A Phase I Multiple Dose Study of a Novel Oral Antifungal PLD-118.

A. SCHROEDTER1, A. BISCHOFF1, K. ORESKOVIC2, J. KNOELLER1, S. RADOSEVIC2, W. SCHOENFELD2, J. PETERSON2

Author address: 

1 FOCUS GmbH, Neuss, Germany, 2 PLIVA d.d., Research Division, Zagreb, Croatia

Abstract: 

Background: PLD-118 is a novel antifungal compound, primarily active against Candida spp., including azole-resistant strains. A double-blind, randomized, placebo-controlled study was performed to assess tolerability, safety and PK of PLD-118 after multiple oral dosing in healthy male volunteers. Following completion of the original protocol, it was realized that maximum tolerated dose has not been reached, so two additional dose levels were tested. Herein we report the final results. Methods: 48 subjects, divided into 6 groups and randomized in a 3:1 ratio for active treatment and placebo, received multiple oral doses of 50, 100, 150 or 200 mg PLD-118 q8h, as well as 150 or 300 mg q12h. Each volunteer received a single dose on the first day, followed by a 72 h wash out period, multiple doses for 7 days, and a single dose on the last dosing day. Plasma samples were collected over 72 h at Day 1 and Day 11, as well as prior to and 1 hour after the morning dose at Days 4-10. Urine samples were collected up to 72 hours after the last dose. Results: 45 subjects completed the study. Two subjects receiving placebo and one on active treatment were withdrawn due to an adverse event. Steady state plasma concentrations were achieved within 2-3 days of multiple dosing. Cmax at the last dosing day ranged from 2.4 to 8.6 µg/mL and Cmin from 0.7 to 2.8 µg/mL in the 50 mg and 200 mg t.i.d group, respectively. Cmin and Cmax after 300 mg b.i.d dosing were 2.6 and 10.9 µg/mL. Half-life of PLD-118 in plasma was around 7 h. Over 80% of the dose was recovered in urine in unchanged form. PLD-118 was very well tolerated, and majority of adverse events were mild to moderate in severity. The most common adverse event was dry mouth, occurring in 6 subjects receiving PLD-118. Conclusion: Repeated dosing of PLD-118, in doses up to 600 mg/day for 1 week, was safe and well tolerated by healthy volunteers. Steady state plasma levels were dose proportional and achieved within 2-3 days of multiple dosing.
2002

abstract No: 

F-815

Full conference title: 

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    • ICAAC 42nd