INVESTIGADORES
BERGADÁ Ignacio
congresos y reuniones científicas
Título:
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
Autor/es:
BRASLAVSKY D; BALLERINI MG; KESELMAN A; CALCAGNO, M.D.L.; MARTINEZ, ALICIA; JASPER, HÉCTOR; 1; DOMENE, H.; ROPELATO, M.G.; BERGADÁ, I.
Lugar:
Playa del Carmen
Reunión:
Congreso; XXIV Reuniòn de la Sociedad Latinoamericana de Endocrinología Pediátrica; 2014
Resumen:
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 IGFI
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 IGFI/
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 ≤6months 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.
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