@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{IsbernerGesierichBalakirouchenaneetal.2022,
  author    = {Isberner, Nora and Gesierich, Anja and Balakirouchenane, David and Schilling, Bastian and Aghai-Trommeschlaeger, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Puszkiel, Alicja and Blanchet, Benoit and Klinker, Hartwig and Scherf-Clavel, Oliver},
  title     = {Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {19},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14194566},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288109},
  year      = {2022},
  abstract  = {Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.},
  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}
}