Zusammenfassung
□ Hintergrund
Die Substitutionstherapie bei hypophyseninsuffizienten Patientten mit rekombinantem, menschlichen Wachstumshormon (rhGH) zusätzlich zur konventionellen Substitution mit Glucocorticoiden, L-Thyroxin und Geschlechtshormonen ist seit 1995 zugelassene Indikation mit der Auflage der Zulassungsbehörden, Anwendungsbeobachtungen zur Dokumentation der Langzeitsicherheit durchzuführen.
□ Patienten und Methode
Es wird über die ersten deutschen Ergebnisse der Kabi-International-Metabolic-Study-(KIMS-) Anwendungsbeobachtung von Pharmacia & Upjohn, Erlangen, berichtet. In KIMS eingeschlossen wurden 404 Patienten aus 35 Zentren (227 Männer=56% und 177 Frauen=44%). 32 Patienten (8%) beendeten die Therapie. 25% der Patienten hatten einen Wachstumshormonmangel (GHD), der in der Kindheit aufgetreten war.
□ Ergebnisse
24% aller Patienten waren im zweiten Jahr ihrer Therapie, 15% in ihrem vierten Jahr, die längste Behandlung dauerte sechs Jahre. Bei der Altersverteilung wurden zwei Spitzen beobachtet: 30 bis 39 Jahre (24%) und 50 bis 59 Jahre (24%). Die Ursachen der Hypophyseninsuffizienz waren wie folgt: Hypophysenadenome (47%), idiopathisch (16%), Kraniopharyngeome (16%) und andere (21%). Die mittlere GH-Dosis lag bei 1,5 IU/Tag (0,4 bis 4 IU/Tag). Hierunter stieg das Serum-IGF-1 (insulinähnlicher Wachstumsfaktor) um 159 bis 192% bei Frauen bzw. Männern nach sechs Monaten Behandlung signifikant an. Der Taillenumfang nahm bei Männern um 2% ab, das Serumcholesterin wurde um 5,5% gesenkt. Bei zwei Patienten wurde während des Beobachtungszeitraums ein neues Karzinom diagnostiziert, eine Patientin verstarb, ein Patient entwickelte einen Diabetes mellitus II. Die Inzidenz unerwünschter Ereignisse (AEs) in KIMS wurde mit der Inzidenz in den Verum-(GH-) Gruppen bzw. Placebo-(Pl-) Gruppen früherer Zulassungsstudien verglichen (in Prozent): Ödeme: KIMS 10, GH 37, Pl3; Arthralgien: KIMS 8, GH 19, Pl 2; Muskelschmerzen: KIMS 2, GH 3, Pl 2; andere: KIMS 2, GH 22, Pl 13. Die angegebene Inzidenz an AEs in KIMS war signifikant niedriger als in den vorangegangenen Zulassungsstudien. Hierfür gibt es drei Gründe: 1. AEs, die scheinbar nicht mit einer GH-Therapie in Zusammenhangstehen, werden weniger häufig gemeldet. 2. Die verwendeten Dosen lagen in KIMS um die Hälfte niedriger als in den Zulassungsstudien. 3. In KIMS erfolgte eine Dosistitrierung für jeden individuellen Patienten.
□ Schlußfolgerung
Die Daten zeigen, daß Anwendungsbeobachtungen gut geeignet sind, um die Langzeitwirkungen und -sicherheit einer GH-Therapie zu dokumentieren. Eine dosistitrierte GH-Substitution bei hypophyseninsuf fizienten Patienten führt zu einer geringeren Nebenwirkungsrate.
Abstract
□ Background
Substitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety.
□ Results
24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/ds. c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (Pl) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients.
□ Conclusion
Surveillance programs are important for monitoring of drug long-term efficacy and safety.
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Untersucher der KIMS-Studiengruppe siehe Anhang.
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Wüster, C., Melchinger, U., Eversmann, T. et al. Verminderte Inzidenz von Nebenwirkungen einer Wachstumshormonsubstitution bei 404 Patienten mit Hypophyseninsuffizienz. Med Klin 93, 585–591 (1998). https://doi.org/10.1007/BF03042673
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DOI: https://doi.org/10.1007/BF03042673