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In der taglichen Praxis stehen Onkologen vor vielen Herausforderungen, um ihre Patienten optimal zu versorgen. Nicht nur der Einsatz innovativer und teurer Medikamente, sondern auch die individuelle Dosisanpassung der eingesetzten Medikamente kann im Einzelfall die Therapie erheblich verbessern. In den letzten Jahren ist die Dosisanpassung anhand gemessener Plasmakonzentrationen (Therapeutisches Drug Monitoring) als Alternative zur traditionellen Dosierung nach Korperoberflache in der Onkologie zunehmend in den Fokus geruckt. Doch wie funktioniert diese „alternative“ Art der Dosisanpassung in der Praxis, und welchen Nutzen bringt sie fur die Patienten?

Background Pharmacogenetic (PGx) testing may enhance patients’ confidence in the safety and efficacy of prescribed medications. Purpose To evaluate public perception of PGx testing. Material and methods A self-administered questionnaire was developed and psychometrically evaluated using a two round Delphi technique for validation and test–retest for reliability. The questionnaire consisted of two sections (A and B) with a total of 20 questions. Section A dealt with general questions about PGx testing and section B focused on participants’ willingness towards PGx testing. Following ethics approval, 500 participants were recruited by convenience sampling over 6 weeks (June and July 2016); 250 from public places in 11 different localities and 250 from 5 community pharmacies in different localities. Participants in health oriented occupations were excluded. Descriptive statistics were calculated with IBM SPSS V.23. Results Of the 500 participants, the majority (61%) were women, mean age was 45 years (range 18–86 years) and most (37%) were educated to post-secondary level. The majority (85%) were not aware of the term PGx testing. Following an explanation by the investigator, most participants indicated that they would be ‘very willing’ to have a PGx test performed to assess the effectiveness (37%) and safety (39%) of their prescribed medications and the majority (51%) ‘strongly agreed’ that a PGx test would prevent them from taking an inappropriate drug or dose. The majority (70%) of participants identified drugs to treat cancer as the drug class for which they perceived PGx testing to be most important. The majority (67%) of participants selected the physician as the professional who should perform the test. As regards the preferred location to have the test performed, the majority (61%) selected the hospital. When asked about the cost of PGx testing, most (42%) participants thought the test should be free of charge. As regards time for result, the majority (56%) of participants would expect to have the result within a few days. Most participants (40%) ‘strongly agreed’ that PGx testing should be performed routinely. Conclusion Participants in this study had a positive overall perception of PGx testing and presented expectations of PGx testing as a means to assess efficacy and safety of prescribed medications. No conflict of interest

Viele Patienten weichen bei der Einnahme von Arzneimitteln vom verordneten Therapieschema ab. Noncompliance kann sehr unterschiedliche Grunde haben, welche von der Vergesslichkeit des Patienten bis hin zu gesundheitspolitischen Rahmenbedingungen reichen. Neben jahrlich verursachten Kosten in Milliardenhohe stellt mangelhafte Therapietreue eine Gefahrdung der Patienten sowie der angestrebten Therapieziele dar. Demnach ist es dringend erforderlich, der Forderung der Compliance in der Patientenbetreuung eine hohe Prioritat zu geben. Am Anfang dieses Prozesses steht zunachst die Erkennung von Noncompliance in der taglichen Routine. Verschiedene Erfassungsmethoden konnen daruber hinaus Aufschluss uber Einnahmegewohnheiten und Ursachen fur eine mangelnde Therapietreue der Patienten geben. Basierend auf den gewonnenen Erkenntnissen konnen schlieslich geeignete Masnahmen zur Forderung der Compliance ergriffen werden. In diesem Beitrag werden Chancen und Grenzen der Complianceforderung diskutiert.

Doripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa . While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.

Albeit platinum complexes are widely used in cancer chemotherapy, their cellular processing has not been completely elucidated so far. In this study the effects of modulating multidrug resistance-associated protein (MRP)-mediated efflux and glutathione (GSH) depletion on the cytotoxicity of oxaliplatin were assessed in a human ileocecal colorectal adenocarcinoma cell line and its oxaliplatin-resistant variant. Upon oxaliplatin exposure, DNA platination was elevated by co-incubation with Gü83, a MRP1 and MRP2 inhibitor, but cytotoxicity was not increased. Addition of oxaliplatin did not alter the cellular GSH content. Following GSH depletion, platinum accumulation was unchanged but cytotoxicity was increased in oxaliplatin-sensitive cells. In conclusion, modulation of MRP-mediated efflux did not affect oxaliplatin cytotoxicity in the investigated cell lines. Intracellular GSH depletion seems to sensitize the cells but does not overcome resistance.

In the execution of their pharmacotherapy, many patients deviate from the prescribed treatment regimen. Reasons for noncompliance can be diverse and range from forgetfulness of the patient to attributes of the health care system. Besides increased health care costs, poor compliance causes both an endangerment to the patient and poor health outcomes. Therefore, it is crucial that compliance enhancement receives high priority. In the beginning of this process, noncompliance must be detected in daily practice. Moreover, various methods can provide valuable information about medication-taking behavior, time patterns, and reasons for noncompliance. Based on this assessment, appropriate measures to enhance compliance can be taken. In this article, the opportunities and limitations of compliance enhancement are discussed.

Background: In contrast to other breast cancer subtypes, triple negative breast cancers are characterized by an absence of recurrent genetic alterations. However, alterations in the PI3K pathway are frequently observed, either through mutation or amplification of PIK3CA or the loss of the negative regulator PTEN. As a result, inhibitors of this pathway, including inhibitors of mTOR, the downstream target of the PI3K pathway, have been explored in the clinic. It has been found that mutational activation of PI3K represents an important determinant of sensitivity to mTOR inhibitors. Nevertheless, a number of PI3K wild-type cell lines also show sensitivity to these inhibitors, although the regulators of this response are still unknown. We set out to find such modulators of response to mTOR inhibitors in a panel of triple negative breast cancer cell lines initially using high throughput approaches. Material and Methods: We determined the sensitivity of a panel of triple negative breast cancer cell lines to AZD8055 (mTOR inhibitor) and BEZ235 (mTOR/PI3K dual inhibitor). This data was then used together with additional datasets generated for this panel, including RNA expression (by RNA-seq), (phospho-)protein levels (by Reverse Phase Protein Arrays) and mutational status (by post-capture DNA-seq), to carry out regression analysis to identify features correlated with response. Results: We found that the protein expression levels of 4E-BP1, a downstream target of mTOR involved in regulating cap-dependent protein synthesis, correlated with response to both inhibitors. In poorly responding cell lines expressing low levels of 4E-BP1, overexpression of the protein increased sensitivity. Conversely, in sensitive cell lines expressing high levels of 4E-BP1, knock-down of 4E-BP1 led to reduced sensitivity to mTOR inhibition. Conclusions: These results indicate that effective inhibition of protein synthesis downstream of PI3K/mTOR is an important determinant of mTOR inhibitor activity. Given that approximately 20% of breast cancer tumors annotated in The Cancer Genome Atlas show an amplification of the 4E-BP1 locus, such patients would likely benefit from mTOR inhibitor treatment. Furthermore, we hypothesize that mTOR inhibitor response can be improved even in patients expressing low 4E-BP1 by co-treating with agents that induce its expression. To this end, we are currently screening for genes and drugs that modulate 4E-BP1 levels.

Platinum adducts are supposed to be the cytotoxic lesions in DNA after platinum-containing anticancer therapy. Various adducts are formed upon interaction of platinum complexes with nucleotides, but contribution of individual adducts to antitumor activity and toxicity of platinum complexes still remains to be examined. A capillary zone electrophoresis (CZE) method is described that is suitable to separate individual platinum adducts. We investigated the formation of adducts following the reaction of cis-diamminedichloroplatinum (II) (cisplatin) with various DNA nucleotides. Baseline separation of unmodified and modified nucleotides (adducts) was achieved using uncoated fused-silica capillaries and basic separation buffers. In order to elucidate the observed peak pattern, a coupled CZE-electrospray ionization-mass spectrometry (ESI)-MS approach was applied. After incubation of mononucleotides with cisplatin, monochloro, monoaqua and bifunctional adduct species were detected. Consequently, the migration order of nucleotides and individual platinum adducts could be determined. Moreover, the time-dependent conversion from monochloro to monoaqua and subsequently to bifunctional adducts was monitored. In conclusion, individual platinum adducts were separated by CZE and identified by CZE-ESI-MS. Formation and conversion of distinct species were confirmed. Potential applications comprise studies of novel platinum complexes, investigations of platinum-adduct formation with DNA, and determination of platinum-DNA adducts in cells.

The optimum dose of calcium folinate (leucovorin) as modulator of fluorouracil has not been defined yet. We conducted a randomized trial to compare the pharmacokinetics/pharmacodynamics of two doses of calcium folinate. 16 patients with advanced colorectal cancer were treated with 650 mg/m2/d fluorouracil as 5 day continuous infusion and randomized to receive either 20 mg/m2 or 100 mg/m2 calcium folinate as short infusion twice daily. The two diastereoisomers of calcium folinate were analyzed separately by chiral HPLC to account for differences in their pharmacokinetics. The pharmacokinetics of fluorouracil was not affected by folinate dosing. Total clearance of the active (6S)-diastereoisomer was found to be lower after the higher dose of folinate which can be explained by nonlinear metabolism. The incidence of treatment-induced mucositis significantly increased with (6S)-folinate exposure, whereas fluorouracil exposure was not related to this type of toxicity. In conclusion, exposure to folinate is more important for toxicity in this regimen than fluorouracil pharmacokinetics. Therefore, monitoring of fluorouracil plasma levels is not useful in this combination. Our results show that folinate dose should be carefully selected. Lower doses of folinate might be preferred because of less toxicity compared to higher doses.

Summary Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m2 to be the maximum tolerable dose of 5-fluorouraci l (5-FU) administered as a five-day continuous infusion modu- lated by short infusions of 100 mg/m2 folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effective- ness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m2 recommended dose of 5-FU and 100 mg/m2 folinic acid twice daily every three weeks. Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemo- therapy were included in this trial. Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months. Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.

Confocal laser scanning microscopy (CLSM) was used to quantify and visualize the transport of the octapeptide and somatostatin analogue, octreotide (SMS 201-995, Sandostatin), across monolayers of bovine cerebrovascular endothelial cells, an in vitro model of the blood-brain barrier. The concentrations of octreotide and its conjugates in the cell culture medium were determined by radioimmunoassay (RIA). Two fluorescent conjugates of octreotide (FITC- and NBD-octreotide) were used to obtain CLSM images. The peptides did not undergo significant degradation in the presence of brain endothelial cell monolayers. The transport rate of octreotide expressed as clearance (Cl) and endothelial permeability (Pe) did not depend on either the initial concentration (between 10 nM and 1 microM) or the site of administration (luminal or abluminal side of the monolayer), indicating the absence of saturable and/or asymmetrical transport mechanisms. The Pe of octreotide and that of the paracellular permeability marker fluorescein correlated well. Although the conjugates are more lipophilic than octreotide itself, they exhibited lower Cl and Pe, values probably because of their larger molecular size. On the CLSM images, FITC-octreotide was present only in the intercellular space, while the cells did not exhibit detectable fluorescence. Transport studies and CLSM images suggest that octreotide passes the endothelial monolayer primarily via the paracellular route without significant contribution of carrier-mediated transport.

The transport of the antiviral nucleoside analogue zidovudine (3'-azido-3'-deoxythymidine; AZT) into the central nervous system (CNS) was characterized in vitro and in vivo. The in vitro model consisted of primary cultures of isolated bovine capillary endothelial cells. The transport rate of AZT across the monolayer, expressed as endothelial permeability P, was determined following luminal and abluminal administration. P did not differ between the two administration sites (luminal, 1.65 +/- 0.44 cm/min/10(3); abluminal, 1.63 +/- 0.28 cm/min/10(3)). The transport of AZT across the endothelial cell monolayer was found to be concentration independent in the range between 0.4 and 50 micrograms/mL. AZT transport was not affected by pretreatment of the cells with either metabolic inhibitors (DODG and DODG/NaN3) or probenecid. This suggests that AZT passes the monolayer mainly by passive diffusion. The in vivo transport of AZT across the blood-brain barrier and the blood-CSF barrier was studied in male Wistar rats after coadministration of potential inhibitors of active transport of AZT: probenecid (organic anion transport) and thymidine (nucleoside transport). Intracerebroventricular and intravenous coadministration of probenecid caused a significant (P0.001) increase in the CSF/plasma concentration ratio compared to the control phase, indicating that the organic anion carrier is involved in AZT transport from CSF to blood. Since there was no effect of probenecid on the transport of AZT in vitro, it is suggested that this carrier is located at the choroid plexus. Coadministration of thymidine did not affect the CSF/plasma concentration ratio, suggesting that a nucleoside carrier system is not involved in AZT transport into or out of the CNS.

The disposition of ciprofloxacin and pefloxacin in the rat cerebrospinal fluid (CSF) was investigated after i.v. and i.c.v. administration. After injection into the lateral ventricle, the terminal half-life of pefloxacin was shorter than that of ciprofloxacin. After i.v. infusions, the relative CSF exposure, expressed as CSF: area under the plasma concentration time curve ratio, were found to be 10.4 +/- 2.8% for ciprofloxacin and 42.4 +/- 3.0% for pefloxacin. The unit impulse response methodology was applied in order to assess the CSF transport profile. The plasma-CSF transport clearance of pefloxacin and the total amount of drug transported into the CSF were significantly higher compared with ciprofloxacin. Although pefloxacin exhibited a linear CSF transport profile, the plasma-CSF transport clearance of ciprofloxacin was found to be nonlinear at the dose level studied. Pefloxacin was converted in the brain to the active metabolite norfloxacin (N-desmethyl pefloxacin). The difference in CSF exposure of both quinolones and the presence of active metabolites of N-methylated quinolones in the CSF may be of clinical relevance in the treatment of CNS infections, but differences in antimicrobial activity have to be taken into account as well.

Background/Aims The BEACOPP chemotherapy regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) used for Hodgkin's disease has a superior outcome, but pronounced and variable toxicity (mainly hematotoxicity). The present study was carried out to identify the impact of individual pharmacokinetics on the degree of hematotoxicity. Methods In 30 patients treated with BEACOPP, three plasma samples and urine collected over 24h on the first day of the first three cycles were analysed. Demographic data, doses, infusion times and blood cell counts were recorded. Pharmacokinetics parameters of the antineoplastic agents were estimated with population pharmacokinetic methods (NONMEM software); factors with potential influence on platelet counts were identified by ANOVA using a general linear model. Results Pharmacokinetic parameters could be calculated successfully for cyclophosphamide, etoposide, doxorubicin, and procarbazine. Creatinine clearance, infusion rates of etoposide and urinary excretion rates of N-dechloroethylcyclo-phosphamide and carboxycyclophosphamide had a significant effect on the decrease in platelet count from day 1 to day 8 of each cycle, explaining 46% of the interindividual variability of this parameter. Conclusions Individualization of treatment based on the factors identified here may decrease toxicity of the BEACOPP polychemotherapy regimen. Clinical Pharmacology & Therapeutics (2005) 77, P18–P18; doi: 10.1016/j.clpt.2004.11.070

A postoperatively reduced concentration of AA in plasma ( 45.5 μmol/l in 89.6% overnight. In conclusion, the investigated substitution procedure is sufficient to increase the AA plasma concentration overnight to high normal values in postoperative ICU patients.

A new anticancer-active platinum(II) compound [Pt(A9pyp)(dmso)(cbdca)], containing the E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone ligand (abbreviated as A9pyp) has been synthesized by the replacement of the anionic chloride ligands in cis -[Pt(A9pyp)(dmso)Cl 2 ] by the dianionic chelating cyclobutanedicarboxylate ligand (abbreviated as cbdca). The in vitro relevance of the leaving group of these new platinum(II) compounds has been investigated. Measurements of the time-dependent intracellular accumulation of both compounds in human ovarian carcinoma cell lines show that the leaving group affects their cellular uptake. In addition, the leaving group also influences DNA platination, and, therefore, has an effect on the biological activity against a pair of human ovarian carcinoma cell lines, i.e. sensitive and resistant to cisplatin.