1676. PK, Safety and Tolerability of VABOMERE® (meropenem-vaborbactam) in Infants, Children and Adolescents

• Published in: Open forum infectious diseases Vol. 10; no. Supplement_2
• Main Authors: Bokesch, Paula M, Arrieta, Antonio C, Bradley, John S, Hoover, Randall K, McCurdy, Sandra
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 27.11.2023
• ISSN: 2328-8957; 2328-8957
• DOI: 10.1093/ofid/ofad500.1509

Abstract Background The worldwide spread of serine carbapenemases threatens carbapenems. VABOMERE (combination of meropenem and vaborbactam (MV), is a new class of beta-lactamase inhibitors including inhibition of Klebsiella pneumoniae. The PK, safety, and efficacy data of MV in adults support study in pediatrics. Methods Phase 1, open-label, dose-finding study. Pediatric subjects, 3 mos. to < 18 yrs already on antibiotics received a single-dose weight based infusion of MV over 3 hr. Blood samples were drawn pre-dose, 3,4, and 6 hr. for PK parameters. Population PK model included weight as a covariate. Safety assessments included AEs, vital signs, safety labs, physical exams, infusion tolerance, ECG. A DSMB reviewed safety and PK data before enrolling next cohort. Results MV was well-tolerated and safe in all age groups. Clearance per kg body weight of both M and V increased with decreasing body weight over all age groups suggesting an allometric relationship. Table 1. Meropenem PK 12-17 yrs 40 mg/kg n=8 6-11 yrs 40 mg/kg n=8 6-10 yrs 60 mg/kg n=4 2-5 yrs 60 mg/kg n=8 5-22 mos 60 mg/kg n=3 2-10 yrs 60 mg/kg n=7 Cmax ug/ml 62.4 ± 14.7 41.3 ± 17.4 41.1 ± 9.9 73.0 ± 34.8 62.6 ± 9.2 54.1 ± 22.6 Cmin ug/ml 1.4 ± 1.2 0.25 ± 0.25 0.11 ± 0.08 0.95 ± 1.19 0.68 ± 0.18 0.24 ± 0.28 AUC 0-8 209 ± 47.7 134 ± 58.7 127 ± 30.8 238 ± 115 199 ± 30.2 173 ± 70.0 t1/2 h 0.87 ± 0.17 0.61 ± 0.11 0.56 ± 0.07 0.71 ± 0.17 0.77 ± 0.03 0.60 ± 0.09 Vss L/kg 0.223 ± 0.062 0.291 ± 0.094 0.391 ± 0.099 0.303 ± 0.145 0.342 ± 0.052 0.457 ± 0.238 CL L.hr/kg 0.182 ± 0.059 0.344 ± 0.131 0.487 ± 0.155 0.313 ± 0.166 0.308 ± 0.044 0.533 ± 0.267 Table 2. Vaborbactam PK 12-17 yrs. 40 mg/kg n=8 6-11yrs. 40 mg/kg n=8 6-10 yrs. 60mg/kg n=4 2-5 yrs.60 mg/kg n=8 5-22 mos 60 mg/kg n=3 2-‹ 10 yrs80 mg/kg n=7 Cmax ug/ml 60.8 ± 17.8 37.1 ± 17.3 45.6 ± 9.50 88.1 ± 45.2 105 ± 45.7 56.8 ± 24.4 Cmin ug/mL 2.8 ± 2.2 0.68 ± 0.72 0.27 ± 0.21 0.28 ± 0.12 2.86 ± 2.51 0.47 ± 0.46 AUC 0-8 209 ± 59.9 125 ± 61.5 144 ± 31.0 294 ± 154 164 ± 46.9 183 ± 76.1 T1/2 (h) 108 ± 0.23 0.78 ± 0.16 0.65 ± 0.083 0.82 ± 0.22 0.93 ± 0.11 0.69 ± 0.12 Vss L/kg 0.273 ± 0.085 0.412 ± 0.177 0.393 ± 0.070 0.280 ± 0.124 0.260 ± 0.103 0.479 ± 0.21 CL L/hr/kg 0.180 ± 0.06 0.384 ± 0.16 0.425 ± 0.12 0.251 ± 0.12 0.199 ± 0.09 0.483 ± 0.19 Conclusion Targeted AUC0-8 efficacious in adult trials ranges of 91.7-513 mg•hr/L (meropenem) and 131-494 mg•hr/L (vaborbactam) were achieved in all pediatric cohorts. Disclosures Paula M. Bokesch, MD, Melinta Therapeutics: Advisor/Consultant Antonio C. Arrieta, MD, FIDSA, FPIDS, Astellas Pharma Global Development, Inc.: Advisor/Consultant|Astellas Pharma Global Development, Inc.: Grant/Research Support|Astellas Pharma Global Development, Inc.: Honoraria|Cumberland Pharmaceutical: Grant/Research Support|IDbyDNA: Advisor/Consultant|IDbyDNA: Grant/Research Support|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Nabriva: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Pfizer, Inc: Advisor/Consultant|Pfizer, Inc: Grant/Research Support|Roche/Genentech: Grant/Research Support|The Medicine Company: Grant/Research Support Randall K. Hoover, Ph.D., Melinta Therapeutics: Advisor/Consultant Sandra McCurdy, MS, Melinta Therapeutics: Employee