Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs

Pharmaceutical Research
Anders N KristofferssonElisabet I Nielsen

Abstract

Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa. A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated. The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2. A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than us...Continue Reading

References

Jan 1, 1976·Nephron·D W Cockcroft, M H Gault
Dec 1, 1995·Journal of Pharmacokinetics and Biopharmaceutics·M O KarlssonL B Sheiner
Apr 1, 1996·Journal of Pharmacokinetics and Biopharmaceutics·E N JonssonM O Karlsson
Feb 10, 1998·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·W A Craig
Jul 24, 1998·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·J D Turnidge
Jan 8, 2003·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·G L Drusano
Mar 18, 2005·The Journal of Antimicrobial Chemotherapy·Johan W MoutonGeorge L Drusano
Sep 22, 2006·Journal of Clinical Pharmacology·Chonghua LiDavid P Nicolau
Aug 21, 2007·Journal of Pharmaceutical Sciences·Takayuki KatsubeYoshitaka Yano
Dec 25, 2007·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·G Kahlmeter
Jul 8, 2009·Antimicrobial Agents and Chemotherapy·John N van den AnkerFritz Sorgel
Dec 23, 2009·The Journal of Antimicrobial Chemotherapy·Julia GloedeCharlotte Kloft
Sep 22, 2010·Annual Review of Pharmacology and Toxicology·Malcolm RowlandGeoffrey Tucker
May 18, 2011·Antimicrobial Agents and Chemotherapy·G L DrusanoA Louie
Aug 25, 2011·Current Opinion in Pharmacology·Alasdair MacGowan
Jan 24, 2012·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·J W MoutonG Kahlmeter
Jun 28, 2013·Pharmacological Reviews·Elisabet I Nielsen, Lena E Friberg
Jan 17, 2014·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jason A RobertsUNKNOWN DALI Study
Jul 19, 2015·The Journal of Antimicrobial Chemotherapy·Angela HuttnerJason A Roberts

❮ Previous
Next ❯

Citations

Mar 27, 2018·Clinical Pharmacology and Therapeutics·Joseph F StandingUNKNOWN FLACSAM-PK Study Group
Feb 15, 2018·Antimicrobial Agents and Chemotherapy·M A ZuurJ W C Alffenaar
Apr 28, 2018·Clinical Pharmacology and Therapeutics·Sebastian G WichaUlrika S H Simonsson
Apr 24, 2018·The Journal of Antimicrobial Chemotherapy·Eva GermovsekUNKNOWN NeoMero Consortium
Apr 15, 2017·Intensive Care Medicine·T TängdénUNKNOWN Infection Section for the European Society of Intensive Care Medicine, the Pharmacokinetics and Pharmacodynamics Study Group
Nov 6, 2018·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·S K B SyH Derendorf
Feb 12, 2021·Clinical Pharmacology and Therapeutics·Cornelia B Landersdorfer, Roger L Nation
Feb 9, 2021·Clinical Pharmacology and Therapeutics·Craig R RaynerKaren Rowland-Yeo
Feb 2, 2021·Clinical Pharmacology and Therapeutics·Lena E Friberg
Feb 11, 2021·Clinical Pharmacology and Therapeutics·Sebastian G WichaUNKNOWN International Society of Anti-Infective Pharmacology (ISAP), the PK/PD study group of the European Society of Clinical Micro
Jun 1, 2021·International Journal of Antimicrobial Agents·Gauri G Rao, Cornelia B Landersdorfer
Jun 6, 2021·Journal of Pharmaceutical Sciences·Victoria Lima-RogelSilvia Romano-Moreno

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Carbapenems

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Carbapenems (ASM)

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.