AAC Accepted Manuscript Posted Online 16 February 2016 Antimicrob. Agents Chemother. doi:10.1128/AAC.02665-15 Copyright © 2016, American Society for Microbiology. All Rights Reserved.
1
AAC02665-15
2
Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment
3
of Experimental Invasive Pulmonary Aspergillosis
4 a
a
a
a
5
Vidmantas Petraitis , Ruta Petraitiene , Patriss W. Moradi , Gittel E. Strauss ,
6
Aspasia Katragkou , Laura L. Kovandab, William W. Hope , and Thomas J. Walsha, d
a
c
7 8
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases,
9
Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York,
10
USAa; Astellas Pharma Global Development, Inc., Northbrook, Illinois, USAb; Antimicrobial
11
Pharmacodynamics and therapeutics, Department of Molecular and Clinical Pharmacology,
12
University of Liverpool, Liverpool, United Kingdomc; Departments of Pediatrics and
13
Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, New
14
York, USAd
15 16
Running Title: Isavuconazole for treatment of pulmonary aspergillosis
17 18 19 20 21 22 23 24
Address correspondence to Thomas J. Walsh, MD, [email protected] and Vidmantas Petraitis, MD, [email protected] Correspondence: Thomas J. Walsh, MD, Weill Cornell Medicine, 1300 York Ave., Room A-421, New York, NY, USA, 10065, Phone number: 1 212 746 6320, Fax number: 1 212 746 8675, Email: [email protected]
25
Keywords.
26
galactomannan, (1→3)-β-D-glucan, neutropenia
Isavuconazole,
Aspergillus
fumigatus,
aspergillosis,
pharmacokinetics,
1
27
ABSTRACT
28
We studied the pharmacokinetics and efficacy of the third-generation broad-spectrum triazole
29
isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in
30
persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of A.
31
fumigatus
32
isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (BAL4815, ISA)
33
at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day with an initial loading dose of 90 mg/kg
34
(ISA90), or untreated rabbits (UC). There was a significant concentration-dependent reduction
35
of residual fungal burden (log CFU/g) and of organism-mediated pulmonary injury, lung weights
36
and pulmonary infarct score in ISA40- and ISA60-treated rabbits in comparison to those of UC
37
(p3)-beta-D-glucan as surrogate markers for detection and monitoring of therapeutic response
441
in experimental hematogenous Candida meningoencephalitis. Antimicrobial agents and
442
chemotherapy 52:4121-4129.
443
27. Schmitt-Hoffmann A, Roos B, Heep M, Schleimer M, Weidekamm E, Brown T, Roehrle
444
M, Beglinger C. 2006. Single-ascending-dose pharmacokinetics and safety of the novel
445
broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200
446
milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557,
447
in healthy volunteers. Antimicrobial agents and chemotherapy 50:279-285.
448
28. Francis P, Lee JW, Hoffman A, Peter J, Francesconi A, Bacher J, Shelhamer J, Pizzo
449
PA, Walsh TJ. 1994. Efficacy of unilamellar liposomal amphotericin B in treatment of
450
pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of
451
bronchoalveolar D-mannitol and serum galactomannan as markers of infection. J Infect Dis
452
169:356-368.
453
29. Hope WW, Petraitis V, Petraitiene R, Aghamolla T, Bacher J, Walsh TJ. 2010. The
454
initial 96 hours of invasive pulmonary aspergillosis: histopathology, comparative kinetics of
455
galactomannan and (1->3) beta-d-glucan and consequences of delayed antifungal therapy.
456
Antimicrob Agents Chemother 54:4879-4886.
20
457
30. Schmitt-Hoffmann A, Roos B, Maares J, Heep M, Spickerman J, Weidekamm E,
458
Brown T, Roehrle M. 2006. Multiple-dose pharmacokinetics and safety of the new
459
antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug,
460
BAL8557, in healthy volunteers. Antimicrobial agents and chemotherapy 50:286-293.
461
31. Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ. 2015. Safety and
462
pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia
463
patients with neutropenia: results of a phase 2, dose escalation study. Antimicrobial agents
464
and chemotherapy 59:2078-2085.
465
32. Maertens J PT, Rahav G, Kontoyiannis D, Marr K, Maher R, Lee M, Zeiher B,
466
Ullmann A. 2014. A Phase 3 Randomized, Double-Blind Trial Evaluating Isavuconazole Vs.
467
Voriconazole For The Primary Treatment Of Invasive Fungal Disease Caused By Aspergillus
468
spp. Or Other Filamentous Fungi (Secure), abstr ECCMID, Barcelona, Spain, May 10, 2014,
469
33. Desai A, Kovanda L, Kowalski D, Lu Q, Townsend RW. 2014. Isavuconazole (ISA)
470
Population Pharmacokinetic Modeling from Phase 1 and Phase 3 Clinical Trials and Target
471
Attainment Analysis, abstr abstr ICAAC, Washington D.C., USA, September 2014,
472
34. Benjamin DK, Jr., Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, Clark K,
473
Dowell JA, Schranz J, Walsh TJ. 2006. Safety and pharmacokinetics of intravenous
474
anidulafungin in children with neutropenia at high risk for invasive fungal infections.
475
Antimicrob Agents Chemother 50:632-638.
476 477
21
478
FIGURE LEGENDS
479 480
FIG 1. Response of primary pulmonary aspergillosis in persistently neutropenic rabbits to
481
antifungal therapy measured by mean pulmonary tissue residual fungal burden (log CFU/g),
482
mean lung weight, mean pulmonary infarct score, and survival in untreated controls (UC) and
483
rabbits receiving oral isavuconazole (BAL4815). An initial loading dose of 90 mg/kg of
484
isavuconazole administered orally, and thereafter daily at 20 mg/kg (ISA20), 40 mg/kg (ISA40),
485
and 60 mg/kg (ISA60). Values are given as means ± SEMs. For the measure of survival, the
486
values on the y-axis are probability of survival. Survival was plotted by Kaplan-Meier analysis.
487
Differences in survival of treatment groups and untreated controls were analyzed by log-rank test.
488
P values are indicated as follows: *, P
1
AAC02665-15
2
Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment
3
of Experimental Invasive Pulmonary Aspergillosis
4 a
a
a
a
5
Vidmantas Petraitis , Ruta Petraitiene , Patriss W. Moradi , Gittel E. Strauss ,
6
Aspasia Katragkou , Laura L. Kovandab, William W. Hope , and Thomas J. Walsha, d
a
c
7 8
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases,
9
Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York,
10
USAa; Astellas Pharma Global Development, Inc., Northbrook, Illinois, USAb; Antimicrobial
11
Pharmacodynamics and therapeutics, Department of Molecular and Clinical Pharmacology,
12
University of Liverpool, Liverpool, United Kingdomc; Departments of Pediatrics and
13
Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, New
14
York, USAd
15 16
Running Title: Isavuconazole for treatment of pulmonary aspergillosis
17 18 19 20 21 22 23 24
Address correspondence to Thomas J. Walsh, MD, [email protected] and Vidmantas Petraitis, MD, [email protected] Correspondence: Thomas J. Walsh, MD, Weill Cornell Medicine, 1300 York Ave., Room A-421, New York, NY, USA, 10065, Phone number: 1 212 746 6320, Fax number: 1 212 746 8675, Email: [email protected]
25
Keywords.
26
galactomannan, (1→3)-β-D-glucan, neutropenia
Isavuconazole,
Aspergillus
fumigatus,
aspergillosis,
pharmacokinetics,
1
27
ABSTRACT
28
We studied the pharmacokinetics and efficacy of the third-generation broad-spectrum triazole
29
isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in
30
persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of A.
31
fumigatus
32
isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (BAL4815, ISA)
33
at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day with an initial loading dose of 90 mg/kg
34
(ISA90), or untreated rabbits (UC). There was a significant concentration-dependent reduction
35
of residual fungal burden (log CFU/g) and of organism-mediated pulmonary injury, lung weights
36
and pulmonary infarct score in ISA40- and ISA60-treated rabbits in comparison to those of UC
37
(p3)-beta-D-glucan as surrogate markers for detection and monitoring of therapeutic response
441
in experimental hematogenous Candida meningoencephalitis. Antimicrobial agents and
442
chemotherapy 52:4121-4129.
443
27. Schmitt-Hoffmann A, Roos B, Heep M, Schleimer M, Weidekamm E, Brown T, Roehrle
444
M, Beglinger C. 2006. Single-ascending-dose pharmacokinetics and safety of the novel
445
broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200
446
milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557,
447
in healthy volunteers. Antimicrobial agents and chemotherapy 50:279-285.
448
28. Francis P, Lee JW, Hoffman A, Peter J, Francesconi A, Bacher J, Shelhamer J, Pizzo
449
PA, Walsh TJ. 1994. Efficacy of unilamellar liposomal amphotericin B in treatment of
450
pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of
451
bronchoalveolar D-mannitol and serum galactomannan as markers of infection. J Infect Dis
452
169:356-368.
453
29. Hope WW, Petraitis V, Petraitiene R, Aghamolla T, Bacher J, Walsh TJ. 2010. The
454
initial 96 hours of invasive pulmonary aspergillosis: histopathology, comparative kinetics of
455
galactomannan and (1->3) beta-d-glucan and consequences of delayed antifungal therapy.
456
Antimicrob Agents Chemother 54:4879-4886.
20
457
30. Schmitt-Hoffmann A, Roos B, Maares J, Heep M, Spickerman J, Weidekamm E,
458
Brown T, Roehrle M. 2006. Multiple-dose pharmacokinetics and safety of the new
459
antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug,
460
BAL8557, in healthy volunteers. Antimicrobial agents and chemotherapy 50:286-293.
461
31. Cornely OA, Bohme A, Schmitt-Hoffmann A, Ullmann AJ. 2015. Safety and
462
pharmacokinetics of isavuconazole as antifungal prophylaxis in acute myeloid leukemia
463
patients with neutropenia: results of a phase 2, dose escalation study. Antimicrobial agents
464
and chemotherapy 59:2078-2085.
465
32. Maertens J PT, Rahav G, Kontoyiannis D, Marr K, Maher R, Lee M, Zeiher B,
466
Ullmann A. 2014. A Phase 3 Randomized, Double-Blind Trial Evaluating Isavuconazole Vs.
467
Voriconazole For The Primary Treatment Of Invasive Fungal Disease Caused By Aspergillus
468
spp. Or Other Filamentous Fungi (Secure), abstr ECCMID, Barcelona, Spain, May 10, 2014,
469
33. Desai A, Kovanda L, Kowalski D, Lu Q, Townsend RW. 2014. Isavuconazole (ISA)
470
Population Pharmacokinetic Modeling from Phase 1 and Phase 3 Clinical Trials and Target
471
Attainment Analysis, abstr abstr ICAAC, Washington D.C., USA, September 2014,
472
34. Benjamin DK, Jr., Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, Clark K,
473
Dowell JA, Schranz J, Walsh TJ. 2006. Safety and pharmacokinetics of intravenous
474
anidulafungin in children with neutropenia at high risk for invasive fungal infections.
475
Antimicrob Agents Chemother 50:632-638.
476 477
21
478
FIGURE LEGENDS
479 480
FIG 1. Response of primary pulmonary aspergillosis in persistently neutropenic rabbits to
481
antifungal therapy measured by mean pulmonary tissue residual fungal burden (log CFU/g),
482
mean lung weight, mean pulmonary infarct score, and survival in untreated controls (UC) and
483
rabbits receiving oral isavuconazole (BAL4815). An initial loading dose of 90 mg/kg of
484
isavuconazole administered orally, and thereafter daily at 20 mg/kg (ISA20), 40 mg/kg (ISA40),
485
and 60 mg/kg (ISA60). Values are given as means ± SEMs. For the measure of survival, the
486
values on the y-axis are probability of survival. Survival was plotted by Kaplan-Meier analysis.
487
Differences in survival of treatment groups and untreated controls were analyzed by log-rank test.
488
P values are indicated as follows: *, P
