Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older

Richard C Franzese, Lynn McFadyen, Kenny J Watson, Todd Riccobene, Timothy J Carrothers, Manoli Vourvahis, Phylinda L S Chan, Susan Raber, John S Bradley, Mark Lovern, Richard C Franzese, Lynn McFadyen, Kenny J Watson, Todd Riccobene, Timothy J Carrothers, Manoli Vourvahis, Phylinda L S Chan, Susan Raber, John S Bradley, Mark Lovern

Abstract

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Conflict of interest statement

R.C.F., K.J.W., and M.L. are employees of Certara Strategic Consulting, which received funding from Pfizer for the population PK analyses. P.L.S.C., M.V., and S.R. are employees of and shareholders in Pfizer. L.M. is a former employee of and shareholder in Pfizer. T.R. is an employee of and shareholder in AbbVie. T.J.C. is a former employee of and shareholder in AbbVie. J.S.B.’s employer, the University of California, received institutional funds from AstraZeneca and Pfizer to conduct and consult on the ceftazidime‐avibactam pediatric clinical trials.

© 2021 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Observed (points) and simulated ceftazidime and avibactam steady‐state exposures by body weight and indication for pediatric subjects (blue shaded area), compared with simulated adult populations (gray shaded area). (a) AUCss,0–24; (b) Cmax,ss. AUCss,0–24, total daily area under the plasma concentration‐time curve at steady state; Cmax,ss, maximum plasma concentration at steady state; cIAI, complicated intra‐abdominal infection; cUTI, complicated urinary tract infection, NP, nosocomial pneumonia. Each symbol represents an individual exposure variable. The red line represents the median simulated values, blue shading represents the 90% prediction interval for each pediatric indication, and gray shading represents the 90% prediction interval for adults with normal renal function or mild renal impairment.

References

    1. Cerceo, E. , Deitelzweig, S.B. , Sherman, B.M. & Amin, A.N. Multidrug‐resistant gram‐negative bacterial infections in the hospital setting: overview, implications for clinical practice, and emerging treatment options. Microb. Drug Resist. 22, 412–431 (2016).
    1. European Centre for Disease Prevention and Control . Antimicrobial resistance in the EU/EEA (EARS‐Net): Annual Epidemiological Report for 2019 <> (2020).
    1. Centers for Disease Control and Prevention . Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report) <> (2019).
    1. Meropol, S.B. , Haupt, A.A. & Debanne, S.M. Incidence and outcomes of infections caused by multidrug‐resistant enterobacteriaceae in children, 2007–2015. J. Pediatric. Infect. Dis. Soc. 7, 36–45 (2018).
    1. Aguilera‐Alonso, D. , Escosa‐García, L. , Saavedra‐Lozano, J. , Cercenado, E. & Baquero‐Artigao, F. Carbapenem‐resistant gram‐negative bacterial infections in children. Antimicrob. Agents Chemother. 64, e02183‐19 (2020).
    1. Ara‐Montojo, M.F. et al. Predictors of mortality and clinical characteristics among carbapenem‐resistant or carbapenemase‐producing Enterobacteriaceae bloodstream infections in Spanish children. J. Antimicrob. Chemother. 76, 220–225 (2021).
    1. Chiotos, K. , Hayes, M. , Gerber, J.S. & Tamma, P.D. Treatment of carbapenem‐resistant Enterobacteriaceae infections in children. J. Pediatric. Infect. Dis. Soc. 9, 56–66 (2020).
    1. Lagacé‐Wiens, P. , Walkty, A. & Karlowsky, J.A. Ceftazidime‐avibactam: an evidence‐based review of its pharmacology and potential use in the treatment of Gram‐negative bacterial infections. Core Evid. 9, 13–25 (2014).
    1. Aktas, Z. , Kayacan, C. & Oncul, O. In vitro activity of avibactam (NXL104) in combination with beta‐lactams against Gram‐negative bacteria, including OXA‐48 beta‐lactamase‐producing Klebsiella pneumoniae. Int. J. Antimicrob. Agents 39, 86–89 (2012).
    1. Stachyra, T. et al. In vitro activity of the β‐lactamase inhibitor NXL104 against KPC‐2 carbapenemase and Enterobacteriaceae expressing KPC carbapenemases. J. Antimicrob. Chemother. 64, 326–329 (2009).
    1. Mushtaq, S. , Warner, M. , Williams, G. , Critchley, I. & Livermore, D.M. Activity of chequerboard combinations of ceftaroline and NXL104 versus beta‐lactamase‐producing Enterobacteriaceae. J. Antimicrob. Chemother. 65, 1428–1432 (2010).
    1. Zavicefta [summary of product characteristics]. (Pfizer Ireland Pharmaceuticals, Ringaskiddy, Ireland, 2021). (
    1. Avycaz [highlights of prescribing information]. (Allergan, Madison, NJ, 2020) 〈〉.
    1. Li, J. et al. Considerations in the selection of renal dosage adjustments for patients with serious infections and lessons learned from the development of ceftazidime‐avibactam. Antimicrob. Agents Chemother. 64, e02105‐19 (2020).
    1. Li, J. et al. Ceftazidime‐avibactam population pharmacokinetic modeling and pharmacodynamic target attainment across adult indications and patient subgroups. Clin. Transl. Sci. 12, 151–163 (2019).
    1. Bradley, J.S. et al. Phase I study assessing the pharmacokinetic profile, safety, and tolerability of a single dose of ceftazidime‐avibactam in hospitalized pediatric patients. Antimicrob. Agents Chemother. 60, 6252–6259 (2016).
    1. Bradley, J.S. et al. Safety and efficacy of ceftazidime‐avibactam plus metronidazole in the treatment of children ≥3 months to <18 years with complicated intra‐abdominal infection: results from a phase 2, randomized, controlled trial. Pediatr. Infect. Dis. J. 38, 816–824 (2019).
    1. Bradley, J.S. et al. Safety and efficacy of ceftazidime‐avibactam in the treatment of children ≥3 months to <18 years with complicated urinary tract infection: results from a phase 2 randomized, controlled trial. Pediatr. Infect. Dis. J. 38, 920–928 (2019).
    1. Li, J. et al. Population PK modeling and dosing evaluations for ceftazidime‐avibactam (CAZ‐AVI) in children aged ≥3 months to <18 years receiving systemic antibiotic therapy for suspected or confirmed infection. American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, Orlando, FL, October 25–29, 2015.
    1. Das, S. , Armstrong, J. , Mathews, D. , Li, J. & Edeki, T. Randomized, placebo‐controlled study to assess the impact on QT/QTc interval of supratherapeutic doses of ceftazidime‐avibactam or ceftaroline fosamil‐avibactam. J. Clin. Pharmacol. 54, 331–340 (2014).
    1. Das, S. , Li, J. , Armstrong, J. , Learoyd, M. & Edeki, T. Randomized pharmacokinetic and drug‐drug interaction studies of ceftazidime, avibactam, and metronidazole in healthy subjects. Pharmacol. Res. Perspect. 3, e00172 (2015).
    1. Vishwanathan, K. et al. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug‐drug interaction potential. Drug Metab. Dispos. 42, 932–942 (2014).
    1. Hu, T.M. & Hayton, W.L. Allometric scaling of xenobiotic clearance: uncertainty versus universality. AAPS PharmSci. 3, E29 (2001).
    1. Schwartz, G.J. & Work, D.F. Measurement and estimation of GFR in children and adolescents. Clin. J. Am. Soc. Nephrol. 4, 1832–1843 (2009).
    1. Schwartz, G.J. et al. New equations to estimate GFR in children with CKD. J. Am. Soc. Nephrol. 20, 629–637 (2009).
    1. Rhodin, M.M. et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr. Nephrol. 24, 67–76 (2009).
    1. Cockcroft, D.W. & Gault, M.H. Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41 (1976).
    1. Nichols, W.W. et al. Ceftazidime‐avibactam susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa . Antimicrob. Agents Chemother. 62, e02590‐17 (2018).
    1. Nichols, W.W. , Newell, P. , Critchley, I.A. , Riccobene, T. & Das, S. Avibactam pharmacokinetic/pharmacodynamic targets. Antimicrob. Agents Chemother. 62, e02446 ‐17 (2018).
    1. Centers for Disease Control and Prevention . Clinical growth charts 〈〉 (2017).
    1. Mazuski, J.E. et al. Efficacy and safety of ceftazidime‐avibactam plus metronidazole versus meropenem in the treatment of complicated intra‐abdominal infection: results from a randomized, controlled, double‐blind, phase 3 program. Clin. Infect. Dis. 62, 1380–1389 (2016).
    1. Qin, X. et al. A randomised, double‐blind, phase 3 study comparing the efficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem for complicated intra‐abdominal infections in hospitalised adults in Asia. Int. J. Antimicrob. Agents 49, 579–588 (2017).
    1. Carmeli, Y. et al. Ceftazidime‐avibactam or best available therapy in patients with ceftazidime‐resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra‐abdominal infections (REPRISE): a randomised, pathogen‐directed, phase 3 study. Lancet Infect. Dis. 16, 661–673 (2016).
    1. Wagenlehner, F.M. et al. Ceftazidime‐avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin. Infect. Dis. 63, 754–762 (2016).
    1. Torres, A. et al. Randomized trial of ceftazidime‐avibactam vs meropenem for treatment of hospital‐acquired and ventilator‐associated bacterial pneumonia (REPROVE): analyses per US FDA‐specified end points. Open Forum Infect. Dis. 6, ofz149 (2019).
    1. Torres, A. et al. Ceftazidime‐avibactam versus meropenem in nosocomial pneumonia, including ventilator‐associated pneumonia (REPROVE): a randomised, double‐blind, phase 3 non‐inferiority trial. Lancet Infect. Dis. 18, 285–295 (2018).
    1. Cheng, K. et al. Safety profile of ceftazidime‐avibactam: pooled data from the adult phase II and phase III clinical trial programme. Drug Saf. 43, 751–766 (2020).
    1. Friberg, L.E. Pivotal role of translation in anti‐infective development. Clin. Pharmacol. Ther. 109, 856–866 (2021).
    1. Dunne, J. et al. Extrapolation of adult data and other data in pediatric drug‐development programs. Pediatrics 128, e1242–e1249 (2011).
    1. Mulugeta, Y. et al. Exposure matching for extrapolation of efficacy in pediatric drug development. J. Clin. Pharmacol. 56, 1326–1334 (2016).
    1. Ollivier, C. , Mulugeta, Y.L. , Ruggieri, L. , Saint‐Raymond, A. & Yao, L. Paediatric extrapolation: A necessary paradigm shift. Br. J. Clin. Pharmacol. 85, 675–679 (2019).
    1. Pansa, P. et al. Evaluating safety reporting in paediatric antibiotic trials, 2000–2016: A systematic review and meta‐analysis. Drugs 78, 231–244 (2018).
    1. Bratton, S.L. , Haberkern, C.M. & Waldhausen, J.H. Acute appendicitis risks of complications: age and Medicaid insurance. Pediatrics 106, 75–78 (2000).
    1. Thompson, A.E. , Marshall, J.C. & Opal, S.M. Intraabdominal infections in infants and children: descriptions and definitions. Pediatr. Crit. Care Med. 6, S30–S35 (2005).
    1. Newman, N. , Wattad, E. , Greenberg, D. , Peled, N. , Cohen, Z. & Leibovitz, E. Community‐acquired complicated intra‐abdominal infections in children hospitalized during 1995–2004 at a paediatric surgery department. Scand. J. Infect. Dis. 41, 720–726 (2009).
    1. Sader, H.S. , Castanheira, M. , Streit, J.M. , Carvalhaes, C.G. & Mendes, R.E. Frequency and antimicrobial susceptibility of bacteria causing bloodstream infections in pediatric patients from United States (US) medical centers (2014–2018): therapeutic options for multidrug‐resistant bacteria. Diagn. Microbiol. Infect. Dis. 98, 115108 (2020).
    1. Sader, H. , Huband, M. , Duncan, L.R. & Flamm, R.K. Ceftazidime‐avibactam antimicrobial activity and spectrum when tested against Gram‐negative organisms from pediatric patients: Results from the INFORM surveillance program (United States, 2011–2015). Pediatr. Infect. Dis. J. 37, 549–554 (2018).
    1. Lin, L.‐Y. , Riccobene, T. & Debabov, D. Antimicrobial activity of ceftazidime‐avibactam against contemporary pathogens from urinary tract infections and intra‐abdominal infections collected From US children during the 2016–2019 INFORM surveillance program. Pediatr. Infect. Dis. J. 40, 338–343 (2021).
    1. Folgori, L. et al. Standardising neonatal and paediatric antibiotic clinical trial design and conduct: the PENTA‐ID network view. BMJ Open 9, e032592 (2019).

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren