(2007). Paediatric and geriatric drug delivery. Expert Opinion on Drug Delivery: Vol. 4, No. 1, pp. 37-45.

During the last century broad medical progress arose from the development of treatment strategies from natural remedies and the industrial production of drugs. Where there used to be a direct relationship between the natural healer or physician recommending an individualised treatment, the pharmacist preparing a custom-made prescription and the single patient, there is now a drugs market with the pharmaceutical industry on the supplier side, the patient as consumer and physicians who ideally prescribe drugs based on evidence and according to pertinent guidelines. The reproducibility and quality of diagnostic procedures as well as the drug supply have increased and the general benefit for society and individual patients is obvious. Cancer patients have benefited significantly from this process and the overall cure rate of >70% in paediatric malignancies would not have been achieved without cytostatic drugs developed and provided by the pharmaceutical industry.

Rhabdoid tumors mainly affect infants and other very young children with a marked vulnerability towards intensive therapy such as invasive surgery, high dose chemotherapy (HDCT) and dose intense radiotherapy. Radiotherapy (RT) is a promising option in rhabdoid tumors but its application in infants remains controversial. Neurocognitive and vascular side effects occur even long after completion of therapy. Therapeutic recommendations suggested by the European Rhabdoid Registry including RT, high dose chemotherapy (HDCT) and methotrexate (MTX) were developed by a consensus committee. Unique to our EU-RHAB database is the ability to analyze data of 64 of 81 registered infants (under one year of age) separate from older children. 20 (age at diagnoses 2–12 months) of these had received radiotherapy. To our knowledge, this is the first report specifically analyzing treatment data of infants suffering from malignant rhabdoid tumors. Our results suggest that radiotherapy significantly increases the mean survival time as well as the 3 year overall survival in infants. We detected a doubling of survival times in infants who received RT. Overall, our results suggest that infants benefit from RT with tolerable acute side effects. Severe long term sequelae likely due to intraventricular MTX and/or RT were reported in 4 patients (leukoencephalopathy). No differences in chemotherapy-related toxicity were observed between infants and children. We suggest that a nihilistic therapeutic approach towards young infants is not warranted and that RT may not be a priori rejected as a therapeutic option in infants. Rhabdoide Tumoren betreffen hauptsächlich Säuglinge und Kleinkinder. Gerade diese Patientengruppe ist jedoch anfällig für die Nebenwirkungen intensiver Therapien. So können u. a. Hochdosischemotherapie oder Bestrahlung noch lange nach Ende der Behandlung neurokognitive und vaskuläre Schädigungen hervorrufen. Die therapeutischen Empfehlungen der EU-RHAB-Expertengruppe zur Behandlung rhabdoider Tumoren beinhalten Radiotherapie, Hochdosischemotherapie sowie die intraventrikuläre Gabe von Methotrexat (MTX). Die EU-RHAB-Datenbank bietet die einzigartige Möglichkeit, Therapiedaten von Säuglingen (unter 1 Jahr) getrennt von Kindern (über 1 Jahr) analysieren zu können. 64 von 81 registrierten Säuglingen wurden ausgewertet – 20 hiervon erhielten eine Radiotherapie (Alter bei Diagnose: 2–12 Monate). Unsere Ergebnisse zeigen einen signifikanten Anstieg der durchschnittlichen Überlebenszeiten wie auch des 3-Jahre-Überlebens nach einer Radiotherapie. Bei akzeptablen Akutnebenwirkungen sahen wir eine Verdopplung der Überlebenszeit bei Säuglingen, die einer Radiotherapie unterzogen wurden. Schwere neurologische Langzeitnebenwirkungen (Leukoenzephalopathie) wurden bislang bei 4 der mittels Radiotherapie und/oder MTX intraventrikular behandelten Säuglinge registriert. Wir konnten keinerlei Unterschiede im Auftreten von Chemotherapie-bedingten Toxi­zitäten zwischen Säuglingen und Kindern über 1 Jahr feststellen. Wir folgern, dass ein nihilistisches therapeutisches Vorgehen auch im Säug­lingsalter nicht gerechtfertigt ist und gerade die Option einer Radiotherapie in dieser Patientengruppe nicht von vornherein ausgeschlossen werden sollte.

Use of asparaginase (ASNase) in the treatment of relapsed childhood acute lymphoblastic leukaemia (ALL) is associated with a high rate of hypersensitive reactions. ‘Silent’ inactivation may additionally reduce treatment intensity. Therefore, PEG-ASNase (Oncaspar^tm), a polyethylene glycol conjugate of the native Escherichia coli-ASNase, was introduced into the Berlin-Frankfurt-Münster (BFM) 96 treatment protocol for relaped ALL under drug monitoring conditions. A single i.v. dose of 500 IU/m² PEG-ASNase, substituted for the native ASNases, was administered to supply a plasma activity of 100 IU/l for 1 week. From November 1997 to March 2000, 35 patients from 23 BFM-associated hospitals, with or without a previous allergic reaction to one or both native preparations, underwent monitoring. After 82 applications, a total of 270 samples were submitted to be tested for ASNase activity. The ASNase activity on the day of the administration and the following day ranged between < 20 and 693 IU/l, with a median of 413 IU/l (53 samples). The median on d 7 ± 1 was 199 IU/l (range <20–421 IU/l; 41 samples) and on d 14 ± 1, 105 IU/l (range 100 IU/l was seen on d 7 in 36 activity time courses of 52 interpretable applications (69%). Intraindividual variability of activity time courses was low. However, a rapid decrease in ASNase activity after repeated applications was observed in 4 out of 20 children. Previously experienced allergic reactions to native ASNases did not influence PEG-ASNase pharmacokinetics. PEG-ASNase is a useful alternative to the native ASNases in children with relapsed ALL. Whenever possible, drug monitoring should be performed to identify patients with ‘silent’ inactivation.

Purpose Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. Methods We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited. Doses of doxorubicin ranged from 10.4 to 57.7 mg/m². Blood samples for measurement of doxorubicin and its metabolite doxorubicinol were collected after two administrations, with five samples collected in children <3 years and eight in children ≥3 years. A population pharmacokinetic approach was used for analysis, including pharmacogenetic covariates. Natriuretic peptides and cardiac troponins were measured to evaluate their role as early indicators of cardiotoxicity. Results Age dependence of doxorubicin clearance was demonstrated, with children less than 3 years having a statistically significant lower clearance (21.1 ± 5.8 l/h/m²) than older children (26.6 ± 6.7 l/h/m²) (p = 0.0004) after correcting for body surface area. No effect of the investigated genetic polymorphisms on the pharmacokinetics could be observed. Although natriuretic peptides were transiently elevated after each doxorubicin administration and troponin levels increased with increasing doxorubicin exposure, only limited correlation could be observed between their blood levels and doxorubicin pharmacokinetics. Conclusion In the European framework of funding and regulatory support, an add-on study to existing therapeutic trials was developed. The pediatric need concerning missing PK data could be addressed with limited burden for the patients. Empirically used dose adaptations for infants were generally found to be justified based on our PK analyses.