Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen.
Adolescent
Anti-Bacterial Agents
/ pharmacokinetics
Bacterial Infections
/ drug therapy
Body Weight
/ drug effects
Child
Child, Preschool
Female
Fever
/ drug therapy
Glomerular Filtration Rate
/ drug effects
Humans
Infant
Male
Microbial Sensitivity Tests
/ methods
Neoplasms
/ drug therapy
Piperacillin
/ administration & dosage
Piperacillin, Tazobactam Drug Combination
/ administration & dosage
Tazobactam
/ administration & dosage
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
10
02
2019
revised:
22
05
2019
accepted:
28
05
2019
pubmed:
6
7
2019
medline:
21
8
2020
entrez:
6
7
2019
Statut:
ppublish
Résumé
The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights. Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination. The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).
Sections du résumé
BACKGROUND
The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target.
OBJECTIVES
To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights.
METHODS
Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights.
RESULTS
A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination.
CONCLUSIONS
The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).
Identifiants
pubmed: 31273375
pii: 5528381
doi: 10.1093/jac/dkz270
pmc: PMC6916132
doi:
Substances chimiques
Anti-Bacterial Agents
0
Piperacillin, Tazobactam Drug Combination
157044-21-8
Tazobactam
SE10G96M8W
Piperacillin
X00B0D5O0E
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2984-2993Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Références
J Antimicrob Chemother. 2015 Dec;70(12):3178-83
pubmed: 26188037
CPT Pharmacometrics Syst Pharmacol. 2012 Sep 26;1:e6
pubmed: 23835886
Antimicrob Agents Chemother. 2017 Oct 24;61(11):
pubmed: 28807922
Pharm Res. 1998 Sep;15(9):1463-8
pubmed: 9755901
J Antimicrob Chemother. 2017 Jul 1;72(7):2002-2011
pubmed: 28387840
Clin Pharmacokinet. 2019 Feb;58(2):223-233
pubmed: 29862466
Antimicrob Agents Chemother. 2014 Jun;58(6):3533-7
pubmed: 24687508
Lancet Infect Dis. 2018 Jan;18(1):108-120
pubmed: 29102324
Eur J Clin Pharmacol. 2017 Dec;73(12):1609-1613
pubmed: 28920154
Nat Rev Microbiol. 2004 Apr;2(4):289-300
pubmed: 15031728
Clin Infect Dis. 2011 Feb 15;52(4):e56-93
pubmed: 21258094
Emerg Med Clin North Am. 2009 Aug;27(3):525-44
pubmed: 19646652
Pediatr Blood Cancer. 2015 Mar;62(3):477-82
pubmed: 25328131
Pediatr Nephrol. 2009 Jan;24(1):67-76
pubmed: 18846389
J Clin Oncol. 2012 Dec 10;30(35):4427-38
pubmed: 22987086
Br J Clin Pharmacol. 2015 Jan;79(1):6-17
pubmed: 24548174
Br J Clin Pharmacol. 2017 Feb;83(2):247-254
pubmed: 27567102
Cancer. 2010 Dec 1;116(23):5555-63
pubmed: 20715160
CPT Pharmacometrics Syst Pharmacol. 2013 Jun 26;2:e50
pubmed: 23836189
J Pharmacokinet Pharmacodyn. 2001 Oct;28(5):481-504
pubmed: 11768292
Antimicrob Agents Chemother. 2009 Feb;53(2):505-11
pubmed: 19075067
Crit Care Med. 2008 Aug;36(8):2433-40
pubmed: 18596628
Clin Microbiol Infect. 2001 May;7(5):283-4
pubmed: 11422259
Int J Antimicrob Agents. 2007 Oct;30(4):320-4
pubmed: 17631983
Clin Pharmacokinet. 2014 Apr;53(4):327-46
pubmed: 24515100
AAPS J. 2011 Jun;13(2):143-51
pubmed: 21302010
Antimicrob Agents Chemother. 2015 Nov;59(11):7018-26
pubmed: 26349823
Antimicrob Agents Chemother. 2018 Apr 26;62(5):
pubmed: 29507062
Pediatr Infect Dis J. 2014 Feb;33(2):168-73
pubmed: 23907263
Antimicrob Agents Chemother. 2015 Nov 09;60(1):522-31
pubmed: 26552978
Crit Care Med. 2009 Mar;37(3):926-33
pubmed: 19237898
J Antimicrob Chemother. 2009 Jul;64(1):142-50
pubmed: 19398460
J Am Soc Nephrol. 2009 Mar;20(3):629-37
pubmed: 19158356
J Pharmacokinet Pharmacodyn. 2001 Jun;28(3):231-52
pubmed: 11468939
Antimicrob Agents Chemother. 2017 Aug 24;61(9):
pubmed: 28717035
Lancet Infect Dis. 2008 Oct;8(10):612-20
pubmed: 18922483
J Clin Oncol. 2005 Nov 1;23(31):7958-66
pubmed: 16258096
Int J Antimicrob Agents. 2010 Feb;35(2):156-63
pubmed: 20018492
Expert Rev Anti Infect Ther. 2007 Jun;5(3):365-83
pubmed: 17547502
Int J Clin Pharmacol Ther. 1996 Nov;34(11):482-8
pubmed: 8937930