THLBB02 - Oral Abstract Session
Safety, tolerability and early bactericidal activity in sputum of PNU-100480 (sutezolid) in patients with pulmonary tuberculosis
Presented by Robert Steven Wallis (United States).
R.S. Wallis1, A.H. Diacon2, R. Dawson3, A. Venter2, S.O. Friedrich2, D. Paige1, T. Zhu1, A. Silvia1, J. Gobey1, C. Ellery1, Y. Zhang1, E. Kadyszewski1
1Pfizer, Groton, United States, 2Stellenbosch University, Stellenbosch, South Africa, 3U Cape Town, Cape Town, South Africa
Background: PNU-100480 is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models that is time-dependent and unaffected by resistance mutations for standard TB drugs. PNU-100480 neither induces nor inhibits CYP3A4. This study is its first in TB patients.
Methods: Sputum AFB smear positive South African patients (incl. HIV+ not requiring ART) were randomly assigned to PNU-100480 600 mg BID (N=25) or 1200 mg QD (N=25), or standard 4-drug therapy (HREZ, N=9) for the first 14 days of treatment. Sputum mycobacterial burden was monitored both as log CFU/ml and time to detection (TTP) in automated liquid culture system (MGIT).
Results: 20% of subjects were women; 7% were HIV+. All subjects completed assigned treatments. There were no treatment-related serious adverse events nor any permanent discontinuations or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. At baseline, the mean log CFU/ml and TTP were 6.95 and 116 hrs, respectively. Changes in mycobacterial burden during treatment are shown below. Lines indicate estimates by mixed-effect model repeated measures (MMRM) analysis; shading indicates 90% CI. MMRM analysis revealed that the 90% CI after the full treatment period excluded zero for all 3 treatments and for both monitoring methods. Seven PNU-treated patients (14%) had transient, asymptomatic ALT elevations on day 14 to 2-3x ULN that subsequently returned promptly to normal; none met Hy's law criteria.
Conclusions: Treatment with PNU-100480 600 mg BID or 1200 mg QD reduced the mycobacterial burden in sputum during 14 days of treatment. Both treatments were safe and reasonably well tolerated. Further studies of PNU-100480 in tuberculosis are warranted.
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