Surveillance of rhGH therapy: Monitoring serum IGF-I and IGF-I/IGFBP3 molar ratio on a IGF-I based dosing titration strategy for optimizing rhGH therapy in children.

BRASLAVSKY D; BALLERINI MG; KESELMAN A; CALCAGNO, M.D.L.; MARTINEZ, ALICIA; JASPER, HÉCTOR; 1; DOMENE, H.; ROPELATO, M.G.; BERGADÁ, I.

Playa del Carmen

Congreso; XXIV Reunión Anual de la Sociedad Latinoamericana de Endocrinología Pediátrica & Sociedad Mexicana de Endocrinología Pediátrica; 2014

Surveillance of rhGH Therapy: Monitoring Serum IGF-I and IGF-I/IGFBP3 Molar Ratio on a IGF-I Based Dosing Titration Strategy for Optimizing rhGH Therapy in Children Braslavsky, D.1; Ballerini, M.G.1; Keselman, A.1; Calcagno, M.D.L.2; Martinez, A.1; Jasper, H.1; Domene, H.1; Ropelato, M.G.1; Bergadá, I.11Centro de Investigaciones Endocrinológica (CEDIE), ?Dr Cesar Bergadá? ? FEI-División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, 2Cátedra de Matemática, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina Introduction: Elevated serum IGF-I and probably IGF-I/IGFBP-3 molar ratio levels are frequently found in children throughout rhGH therapy. Whether sustained elevated serum IGF-I is a harbinger for serious long term adverse events (AE) requires further follow up. Meanwhile surveillance of circulating IGF-I and IGFBP-3 may be useful to identify those children in whom rhGH dose titration might improve safety. Objective: To determine IGF-I and IGF-I/IGFBP-3 ratio in children on rhGH and dose titration in those with persistently elevated IGF-I to achieve serum IGF-I concentrations within the normal range. Subjects and Methods: Prospective and interventional study, including prepubertal patients with either growth hormone deficiency (GHD), or born small for gestational age (SGA) without catch up growth, or Turner Syndrome (TS), naïve for rhGH therapy. rhGH dosing: conventional weight based. IGF-I and IGFBP-3 were determined basally and every 3 months (IMMULITE 2000, Siemens). rhGH dose titration was conducted (10% reduction) when IGF-I was above + 2 SDS in two consecutive controls. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio are expressed as SDS according to local data. Fostering other clinical and biochemical tools of pharmacovigilance serum anti-GH antibodies were analyzed by an in-house ELISA and AE occurrence on rhGH were obtained.  Results: Thirty five patients were enrolled (26 boys and 9 girls) aged 7.0±3.5 years: 14 GHD, 17 SGA and 4 TS. Three patients were excluded from the study, two due to poor compliance and one with a serious AE probably not related to rhGH. Basal IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratios (mean ± SD), were as follows: in GHD ?3.02±2.81, ?2.15±1.02, ?0.8±0.17 respectively; in SGA ?0.55±0.73, ?0.62±0.88, ?0.22±0.65, respectively and in TS 0.53±1.08, ?0.35±2.61, 0.17±0.14, respectively. Median follow up was 12 months (range 0 to 20 months). Considering those patients with follow up ≥6 months, the proportion of patients that required rhGH dose titration was 30% (3/10) in GHD, 50% (6/12) in SGA and 66% (2/3) in TS at a median (range) time of 12 (9?20), 9 (6?12) and 7.5 (6?9) months, respectively. The time of occurrence of the event (need to titrate) was not significantly different for GHD and SGA (Kaplan Meier). The need to titrate according to dichotomized (positive or negative) basal IGF-I SDS had a hazard ratio of 8.87 (CI: 1.4?55.0, p = 0.0204) adjusted for pathology, age and dose of rhGH. The overall proportion of IGF-I/IGFBP3 molar ratios above + 2 SDS in basal, 6 and 12 months was 0%, 20% and 7%, respectively. At titration indication, IGF-I and IGFI/IGFBP3 molar ratio were concomitantly elevated in all GHD, 2/6 SGA and 1/2 TS. Anti-GH antibodies were negative in all but one patient. Prevalence of mild probably related AE was 25.7% (most ≤6 months and 1 concurrent with need of titration); mild not related AE 8.5% and one serious AE. Conclusions: We confirm a marked proportion of patients with elevated IGF-I throughout conventional rhGH weight based dosing. Therefore rhGH titration appears necessary for a more safe approach. We also found an increment in IGF-I/IGFBP-3 molar ratios in many patients; however their value as a safety measurement remains unclear. The variability in response to a given dose of rhGH reflects not only different sensitivity to treatment among different pathologies but also individual variability. Continuous surveillance of GH dependent biomarkers will provide useful information regarding the long term safety and efficacy of individualized IGF-I based rhGH therapy. Horm Res Paediatr 2014;82(suppl 2):pag12