Session Type: ePosters
Session Title: ePosters
Authors(s): G. Patel (1), K. Rodvold (2), V. Gupta (3), J. Bruss (3), L. Gasink (3), F. Bajraktari (3), Y. Lei (3), A. Jain (3), P. Srivastava (3), A. Talley (3)
Authors Affiliations(s): (1) Patel Kwan Consultancy LLC, United States, (2) University of Illinois, United States, (3) Spero Therapeutics, United States
Background:
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem in development for treating complicated urinary tract infections. The active moiety, tebipenem (TBP), has broad spectrum activity against common Enterobacterales uropathogens, including ESBL-producing multi-drug resistant strains.
Methods:TBP pharmacokinetics (PK) and safety/tolerability were evaluated after TBP-PI-HBr in subjects with normal renal function, varying degrees of renal impairment (RI) or end-stage renal disease (ESRD) receiving hemodialysis (HD). Matched healthy subjects (Cohort 1) and those with RI (Cohorts 2-4) received a single oral dose of TBP-PI-HBr 600 mg. Subjects with ESRD (Cohort 5) received a 600 mg dose within 2 hours after completion of regularly scheduled HD on Day 1 (Period 1) and a second dose 1 hour prior to scheduled HD on Day 5 (Period 2). Concentrations of TBP in blood and urine were measured from pre-dose to up to 72 hours post dose using a validated LC-MS/MS assay. ANOVA on noncompartmental PK parameters was used to compare RI groups versus healthy subjects. Values were log-transformed with PK as the response variable and fixed-effect term of Cohort as a categorical variable. Estimated mean difference and associated 90% confidence intervals (CI) were calculated and back transformed for comparisons.
Results:For RI vs. healthy subjects, TBP plasma AUC increased 1.4 to 4.5-fold, Cmax up to 1.3 times higher, and renal clearance decreased from 13.4 L/h to 2.4 L/h as RI increased (Table 1). Plasma concentrations of TBP decreased rapidly in those with normal function and those with mild or moderate RI (Figure 1). Apparent CL/F correlated (R2 = 0.585) with CLCR for Cohorts 1-4 (Figure 2). TBP excretion % in the urine ranged from 38% to 64% of the administered dose for Cohorts 1-4. Subjects with ESRD had approximately a 7-fold increase in AUC and elimination t1/2 for TBP compared to normal subjects. After a 4-hour HD session, mean TBP exposure decreased by approximately 40%. TBP-PI-HBr was well tolerated across all cohorts.
Conclusions:TBP plasma exposure increased with increasing RI. A reduced dosage regimen of TBP-PI-HBr may be needed in subjects with severe RI (CLcr <20 mL/min) and in those with ESRD on HD.
Keyword(s): tebipenem, pharmacokinetics, renal impairmentCOI Other: Gina Patel, Keith Rodvold, Jon Bruss, and Leanne Gasink were consultants to Spero Therapeutics. All other authors were paid employees of Spero Therapeutics, Cambridge, MA.
Session Type: ePosters
Session Title: ePosters
Authors(s): G. Patel (1), K. Rodvold (2), V. Gupta (3), J. Bruss (3), L. Gasink (3), F. Bajraktari (3), Y. Lei (3), A. Jain (3), P. Srivastava (3), A. Talley (3)
Authors Affiliations(s): (1) Patel Kwan Consultancy LLC, United States, (2) University of Illinois, United States, (3) Spero Therapeutics, United States
Background:
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem in development for treating complicated urinary tract infections. The active moiety, tebipenem (TBP), has broad spectrum activity against common Enterobacterales uropathogens, including ESBL-producing multi-drug resistant strains.
Methods:TBP pharmacokinetics (PK) and safety/tolerability were evaluated after TBP-PI-HBr in subjects with normal renal function, varying degrees of renal impairment (RI) or end-stage renal disease (ESRD) receiving hemodialysis (HD). Matched healthy subjects (Cohort 1) and those with RI (Cohorts 2-4) received a single oral dose of TBP-PI-HBr 600 mg. Subjects with ESRD (Cohort 5) received a 600 mg dose within 2 hours after completion of regularly scheduled HD on Day 1 (Period 1) and a second dose 1 hour prior to scheduled HD on Day 5 (Period 2). Concentrations of TBP in blood and urine were measured from pre-dose to up to 72 hours post dose using a validated LC-MS/MS assay. ANOVA on noncompartmental PK parameters was used to compare RI groups versus healthy subjects. Values were log-transformed with PK as the response variable and fixed-effect term of Cohort as a categorical variable. Estimated mean difference and associated 90% confidence intervals (CI) were calculated and back transformed for comparisons.
Results:For RI vs. healthy subjects, TBP plasma AUC increased 1.4 to 4.5-fold, Cmax up to 1.3 times higher, and renal clearance decreased from 13.4 L/h to 2.4 L/h as RI increased (Table 1). Plasma concentrations of TBP decreased rapidly in those with normal function and those with mild or moderate RI (Figure 1). Apparent CL/F correlated (R2 = 0.585) with CLCR for Cohorts 1-4 (Figure 2). TBP excretion % in the urine ranged from 38% to 64% of the administered dose for Cohorts 1-4. Subjects with ESRD had approximately a 7-fold increase in AUC and elimination t1/2 for TBP compared to normal subjects. After a 4-hour HD session, mean TBP exposure decreased by approximately 40%. TBP-PI-HBr was well tolerated across all cohorts.
Conclusions:TBP plasma exposure increased with increasing RI. A reduced dosage regimen of TBP-PI-HBr may be needed in subjects with severe RI (CLcr <20 mL/min) and in those with ESRD on HD.
Keyword(s): tebipenem, pharmacokinetics, renal impairmentCOI Other: Gina Patel, Keith Rodvold, Jon Bruss, and Leanne Gasink were consultants to Spero Therapeutics. All other authors were paid employees of Spero Therapeutics, Cambridge, MA.
Session Type: ePosters
Session Title: ePosters
Authors(s): G. Patel (1), K. Rodvold (2), V. Gupta (3), J. Bruss (3), L. Gasink (3), F. Bajraktari (3), Y. Lei (3), A. Jain (3), P. Srivastava (3), A. Talley (3)
Authors Affiliations(s): (1) Patel Kwan Consultancy LLC, United States, (2) University of Illinois, United States, (3) Spero Therapeutics, United States
Background:
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem in development for treating complicated urinary tract infections. The active moiety, tebipenem (TBP), has broad spectrum activity against common Enterobacterales uropathogens, including ESBL-producing multi-drug resistant strains.
Methods:TBP pharmacokinetics (PK) and safety/tolerability were evaluated after TBP-PI-HBr in subjects with normal renal function, varying degrees of renal impairment (RI) or end-stage renal disease (ESRD) receiving hemodialysis (HD). Matched healthy subjects (Cohort 1) and those with RI (Cohorts 2-4) received a single oral dose of TBP-PI-HBr 600 mg. Subjects with ESRD (Cohort 5) received a 600 mg dose within 2 hours after completion of regularly scheduled HD on Day 1 (Period 1) and a second dose 1 hour prior to scheduled HD on Day 5 (Period 2). Concentrations of TBP in blood and urine were measured from pre-dose to up to 72 hours post dose using a validated LC-MS/MS assay. ANOVA on noncompartmental PK parameters was used to compare RI groups versus healthy subjects. Values were log-transformed with PK as the response variable and fixed-effect term of Cohort as a categorical variable. Estimated mean difference and associated 90% confidence intervals (CI) were calculated and back transformed for comparisons.
Results:For RI vs. healthy subjects, TBP plasma AUC increased 1.4 to 4.5-fold, Cmax up to 1.3 times higher, and renal clearance decreased from 13.4 L/h to 2.4 L/h as RI increased (Table 1). Plasma concentrations of TBP decreased rapidly in those with normal function and those with mild or moderate RI (Figure 1). Apparent CL/F correlated (R2 = 0.585) with CLCR for Cohorts 1-4 (Figure 2). TBP excretion % in the urine ranged from 38% to 64% of the administered dose for Cohorts 1-4. Subjects with ESRD had approximately a 7-fold increase in AUC and elimination t1/2 for TBP compared to normal subjects. After a 4-hour HD session, mean TBP exposure decreased by approximately 40%. TBP-PI-HBr was well tolerated across all cohorts.
Conclusions:TBP plasma exposure increased with increasing RI. A reduced dosage regimen of TBP-PI-HBr may be needed in subjects with severe RI (CLcr <20 mL/min) and in those with ESRD on HD.
Keyword(s): tebipenem, pharmacokinetics, renal impairmentCOI Other: Gina Patel, Keith Rodvold, Jon Bruss, and Leanne Gasink were consultants to Spero Therapeutics. All other authors were paid employees of Spero Therapeutics, Cambridge, MA.
Session Type: ePosters
Session Title: ePosters
Authors(s): G. Patel (1), K. Rodvold (2), V. Gupta (3), J. Bruss (3), L. Gasink (3), F. Bajraktari (3), Y. Lei (3), A. Jain (3), P. Srivastava (3), A. Talley (3)
Authors Affiliations(s): (1) Patel Kwan Consultancy LLC, United States, (2) University of Illinois, United States, (3) Spero Therapeutics, United States
Background:
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral carbapenem in development for treating complicated urinary tract infections. The active moiety, tebipenem (TBP), has broad spectrum activity against common Enterobacterales uropathogens, including ESBL-producing multi-drug resistant strains.
Methods:TBP pharmacokinetics (PK) and safety/tolerability were evaluated after TBP-PI-HBr in subjects with normal renal function, varying degrees of renal impairment (RI) or end-stage renal disease (ESRD) receiving hemodialysis (HD). Matched healthy subjects (Cohort 1) and those with RI (Cohorts 2-4) received a single oral dose of TBP-PI-HBr 600 mg. Subjects with ESRD (Cohort 5) received a 600 mg dose within 2 hours after completion of regularly scheduled HD on Day 1 (Period 1) and a second dose 1 hour prior to scheduled HD on Day 5 (Period 2). Concentrations of TBP in blood and urine were measured from pre-dose to up to 72 hours post dose using a validated LC-MS/MS assay. ANOVA on noncompartmental PK parameters was used to compare RI groups versus healthy subjects. Values were log-transformed with PK as the response variable and fixed-effect term of Cohort as a categorical variable. Estimated mean difference and associated 90% confidence intervals (CI) were calculated and back transformed for comparisons.
Results:For RI vs. healthy subjects, TBP plasma AUC increased 1.4 to 4.5-fold, Cmax up to 1.3 times higher, and renal clearance decreased from 13.4 L/h to 2.4 L/h as RI increased (Table 1). Plasma concentrations of TBP decreased rapidly in those with normal function and those with mild or moderate RI (Figure 1). Apparent CL/F correlated (R2 = 0.585) with CLCR for Cohorts 1-4 (Figure 2). TBP excretion % in the urine ranged from 38% to 64% of the administered dose for Cohorts 1-4. Subjects with ESRD had approximately a 7-fold increase in AUC and elimination t1/2 for TBP compared to normal subjects. After a 4-hour HD session, mean TBP exposure decreased by approximately 40%. TBP-PI-HBr was well tolerated across all cohorts.
Conclusions:TBP plasma exposure increased with increasing RI. A reduced dosage regimen of TBP-PI-HBr may be needed in subjects with severe RI (CLcr <20 mL/min) and in those with ESRD on HD.
Keyword(s): tebipenem, pharmacokinetics, renal impairmentCOI Other: Gina Patel, Keith Rodvold, Jon Bruss, and Leanne Gasink were consultants to Spero Therapeutics. All other authors were paid employees of Spero Therapeutics, Cambridge, MA.