Untersuchungen zur minimalen Resterkrankung bei der akuten myeloischen Leukämie im Kindesalter

Die prognostische Bedeutung der minimalen Resterkrankung (MRD) bei der akuten myeloischen Leukaemie (AML) im Kindesalter ist noch nicht bekannt. Mit einer Sensitivitaet von 10-4 bis 10-5 ist die molekulargenetische Detektion residualer Zellen möglich, jedoch zeigen nur etwa 30 % der Kinder mit AML eine Mutation. Die immunologische Detektion leukaemie-assoziierter Immunphaenotypen (LAIP) gelingt zwar bei 80 - 90 % der Kinder, jedoch ist die Durchflusszytometrie nicht ausreichend standardisiert. Ein 4-Farb-Konsensus-Panel wurde entwickelt und dessen Spezifitaet und Sensitivitaet bestimmt. Es konnten drei Gruppen an LAIP mit unterschiedlicher Spezifitaet für die Detektion der MRD bestimmt werden. Die Untersuchung von 55 Kindern mit AML zeigte, dass ein positives immunologisches MRD-Ergebnis (MRD+) mit einem 1,8-fach erhöhtem Rezidiv-Risiko bei früherem Eintreten des Rezidivs assoziiert ist. Die qualitative Bestimmung AML-spezifisicher Gen-Rearrangements (REAR) AML1/ETO, CBF-beta/MYH11 sowie MLL-REARs sind zur MRD-Detektion nicht geeignet; die quantitative Analyse des AML1/ETO-REARs scheint dahingegen vielversprechender zu sein

Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults : a survey by the Transplant Complications Working Party of the EBMT

A survey was carried out among EBMT centers about the use of busulfan for conditioning in allogeneic stem cell transplantation. Of 109 responding centers, 106 used busulfan for conditioning, 102 in conventional myeloablative doses, and 93 in reduced doses (RIC). The route of administration was mostly intravenous, but similar to 10% of the centers gave the drug orally. The number of doses in i.v. administration varied and was in myeloablative conditioning mostly one (50 centers) or four (43 centers) doses a day. Seventeen of the 106 centers used pharmacokinetics for dose adjustment in myeloablative conditioning, nine in RIC. The details of pharmacokinetic monitoring varied markedly. Three quarters of the centers reported adjusting the dose based on obesity in myeloablative conditioning and about 60% in RIC. The most common method for dose calculation was ideal body weight + 0.25 x (actual body weight - ideal body weight). In conclusion, the present survey showed marked heterogeneity in the current practices of busulfan administration for conditioning. The impact of the heterogeneity is not well known. Due to this and the scarcity of support from controlled clinical studies, no clear guidelines can be presented, but some prevailing policies to be recommended were identified.Peer reviewe

Drug dosing and monitoring in obese patients undergoing allogenic stem cell transplantation

Background The effects of physiological changes in patients with obesity on pharmacokinetic parameters and the time course of drug response, especially in the field of haematology/oncology, are poorly understood. For some antimicrobial drugs, dosing considerations exist, while for cytostatic drugs, dose modifications for obese patients are not consistently recommended. Glomerular filtration rate and renal perfusion appear to be similar in obese and normal weight individuals, thus elimination of hydrophilic and extensively renally cleared drugs mainly depends upon creatinine clearance. Aim of the review To provide information about drug dosing in morbidly obese patients undergoing allogenic haematopoietic stem cell transplantation and to develop dosing recommendations for those patients, based on literature data, pharmacokinetic properties and own experiences. Method A review on the literature on drug dosing in obese patients as well as on the pharmacokinetic properties of drugs which are supposed to be used in the field of stem cell transplantation was combined with own data on drug dosing and pharmacokinetic drug monitoring in a morbidly obese patient undergoing matched-unrelated allogenic peripheral blood stem cell transplantation. Results For hydrophilic and extensively renally cleared drugs (e.g. piperacillin/sulbactam, cotrimoxazole, fludarabine) standard dosages for adult patients or dosing based on ideal body weight (IBW) (e.g. aciclovir, methotrexate) can be used. For ciclosporin and digitoxin we could show that high initial doses are needed to achieve sufficient plasma concentrations. After steady state distribution was completed, maintenance doses comparable to normal weight patients are sufficient. Likewise, distribution of enoxaparin and phenytoin seems to take longer in obese patients. Dosing recommendations of 25 drugs that can be used in morbidly obese patients undergoing allogenic stem cell transplantation are given. Conclusions Pharmacotherapy in morbidly obese patients undergoing allogenic stem cell transplantation is possible, if pharmacokinetic properties of the drugs are considered and close monitoring of plasma concentrations is performed

Evaluation of the Robustness of Therapeutic Drug Monitoring Coupled with Bayesian Forecasting of Busulfan with Regard to Inaccurate Documentation

Background!#!Inaccurate documentation of sampling and infusion times is a potential source of error in personalizing busulfan doses using therapeutic drug monitoring (TDM). Planned times rather than the actual times for sampling and infusion time are often documented. Therefore, this study aimed to evaluate the robustness of a limited sampling TDM of busulfan with regard to inaccurate documentation.!##!Methods!#!A pharmacometric analysis was conducted in NONMEM® 7.4.3 and 'R' by performing stochastic simulation and estimation with four, two and one sample(s) per patient on the basis of a one-compartment- (1CMT) and two-compartment (2CMT) population pharmacokinetic model. The dosing regimens consisted of i.v. busulfan (0.8 mg/kg) every 6 h (Q6H) or 3.2 mg/kg every 24 h (Q24H) with a 2 h- and 3 h infusion time, respectively. The relative prediction error (rPE) and relative root-mean-square error (rRmse) were calculated in order to determine the accuracy and precision of the individual AUC estimation.!##!Results!#!A noticeable impact on the estimated AUC based on a 1CMT-model was only observed if uncertain documentation reached ± 30 min (1.60% for Q24H and 2.19% for Q6H). Calculated rPEs and rRmse for Q6H indicate a slightly lower level of accuracy and precision when compared to Q24H. Spread of rPE's and rRmse for the 2CMT-model were wider and higher compared to estimations based on a 1CMT-model.!##!Conclusions!#!The estimated AUC was not affected substantially by inaccurate documentation of sampling and infusion time. The calculated rPEs and rRmses of estimated AUC indicate robustness and reliability for TDM of busulfan, even in presence of erroneous records

Arzneimittelinteraktionen

Arzneimittelinteraktionen können sowohl zwischen verschiedenen Arzneimitteln auftreten als auch zwischen Arzneimitteln und Nahrungs- oder Genussmitteln. Häufig werden Arzneimittelinteraktionen als unerwünscht bezeichnet, es gibt jedoch auch solche, die bewusst therapeutisch genutzt werden. Als Beispiel seien hier Kombinationschemotherapien oder die Kombination des starken Cytochrom-P-450-Inhibitors Ritonavir mit anderen antiretroviralen Arzneistoffen (Proteaseinhibitoren) genannt, um deren Exposition zu erhöhen. Das Potenzial für unerwünschte Arzneimittelinteraktionen in der Onkologie hat mit der wachsenden Anzahl verschiedener Substanzklassen und der immer größeren Komplexität der Pharmakotherapie schwer kranker Patienten erheblich zugenommen. Die Kenntnisse um solche Interaktionen sind in den letzten Jahren gestiegen – nicht zuletzt durch eindrucksvolle Beispiele aus der klinischen Praxis (z.B. erhebliche Toxizitäten bei gleichzeitiger Verwendung von Vincristin und Azol-Antimykotika oder von hochdosiertem Methotrexat (MTX) mit Arzneistoffen, die um die MTX-Ausscheidung konkurrieren oder andererseits der Wirkungsverlust von CarbapenemAntibiotika bei gleichzeitiger Anwendung von Valproat). Obwohl inzwischen die Verwendung von Interaktionsdatenbanken (ggf. in Verbindung mit einem elektronischen Arzneimittel-Verordnungssystem) weit verbreitet ist, ist es im klinischen Alltag nahezu unmöglich, alle klinisch relevanten Interaktionen am Patienten zu überblicken. Im Folgenden sollen daher die Mechanismen von Arzneimittelinteraktionen sowie allgemeine Grundsätze zu ihrer Vermeidung in der klinischen Praxis vermittelt werden

Clinical pharmacy services in Germany: a national survey

Objectives Clinical pharmacy services in German hospitals appear to be underdeveloped compared with other European countries. However, recent developments have increased the interest in expanding these services. Detailed data about the current state of clinical pharmacy services in Germany are lacking. This survey establishes the current level of pharmacy services in Germany and the barriers to implementation. Methods An online survey conducted in 2017 was distributed to directors of all 389 German hospital pharmacies. The survey contained 26 questions addressing hospital and pharmacy characteristics, clinical pharmacy services provided, the number of clinical pharmacists and the frequency as well as the quality assurance of these services. Results There were 133 responses (34%). Of these, 84 (63%) pharmacies provided some form of clinical pharmacy services. Based on the 389 contacted pharmacies, a clinical pharmacy service is available in at least 22% of hospital pharmacies in Germany. On average there are 2.4 full-time equivalent (FTE) clinical pharmacists per hospital employed, although there is a wide variation in numbers (0.3-22 FTE) and service provision between hospitals. Clinical pharmacy services are generally provided on a daily or weekly basis, with a principal focus on general surgery, critical care and general medicine wards. Conclusions This is the first survey providing a detailed picture of clinical pharmacy services in Germany. There is wide variation in clinical service provision among hospitals, with some hospitals having developed a comprehensive range of clinical services. Compared with other countries, particularly the UK where the focus has shifted to provision of 7-day clinical services, the gap in clinical pharmacy services remains large. The focus should be turned to refining clinical pharmacy services in hospital admissions and discharge planning while also improving Health IT, the opportunities for specialisation and aligning education in accordance with the EAHP common training framework

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study

The aim of the study was to describe the population pharmacokinetics (PK) of meropenem in critically ill patients receiving sustained low-efficiency dialysis (SLED).Prospective population PK study on 19 septic patients treated with meropenem and receiving SLED for acute kidney injury. Serial blood samples for determination of meropenem concentrations were taken before, during and after SLED in up to three sessions per patient. Nonparametric population PK analysis with Monte Carlo simulations were used. Pharmacodynamic (PD) targets of 40% and 100% time above the minimal inhibitory concentration (f T > MIC) were used for probability of target attainment (PTA) and fractional target attainment (FTA) against Pseudomonas aeruginosa.A two-compartment linear population PK model was most appropriate with residual diuresis supported as significant covariate affecting meropenem clearance. In patients without residual diuresis the PTA for both targets (40% and 100% f T > MIC) and susceptible P. aeruginosa (MIC ≤ 2\ua0mg/L) was > 95% for a dose of 0.5\ua0g 8-hourly. In patients with a residual diuresis of 300\ua0mL/d 1\ua0g 12-hourly and 2\ua0g 8-hourly would be required to achieve a PTA of > 95% and 93% for targets of 40% f T > MIC and 100% f T > MIC, respectively. A dose of 2\ua0g 8-hourly would be able to achieve a FTA of 97% for 100% f T > MIC in patients with residual diuresis.We found a relevant PK variability for meropenem in patients on SLED, which was significantly influenced by the degree of residual diuresis. As a result dosing recommendations for meropenem in patients on SLED to achieve adequate PD targets greatly vary. Therapeutic drug monitoring may help to further optimise individual dosing.Clincialtrials.gov, NCT02287493