PMID- 23403430
OWN - NLM
STAT- MEDLINE
DCOM- 20131024
LR  - 20211021
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 57
IP  - 5
DP  - 2013 May
TI  - Monte Carlo simulations based on phase 1 studies predict target attainment of 
      ceftobiprole in nosocomial pneumonia patients: a validation study.
PG  - 2047-53
LID - 10.1128/AAC.02292-12 [doi]
AB  - Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug 
      development to derive predicted target attainment values is frequently used to 
      choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A 
      criticism is that pharmacokinetic (PK) parameter estimates and variability in 
      healthy volunteers are smaller than those in patients. In this study, the initial 
      estimates of exposure from MCS were compared with actual exposure data in 
      patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study 
      (NTC00210964). Results of MCS using population PK data from ceftobiprole derived 
      from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. 
      Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713-1718, 
      2004). Actual individual exposures in patients were derived after building a 
      population pharmacokinetic model and were used to calculate the individual 
      exposure to ceftobiprole (the percentage of time the unbound concentration 
      exceeds the MIC [percent fT > MIC]) for a range of MIC values. For the ranges of 
      percent fT > MIC used to determine the dosage schedule in the phase 3 NP study, 
      the MCS using data from a single phase 1 study in healthy volunteers accurately 
      predicted the actual clinical exposure to ceftobiprole. The difference at 50% fT 
      > MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values 
      of percent fT > MIC and MICs, the MCS slightly underestimated the target 
      attainment, probably due to extreme values in the PK profile distribution used in 
      the simulations. The probability of target attainment based on MCS in healthy 
      volunteers adequately predicted the actual exposures in a patient population, 
      including severely ill patients.
FAU - Muller, Anouk E
AU  - Muller AE
AD  - Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, 
      HB Nijmegen, The Netherlands. muller.research@gmail.com
FAU - Schmitt-Hoffmann, Anne H
AU  - Schmitt-Hoffmann AH
FAU - Punt, Nieko
AU  - Punt N
FAU - Mouton, Johan W
AU  - Mouton JW
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
DEP - 20130212
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Cephalosporins)
RN  - 5T97333YZK (ceftobiprole)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anti-Bacterial Agents/blood/*pharmacokinetics
MH  - Cephalosporins/blood/*pharmacokinetics
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Cross Infection/*blood/drug therapy/microbiology
MH  - *Drug Dosage Calculations
MH  - Female
MH  - Humans
MH  - Male
MH  - Microbial Sensitivity Tests
MH  - Middle Aged
MH  - *Monte Carlo Method
MH  - Pneumonia, Bacterial/*blood/drug therapy/microbiology
PMC - PMC3632954
EDAT- 2013/02/14 06:00
MHDA- 2013/10/25 06:00
PMCR- 2013/11/01
CRDT- 2013/02/14 06:00
PHST- 2013/02/14 06:00 [entrez]
PHST- 2013/02/14 06:00 [pubmed]
PHST- 2013/10/25 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - AAC.02292-12 [pii]
AID - 02292-12 [pii]
AID - 10.1128/AAC.02292-12 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2013 May;57(5):2047-53. doi: 10.1128/AAC.02292-12. 
      Epub 2013 Feb 12.