearance Mechanism and Potential Cytochrome P450 Interactions of Anidulafungin

ABSTRACT Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drugs elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.

Pharmacokinetics and Tissue Distribution of Anidulafungin in Rats

ABSTRACT This study assessed the tissue distribution of anidulafungin in rats. Anidulafungin rapidly distributed into tissues, achieving peak concentrations within 30 min, and maintained levels above MICs for common pathogens over 72 h. In tissues susceptible to fungal infection (liver, lung, spleen, kidney), exposure was 9- to 12-fold higher than in plasma.

Pharmacokinetic‐Pharmacodynamic Modeling of Dalbavancin, a Novel Glycopeptide Antibiotic

Dalbavancin is a novel glycopeptide with a 2‐dose, once‐weekly dosing regimen that is being developed for the treatment of complicated skin and skin structure infections caused by gram‐positive bacteria. Monte Carlo simulations were performed for dalbavancin using population pharmacokinetic data and minimum inhibitory concentrations (MICs) for clinical trial isolates. The time‐dependent target was the maintenance of free drug concentrations above the MIC for 14 days (t > MIC). The concentration‐dependent target was an area under the concentration‐time curve (AUC)/MIC ratio of approximately 1000 for Staphylococcus aureus and 100 for Streptococcussp. These targets were used to estimate susceptibility breakpoints for dalbavancin. For S aureus, the estimated susceptibility breakpoint was ≤0.5 μg/mL using AUC14 days/MIC and ≤1 μg/mL using t > MIC. For Streptococcus sp, the estimated susceptibility breakpoint was at least 2 μg/mL. Because dalbavancin MIC90s for these species are well below these values, the analysis supports the use of once‐weekly dosing regimens of dalbavancin in the treatment of complicated skin and skin structure infections.