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Longitudinal Infusion of a Complex of Insulin-Like Growth Factor- I and IG F

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Longitudinal Infusion of a Complex of Insulin-Like Growth Factor- I and IG F nature publishing group Articles Clinical Investigation Longitudinal infusion of a complex of insulin-like growth ­factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety David Ley1, Ingrid Hansen-Pupp1, Aimon Niklasson2, Magnus Domellöf3, Lena E. Friberg4, Jan Borg5, Chatarina Löfqvist6, Gunnel Hellgren2, Lois E.H. Smith7, Anna-Lena Hård6 and Ann Hellström6 BACKGROUND: In preterm infants, low levels of insulin-like The free/unbound IGF-I is regulated by IGF-binding pro- growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are teins (IGFBPs), of which IGFBP-3 is the main circulating car- associated with impaired brain growth and retinopathy of pre- rier protein. IGFBP-3, together with IGF-I, binds to the acid maturity (ROP). Treatment with IGF-I/IGFBP-3 may be benefi- labile subunit (ALS) to form a ternary complex that prolongs cial for brain development and may decrease the prevalence the half-life of IGF-I (9,10). In addition, low serum IGFBP-3 of ROP. levels in preterm infants have been shown to be associated with METHODS: In a phase II pharmacokinetics and safety study, the development of ROP. In mice, IGFBP-3 has been shown five infants (three girls) with a median (range) gestational age to modulate cellular mechanisms, independent of IGF-I, (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight and to promote retinal vascular regrowth in oxygen-induced of 990 (900–1,212) g received continuous intravenous infusion ­retinopathy (10). of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initi- For a better understanding of the pharmacokinetics of IGF-I ated during the first postnatal day and continued for a median and IGFBP-3 in preterm infants, we have previously performed (range) duration of 168 (47–168) h in dosages between 21 and two studies to evaluate the effects of transfusing fresh-frozen 111 µg/kg/24 h. adult plasma (11) and infusing recombinant human (rh)IGF-1/ RESULTS: Treatment with rhIGF-I/rhIGFBP-3 was associated rhIGFBP-3 over a period of 3 h (12) on serum IGF-I/IGFBP-3 with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) concentrations in preterm infants. than model-predicted endogenous levels. Of 74 IGF-I samples The administration of fresh-frozen plasma significantly measured during study drug infusion, 37 (50%) were within the increased the circulatory levels of IGF-I and IGFBP-3 in the target range, 4 (5%) were above, and 33 (45%) were below. The preterm infants, suggesting that exogenous supplementa- predicted dose of rhIGF-I/rhIGFBP-3 required to establish circu- tion may counterbalance the immediate postnatal decrease of lating levels of IGF-I within the intrauterine range in a 1,000 g IGF-I and IGFBP-3 in these infants. Whereas the half-life of infant was 75–100 µg/kg/24 h. No hypoglycemia or other total IGF-I in adults has been calculated to be ~17 h (13), the adverse effects were recorded. half-life of IGF-I in the preterm infants after plasma infusion CONCLUSION: In this study, continuous intravenous infusion was considerably shorter (~3 h), suggesting that the adminis- of rhIGF-I/rhIGFBP-3 was effective in increasing serum concen- tration of IGF-I to preterm infants should be performed via trations of IGF-I and IGFBP-3, and was found to be safe. continuous intravenous infusion. In the second study (12), five very preterm infants received nsulin-like growth factor-I (IGF-I) is essential for fetal a 3-h intravenous infusion of the drug mecasermin rinfabate, Igrowth and development in late gestation (1,2). During the an equimolar preparation of recombinant protein complex third trimester, fetal IGF-I serum levels are positively corre- of rhIGF-I and IGFBP-3, at a dose of 6–59 µg/kg/3 h. The half- lated with gestational age (GA) and birth weight (3,4). After life of IGF-1 was <1 h, and no adverse effects were observed. preterm birth, serum concentrations of IGF-I fall rapidly This shows that the half-life of the IGF-I in intravenously below normal intrauterine levels (5,6). These low levels have administered mecasermin rinfabate is even shorter than that been found to be associated with slow weight gain and slow of the IGF-I in fresh-frozen plasma, indicating that admin- growth in head ­circumference and, later, with retinopathy of istration via continuous infusion is necessary for achieving prematurity (ROP) (7,8). stable concentrations. 1Department of Pediatrics, Institution of Clinical Sciences, Lund University, Lund, Sweden; 2Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; 3Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden; 4Department of Pharmaceutical ­Biosciences, Uppsala University, Uppsala, Sweden; 5Premacure AB, Uppsala Science Park, Uppsala, Sweden; 6Department of Ophthalmology, Institute of Neuroscience and ­Physiology, ­Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; 7Department of Ophthalmology, Children’s Hospital, Harvard Medical School, Boston, ­Massachusetts. Correspondence: David Ley ([email protected]) Received 23 April 2012; accepted 2 August 2012; advance online publication 28 November 2012. doi:10.1038/pr.2012.146 68 Pediatric RESEArCH Volume 73 | Number 1 | January 2013 Copyright © 2013 International Pediatric Research Foundation, Inc. IGF-I/IGFBP-3 therapy in preterm infants Articles Table 1. Study subjects and study drug characteristics in five very preterm infants receiving longitudinal continuous infusion of IGF-I/IGFBP-3 complex Doses Premiplex Doses IGF-I Patient GA at birth Birth weight Birth weight Weight SDS at Infusion (µg/kg/24 h) (µg/kg/24 h) Total IGF-I no. Gender (weeks) (g) SDS 40 wk PMA duration (h) min–max min–max received (µg) 1 Female 26 + 6 930 −0.76 −0.737 47.2 71–101 15–21 33 2 Male 26 + 5 1,085 0.21 0.103 168.0 21–92 4–19 113 3 Female 26 + 6 990 −0.35 −1.970 168.0 72–111 15–23 141 4 Male 26 + 0 900 −0.38 −1.817 123.9 66–100 14–21 95 5 Female 27 + 2 1,212 0.61 −1.216 168.0 32–72 7–15 97 GA, gestational age; IGF-I, insulin-like growth factor-I; IGFBP-3, insulin-like growth factor-I binding protein 3; PMA, postmenstrual age; SDS, SD score. The aim of the present study was to evaluate the pharmacoki- Table 2. Final pharmacokinetic parameter estimates for endogenous netics and short-term safety of continuous infusion of rhIGF-I IGF-I and IGFBP-3 (95% CI obtained by log-likelihood profiling) administered with its binding protein-3 (rhIGFBP-3) in a new IGF-I IGFBP-3 cohort of very preterm infants. Typical IIV IIV population value (CV%)b Typical value (CV%)b RESULTS CL(l/1kg) 0.0924a 31a 0.0674a NS IGF-I and IGFBP-3 Pharmacokinetics V (l/kg) 0.114 a NS 0.0726 a NS The dose administered, the duration of infusion, and the serum Cendo,0 17.5 (16.6–20.4) 63 1108 (801–1,740) 36 IGF-1 concentrations attained during the study are presented in (µg/l/1kg) Table 1. The developed model, based on IGF-I serum concen- Cendo,mat 17.5 (15.5–19.7) 28 1103 (986–1,259) 22 tration data from this study as well as from our earlier studies, (µg/l/1kg) predicted an initial exponential decline in the endogenous IGF-I t (days) 0.649 (0.421–0.921) 120 1.39 (0.94–2.34) 54 levels (with a minimum at ~day 2 after birth), a return to the 1/2,0 t (days) 2.57 (2.12–3.24) 44 4.38 (3.27–6.59) 88 baseline birth values within 10 d, and thereafter an increase with 1/2,mat POWendo 0.529 (0.410–0.549) NS 0 (Fixed) NS increasing birth weight. The endogenous concentrations (Cendo) with increasing chronological age (Age) can be described as Proportional 26.3 (25.1–28.8) NS 13.7 (12.3–15.3) NS residual error (%) − ⋅ In2/t1/2,0 Age C , concentration of endogenous IGF-I at birth; C , concentration of endogenous CC= ⋅eC+ endo,0 endo,mat endo ()endo,0 endo,mat IGF-I in more mature infants; CI, confidence interval; CL, clearance; CV, coefficient of −In2/t ⋅Age variation; IGF-I, insulin-like growth factor-I; IGFBP, insulin-like growth factor-I binding ⋅ 1− e 1/2,mat ⋅BWPOWendo () protein 3; IIV, interindividual variability; NS, not statistically significant; POWendo, power function of weight dependence for endogenous IGF-1; t1/2, half-life; V, distribution volume. aValues were fixed to previous estimates in the final model. bIIV parameters related to where Cendo,0 is the endogenous concentration at birth and endogenous levels were significantly correlated (2–99%). Cendo,mat is the endogenous concentration approached after the initial phase, i.e., when the infants are more mature. The Short-Term Safety terms t1/2,0 and t1/2,mat denote the half-lives of IGF-1 for the ini- tial decline and the following recovery phases, respectively. An During the study drug infusions, none of the infants developed identical model structure was chosen for IGFBP-3, although hypoglycemia (blood glucose <2.6 mmol/l) and none had per- the exponent describing the weight dependence, POWendo, sisting hyperglycemia requiring insulin treatment. One infant (“power function of weight” dependence for endogenous (patient 4) developed hyperglycemia after withdrawal of the IGF-1) was not significantly different from zero.
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