@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}
}
@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}
}
@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}
}
@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}
}