@phdthesis{Landersdorfer2006,
  author    = {Landersdorfer, Cornelia},
  title     = {Modern pharmacokinetic-pharmacodynamic techniques to study physiological mechanisms of pharmacokinetic drug-drug interactions and disposition of antibiotics and to assess clinical relevance},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19340},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {There are numerous areas of application for which PKPD models are a valuable tool. We studied dose linearity, bone penetration and drug-drug interactions of antibiotics by PKPD modeling. Knowledge about possible saturation of elimination pathways at therapeutic concentrations is important for studying the probability of successful treatment of dosage regimens via MCS at various doses, other modes of administration, or both. We studied the dose linearity of flucloxacillin and piperacillin. For data analysis of the dose linearity studies, population PK modeling and MCS was used. Population PK has been reported to detect saturable elimination at lower doses, and to estimate BSV more precisely than the STS approach. The variability in PK and the expected variability in PD are combined in a MCS to predict the probability of successful treatment. Flucloxacillin showed no saturation of elimination at the studied doses of 500 mg and 1000 mg. Comparison of various dosage regimens showed, that only one third of the daily dose is needed with prolonged or continuous infusion to achieve the same probability of successful treatment as short-term infusions at the full dose. For serious infections with sensitive staphylococci that are treated with intravenous flucloxacillin, prolonged infusion and continuous infusion are an appealing treatment option. Contrary to flucloxacillin, renal elimination and to a lesser extent also nonrenal elimination of piperacillin were saturable at therapeutic concentrations. Renal clearance decreased by 24\% (p = 0.02) after a dose of 3000 mg piperacillin compared to the 1500 mg dose. A model without saturable elimination predicted PTA expectation values that were 6 to 11\% lower for high dose short-term infusions and 2 to 5\% higher for low dose continuous infusions, compared to models with saturable elimination. These differences depend on the MIC distributions of the local hospital. However, more accurate estimates for the PTA expectation value can be obtained by including an existent saturable elimination pathway into the PK model. Developing a mechanistic model of an interaction allows one to predict the extent of the interaction for other doses of drug and inhibitor. We studied the interactions between gemifloxacin and probenecid, between ciprofloxacin, its metabolite M1 and probenecid, and between flucloxacillin and piperacillin. Mechanistic models for drug-drug interactions were developed by the STS approach. This approach directly accounts for the concentration dependence of an interaction and describes the full time course of an interaction. Probenecid significantly inhibited the renal elimination of gemifloxacin, ciprofloxacin and ciprofloxacin's metabolite M1, and slightly decreased nonrenal clearance of gemifloxacin. Piperacillin significantly decreased renal and nonrenal clearance of flucloxacillin, but hardly vice versa. For all three interactions competitive inhibition of a capacity-limited renal elimination pathway was identified as the most likely mechanism. As those drugs are all actively secreted in the renal tubules, competitive interaction is physiologically reasonable. Probenecid had a lower affinity to the renal transporter than gemifloxacin, ciprofloxacin and M1. Due to its substantially higher concentrations, probenecid inhibited the elimination of the quinolones. The affinity of piperacillin for the renal transporter was 13 times higher compared to flucloxacillin. Piperacillin PK was only slightly affected by flucloxacillin. PK interactions with piperacillin are likely to occur also with other betalactam combinations. PK interactions may be useful to improve the PD profile of an antibiotic, however possibly increased risks for side effects (e.g. risk of rash for gemifloxacin and probenecid) have to be considered.},
  subject      = {Populationskinetik},
  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}
}
@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}
}