To assess the relation of cisplatin-induced nephrotoxicity to its pharmacology.
In 22 chemonaive patients (median age, 32 years) receiving 100-150 mg/m2 cisplatin for a total of 54 courses of therapy ...pharmacokinetics of ultra-filtrable platin were analyzed. Nephrotoxicity was sensitively assessed by nephelometric analyses of urinary marker-proteins.
The parameters calculated for ultrafiltrable platin were (two-compartment-model): terminal half-life, 36 hours (coefficient of variation CV, 22%); AUC, 12852 ng h/ml (33%); volume of distribution, 3531 (44%); total clearance, 285 ml/min (30%); renal clearance, 149 ml/min (23%); maximum concentration, 1720 ng/ml (66%); renal elimination, 57% of applied dose (26%). A pathological urinary excretion of albumin > 20 mg/l and alpha-1-microglobulin > 10 mg/l was detected in 39 out of 54 and 42 out of 54 cycles, respectively. The degree of albuminuria was related with urinary monoaquoplatin concentrations (p = 0.003).
Nephrotoxicity of cisplatin appears to depend on the urinary monoaquoplatin concentrations which may be modulated by application of saline.
Zielsetzung:
Die Robinson-Klassifikation spiegelt die Heterogenität der Bronchialkarzinome mit mediastinalem Lymphknotenbefall (N2) wider. Die vorliegende Studie untersucht die Leitlinienadaptiere ...Therapie dieser Patienten.
Methode:
Retrospektive Analyse (1/2009 – 6/2014) von 118 Bronchialkarzinompatienten im Stadium IIIA-N2. Die Therapieempfehlungen erfolgten in Anlehnung an die deutschen S3-Leitlinien in der Tumorkonferenz.
Ergebnis:
Eingruppierung entsprechend Robinson-Klassifizierung: IIIA
1
(n = 28), IIIA
3
(n = 70) und IIIA
4
(n = 20). Eine Zuordnung zu IIIA
2
gab es nicht (kein intraoperativer Schnellschnitt von Lymphknoten). Eine chirurgische Resektion des Tumors erfolgte bei allen Patienten mit Stadium IIIA
1
, bei 47% in IIIA
3
und 10% in IIIA
4
. Die R0-Rate war 93% im Stadium IIIA
1
, 94% in IIIA
3
und 100% in IIIA
4
. Die 30 Tage-Letalität war 3,14%. Das mediane Überleben aller Patienten (n = 115) betrug 29,8 Monate, die 3- bzw. 5-JÜR lagen bei 44,9% bzw. 28,5%. Das Überleben zwischen den einzelnen Gruppen (IIIA
1
bis IIIA
4
) unterschied sich nicht signifikant (p = 0,477).
Patienten mit Resektion des Tumors (n = 60) hatten ein besseres medianes Überleben (43,6 vs. 22,8 Monate; p = 0,013) im Vergleich zu nicht operativ behandelten Patienten (n = 55). Auch im Stadium IIIA
3
spiegelte sich dieser Vorteil wider (OP vs. konservative Therapie: 45,4 vs. 22,8 Monate; p = 0,014).
Die Nicht-Einhaltung der empfohlenen Therapie (Therapieabbruch, -ablehnung) führte zu einer Reduktion des medianen Überlebens (12,9 vs. 31,9 Monate; p = 0,011) im Vergleich zur Einhaltung der vorgeschlagenen Behandlung.
Schlussfolgerung:
Die Einteilung in die Robinson-Klassifikation ist von Bedeutung für die Therapie und Prognose. Die Umsetzung der Therapieempfehlung wirkt sich deutlich auf das Überleben aus. Die Operation führt im Vergleich zu konservativen Therapien zu deutlich besseren Überlebensraten. Die Resektion sollte daher auch im Stadium IIIA
3
und IIIA
4
immer als Therapieoption geprüft werden.
Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.) -- and cannot be applied orally due to its hydrophilic properties. ...These limitations might be overcome by YNK01 -- a lipophilic prodrug of AraC -- that is resistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase I/II study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m2 (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m2 dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic psi and subsequent beta-oxydation of YNK01 the released AraC (and its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve (ng x h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1 (0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m2 plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m2) while at doses of YNK01 of 450-600 mg/m2 concentrations of standard-dose AraC (100 mg/m2) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.
The current study was initiated to explore the mechanisms underlying the previously demonstrated association between the proliferative activity of leukaemic blasts and the response to cytosine ...arabinoside (AraC)‐based therapy in de novo acute myeloid leukaemia (AML). The activity of key enzymes of AraC metabolism–deoxycytidine kinase (DCK), cytidine deaminase (DCD) and polymerase α (PolyA) were determined in blast cells from 33 patients. In addition, formation and retention of intracellular levels of AraC triphosphate (AraCTP) and DNA incorporation of AraC were measured, as was the proliferative activity of leukaemic blasts by 3H‐TdR incorporation before and after stimulation with granulocyte–macrophage colony‐stimulating factor (GM‐CSF) or granulocyte CSF (G‐CSF) for 48 h. AraC incorporation into the DNA (median 0·60 pmol/105 cells) was significantly related to the proliferative activity of AML blasts (r = 0·74, P < 0·001). Similarly, priming with GM‐CSF or G‐CSF increased both the proliferative activity of AML blasts by a median of 1·84‐ and 1·64‐fold, respectively, and the incorporation of AraC into the DNA (1·29‐ and 1·40‐fold respectively). In contrast, no relationship was found between the endogenous proliferative activity (EPA) and enzyme activities regulating AraC activation (DCK; median 4·70 pmol/min/mg protein), inactivation (DCD; median 2·92 pmol/min/mg protein) or inhibitory effects (PolyA; median 1·50 pmol/min/mg protein), nor the formation or retention of AraCTP (median 306·1 ng/107 cell and 1·6 h respectively). When samples were grouped according to EPA (more than or less than the median), slowly proliferating specimens had a higher response to cytokine priming for proliferative activity and incorporation of AraC into DNA. Clinical data of 15 patients were available. Although all eight patients with a high endogenous proliferative activity reached complete remission, only four out of seven patients with a low proliferative activity responded, whereas the other three patients were non‐responders (P = 0·077).
A 19-year old woman with acute myeloid leukemia presented with newly observed liver lesions during ongoing consolidation therapy. Due to unexplained cholestasis during induction, biliary duct ...drainage was performed. Microbiologic and histologic examinations revealed the presence of atypical mycobacteria, namely Mycobacterium abscessus. With an appropriate antiinfective regime which was continuously administered using a portable pump in the outpatient setting, further mycobacterial spread during simultaneous chemotherapy-associated neutropenia was prevented. Despite multiple bacterial resistance mechanisms, proper treatment of leukemia with curative intention could be ensured.
Different metabolites of cytosine arabinoside (AraC) contribute to its cytotoxicity including incorporation of AraCTP into DNA, the incorporation of AraUMP into RNA, inhibition of polymerase α and β ...(AraCMP/CTP), an impairment of repair mechanisms (AraCTP), alterations of phospholipid metabolism (AraCDP‐choline), a direct membrane interaction (AraC), the alteration of signal transduction pathways (AraCDP‐choline, AraCTP) and the induction of apoptosis. Since little is known about the potential differences in AraC metabolism between leukaemic blasts and normal haemopoietic progenitor cells, the formation of all known AraC metabolites was determined in bone marrow samples from patients with acute myeloid leukaemia (AML), healthy volunteers and specimens of cellsorted CD34+ haemopoietic stem cells. Highly significant differences were found for phosphorylated AraC metabolites (AraCMP, ‐CDP, ‐CTP, AraUMP) between AML and normal mononuclear bone marrow (ng/107 cells respectively 1.30 v 2.66; 2.65 v 7.50; 33.68 v 99.0; 1.18 v 5.70). The highest differences were found for formation of AraCDP‐choline (3.75 v 12.86) which might be relevant for the high efficacy of high‐dose AraC regimens. In contrast, no differences were found in the deamination product AraU (2.01 v 2.91). Only minute amounts of phosphorylated AraU derivatives were detected, providing an explanation for the lacking contribution of AraU to cytosine arabinoside cytotoxicity. Results in normal CD34+ haemopoietic stem cells did not differ significantly from normal bone marrow mononuclear cells and therefore justify their use as a surrogate in determining AraC‐induced haematotoxicity. These data suggest a metabolic basis for the relative selectivity of AraC cytotoxicity for AML blasts and provide a means to determine the role of different metabolites and their related mechanism of action for overall AraC cytotoxicity.
To further define the most appropriate way of choosing the dose of carboplatin.
The pharmacokinetics of carboplatin were analyzed in 30 patients with advanced lung cancer receiving a total of 48 ...cycles of carboplatin plus paclitaxel/ docetaxel combination chemotherapy. Platin concentrations of ultrafiltrated plasma and urine samples were determined by flameless atomic absorption spectrometry. A multiple regression analysis was performed for interactions between pharmacokinetic parameters and pretreatment characteristics.
Using a twocompartment-model, the following parameters were obtained (mean, coefficient of variation): initial half-life, 0.903 h (48%); terminal half-life, 13.6 h (116%); maximum plasma concentration (Cmax), 38.5 microM (86%); AUC, 111.9 microM/h (86%); volume of distribution, 411 l (130%); total clearance (Ct), 579 ml/min (75%); renal clearance (Cr), 453 ml/min (80%); renal elimination, 76% of dose (17%). In the univariate analysis, age was significantly related to Cmax (P = 0.0303), AUC (P = 0.0050), Ct (P = 0.0020), Cr (P = 0.0092). Plasma creatinine (Crp) was related to Cmax (P = 0.0228), and 1/Crp was related to Cmax (P = 0.0015) and AUC (P = 0.0054), while body weight was related to Cmax (P = 0.0365). No interaction with the schedule of application of the two drugs was observed. In the multivariate analysis, factors significantly related to AUC were 1/Crp (P < 0.01) and age (P < 0.01). Crp (P < 0.05) and 1/Crp (P < 0.01) were significantly associated with Cmax.
These data stress the importance of dosing carboplatin according to renal function and age and warrant further analyses to validate this concept prospectively.
The clinical effects of cytosine arabinoside (AraC) are highly dependent on schedule and dose. Many regimens administered to patients are derived from artificial model systems involving permanent ...leukemic cell lines. The differences in pharmacokinetics between the in vivo situation and such cell lines are largely neglected. However, cytidine deaminase activity in particular has a major impact on AraC pharmacokinetics by degrading AraC to its inactive metabolite AraU, and it has been shown to be of prognostic relevance in the treatment of acute myeloid leukemia. This study therefore investigated cytidine deaminase activities and AraC deamination in a variety of the most commonly used leukemic cell lines and fresh blasts and their impact on the results of an in vitro model system. It was found that cells from different cell lines (BLIN, CEM, HL60, K562, RAJI, REH, U937) vary greatly in cytidine deaminase activity (e.g., 1.89 nmol per min/mg in K562 versus 0.01 in BLIN cells) and degrade between 18.5 (BLIN) and 96.5% (REH) of AraC to AraU in the incubation medium. This degradation results in highly different AraC exposures for different cells (e.g., AUC of 960 ng per h/ml in REH versus 4048 ng per h/ml in BLIN cells) in spite of identical starting concentrations of the drug. Formation of AraCTP as the main cytotoxic metabolite of AraC is significantly influenced by the differences in cell type-dependent cytidine deaminase activity (e.g., 35.6 ng/10(7) cells in REH versus 180.2 ng/10(7) cells in BLIN cells). In contrast to permanent cell lines, fresh leukemic blasts and normal bone marrow mononuclear cells featured low AraC degradation in the model system.
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