@phdthesis{Bulitta2006,
  author    = {Bulitta, J{\"u}rgen},
  title     = {Innovative techniques for selecting the dose of antibiotics in empiric therapy - focus on beta-lactams and cystic fibrosis patients},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19353},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Background: Population pharmacokinetic-pharmacodynamic (PKPD) modeling and simulations were applied to identify optimal dosage regimens for antibiotics. As the emergence of bacterial resistance is increasing and as only a few new antibiotics became available during the last decade, optimal use of established agents and preserving their effectiveness seems vital. Objectives: 1) To find the descriptor of body size and body composition which allows to achieve target concentrations and target effects in patients with cystic fibrosis (CF) most precisely. 2) To identify the mode of administration with the highest probability of successful treatment for intravenous beta-lactams. 3) To develop formulas for optimal dose selection for patients of various body size. General methods: Drug analysis in plasma and urine was performed by HPLC or LC-MS/MS in a single laboratory, at the IBMP. Drug analysis was not done by the author of this thesis. We used non-compartmental analysis and parametric population PK analysis for all studies. We used non-parametric bootstrapping to assess the uncertainty of PK parameters for our meta-analysis of the PK in CF-patients and healthy volunteers. Plasma concentration time profiles for several thousand virtual subjects were simulated by MCS which account for average PK parameters, their between subject variability (BSV), and patient specific demographic data. Convincing literature data show that the duration of non-protein bound concentration above MIC (fT>MIC) best predicts the microbiological and clinical success of beta-lactams and the area under the non-protein bound concentration curve divided by the MIC (fAUC/MIC) best predicts success for quinolones. We used PKPD targets from literature that were based on the fT>MIC or fAUC/MIC, respectively. Achieving a PKPD target was used as a surrogate measure for successful treatment. In our MCS, we calculated the fT>MIC or fAUC/MIC for all simulated concentration profiles and compared it to the value of the PKPD target. The fraction of subjects who achieved the target at the respective MIC approximates the probability of target attainment (PTA). The PTA can be interpreted as probability of successful treatment under certain assumptions. Studies in CF-patients Methods: We had data from ten studies (seven beta-lactams and three quinolones) in CF-patients which all included a healthy volunteer control group. Clinical procedures were very similar for all ten studies. Both subject groups had study conditions as similar as possible. We had data on 90 CF-patients (average +/- SD, age: 21+/-3.6 yrs) and on 111 healthy volunteers (age: 25+/-3.5 yrs). We compared the average clearance and volume of distribution between CF-patients and healthy volunteers for various body size descriptors including total body weight (WT), fat-free mass (FFM), and predicted normal weight (PNWT). We considered linear and allometric scaling of PK parameters by body size and used a meta-analysis based on population PK parameters for the comparison of CF-patients and healthy volunteers. Target concentrations can be achieved more precisely, if a size descriptor reduces the random, unexplained BSV. Therefore, we studied the reduction of unexplained BSV for each size descriptor relative to linear scaling by WT, since doses for CF-patients are commonly selected as mg/kg WT. Results: Without accounting for body size, average total clearance was 15\% lower (p=0.005) and volume of distribution at steady-state was 17\% lower (p=0.001) in CF-patients compared to healthy volunteers. For linear scaling by WT, average total clearance in CF-patients divided by total clearance in healthy volunteers was 1.15 (p=0.013). This ratio was 1.06 (p=0.191) for volume of distribution. A ratio of 1.0 indicates that CF-patients and healthy volunteers of the same body size have identical average clearances or volumes of distribution. For allometric scaling by FFM or PNWT, the ratio of total clearance and volume of distribution between CF-patients and healthy volunteers was within 0.80 and 1.25 for almost all drugs and the average ratio was close to 1. Allometric scaling by FFM or PNWT reduced the unexplained BSV in renal clearance by 24 to 27\% (median of 10 drugs) relative to linear scaling by WT. The unexplained BSV was reduced for seven or eight of the ten drugs by more than 15\% and the remaining two or three drugs had essentially unchanged (+/-15\%) unexplained BSVs in renal clearance. Conclusions: The PK in CF-patients was comparable to the PK in healthy volunteers after accounting for body size and body composition by allometric scaling with FFM or PNWT. Target concentrations and target effects in CF-patients can be achieved most precisely by dose selection based on an allometric size model with FFM or PNWT. Future studies are warranted to study the clinical superiority of allometric dosing by FFM or PNWT compared to dose selection as mg/kg WT in CF-patients.},
  subject      = {Populationskinetik},
  language  = {en}
}
@article{ShahBulittaKinzigetal.2019,
  author    = {Shah, Nirav R. and Bulitta, J{\"u}rgen B. and Kinzig, Martina and Landersdorfer, Cornelia B. and Jiao, Yuanyuan and Sutaria, Dhruvitkumar S. and Tao, Xun and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Kees, Frieder and Stephan, Ulrich and S{\"o}rgel, Fritz},
  title     = {Novel population pharmacokinetic approach to explain the differences between cystic fibrosis patients and healthy volunteers via protein binding},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {6},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11060286},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196934},
  year      = {2019},
  abstract  = {The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3\% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50\% in male and estimated as 54.5\% in female healthy volunteers as well as 56.3\% in male and 74.4\% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.},
  language  = {en}
}
@article{BulittaJiaoLandersdorferetal.2019,
  author    = {Bulitta, J{\"u}rgen B. and Jiao, Yuanyuan and Landersdorfer, Cornelia B. and Sutaria, Dhruvitkumar S. and Tao, Xun and Shin, Eunjeong and H{\"o}hl, Rainer and Holzgrabe, Ulrike and Stephan, Ulrich and S{\"o}rgel, Fritz},
  title     = {Comparable Bioavailability and Disposition of Pefloxacin in Patients with Cystic Fibrosis and Healthy Volunteers Assessed via Population Pharmacokinetics},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {7},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11070323},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197221},
  pages     = {323},
  year      = {2019},
  abstract  = {Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74\% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90\% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.},
  language  = {en}
}