Multiple-Dose Pharmacokinetics and Safety of the New Antifungal Triazole BAL4815 after Intravenous Infusion and Oral Administration of Its Prodrug, BAL8557, in Healthy Volunteers

Abstract

BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by oncedaily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C max ) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C max values of 2.56 and 2.55 g/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-␤-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50-or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses.The frequency of severe systemic mycoses has steadily increased during the last years, and resistance to currently prescribed antifungals is growing rapidly (8,10,17). Therefore, there is an urgent need for new potent and safe antifungals which can be administered orally as well as intravenously (6, 9, 18).The water-soluble triazole prodrug BAL8557 (for chemical structure, see reference 15) is suitable for oral and intravenous administration. In plasma, it is rapidly and almost quantitatively (Ͼ99%) converted by esterases to BAL8728 (prodrug cleavage product) and to BAL4815 (active drug) (2). Area under the concentration-time curve (AUC) values of BAL8728 were low and amounted to approximately 1% of the corresponding AUCs of BAL4815 (15). BAL4815 is a potent inhibitor of ergosterol biosynthesis and shows in vitro broad-spectrum activity against all major opportunistic fungi and the true pathogenic fungi. In rat and murine models, BAL4815 was highly effective against systemic candidiasis and aspergillosis First pharmacokinetic data of BAL4815 in human were obtained in a single-ascen...

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

“…In studies of healthy volunteers, isavuconazole has been shown to be well tolerated and to have a low clearance, large volume of distribution, high bioavailability, and long elimination half-life (20,31). The present study extends these data to provide PK parameters for two high-and low-dose regimens of i.v.…”

Two Phase 1, Open‐Label, Mass Balance Studies to Determine the Pharmacokinetics of 14C‐Labeled Isavuconazonium Sulfate in Healthy Male Volunteers

“…Pharmacokinetic parameters of isavuconazole measured in this study after a single oral dose or IV infusion of the prodrug were comparable to those obtained in a previous isavuconazole phase 1 study 13. In the current study unchanged isavuconazole was eliminated predominately via feces (33% of total drug dose recovered), and less than 1% of the dose recovered in urine was unchanged isavuconazole.…”

“…Both the prodrug and the BAL8728 cleavage product lack oral bioavailability, but isavuconazole is absorbed readily, and, relative to IV isavuconazonium sulfate (determined by isavuconazole AUC), bioavailability is 98% 7, 13. The pharmacokinetic (PK) properties of isavuconazole are linear and dose proportional 13.…”

In Vitro Activities of Isavuconazole and Comparator Antifungal Agents Tested against a Global Collection of Opportunistic Yeasts and Molds

“…This compound can be administered either orally or intravenously as a prodrug, which then is converted by plasma esterases into the active component (3)(4)(5)(6). Previous in vitro studies have demonstrated potent antifungal activity against both common and uncommon fungal pathogens, including Candida, Aspergillus, non-Candida yeasts, and non-Aspergillus molds (7)(8)(9)(10)(11)(12)(13)(14)(15).…”