Assessment of compatibility of rhIGF-1/rhIGFBP-3 with neonatal intravenous medications.

BACKGROUND: Recombinant human (rh)IGF-1/IGFBP-3 protein complex, administered as a continuous intravenous infusion in preterm infants, is being studied for the prevention of complications of prematurity. METHODS: We conducted in vitro studies to evaluate the physical and chemical compatibility of rhIGF-1/IGFBP-3 with medications routinely administered to preterm neonates. In vitro mixing of rhIGF-1/IGFBP-3 drug product with small-molecule test medications plus corresponding controls was performed. Physical compatibility was defined as no color change, precipitation, turbidity, gas evolution, no clinically relevant change in pH/osmolality or loss in medication content. Chemical compatibility of small molecules was assessed using liquid chromatography (e.g., reverse-phase HPLC and ion chromatography), with incompatibility defined as loss of concentration of ≥ 10%. A risk evaluation was conducted for each medication based on in vitro compatibility data and potential for chemical modification. RESULTS: In vitro physical compatibility was established for 11/19 medications: caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous fat emulsion, midazolam, morphine sulfate, custom-mixed parenteral nutrition solution (with/without electrolytes), parenteral nutrition solution + intravenous fat emulsion, and vancomycin (dosed from a 5 mg/mL solution), but not for 8/19 medications: amikacin, ampicillin, dopamine, dobutamine, furosemide, meropenem, norepinephrine, and penicillin G, largely owing to changes in pH after mixing. Small-molecule compatibility was unaffected post-mixing, with no loss of small-molecule content. For physically compatible medications, risk analyses confirmed low probability and severity of a risk event. CONCLUSION: Co-administration of rhIGF-1/rhIGFBP-3 drug product with various medications was assessed by in vitro studies using case-by-case risk analyses to determine the suitability of the products for co-administration.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Pathophysiology, assessment and management of the child with growth hormone resistance.

Defects in the growth hormone (GH)-insulin-like growth factor (IGF)I axis may cause GH resistance characterized by IGFI deficiency and growth failure. The range of defects causing GH resistance is broad as are their biochemical and phenotypical characteristics. We propose that GH-IGFI axis defects form a continuum of clinical and biochemical effects ranging from GH deficiency to GH resistance. The pathophysiology of GH resistance is described followed by a scheme for investigation of the child with severe short stature and normal GH secretion. We critically discuss GH therapy for such patients and define acceptable growth responsiveness. Finally we discuss therapy with IGF-I within the limits of the USA Food and Drug Administration and European Medicines Agency labels for GH resistance.

Endocrine assessment, molecular characterization and treatment of growth hormone insensitivity disorders.

Advances in the diagnosis and treatment of growth hormone insensitivity disorders have occurred in the past 15 years. We discuss the current status of endocrine and molecular evaluation, focusing on the pediatric age range. All the identified mutations of the growth hormone receptor are included. Treatment with recombinant human insulin-like growth factor (rhIGF) 1 in classical cases is summarized and new targets for treatment are discussed, together with therapy using the complex formed between rhIGF1 and rhIGF-binding protein 3.

Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement.

Growth failure is a clinically important issue in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality. Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis, malnutrition, acidosis, and renal bone disease. The management of growth failure in children with CKD is complicated by the presence of other disease-related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, some practitioners and families have been reluctant to institute GH therapy, citing an unwillingness to comply with daily injections, reimbursement difficulties, or impending renal transplantation. Suboptimal attention to growth failure management may be further compounded by a lack of clinical guidelines for the appropriate assessment and treatment of growth failure in these children. This review of growth failure in children with CKD concludes with an algorithm developed by members of the consensus committee, outlining their recommendations for appropriate steps to improve growth and overall health outcomes in children with CKD.

Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature.

Amyotrophic lateral sclerosis (ALS) is a difficult to diagnose, fatal, progressive degenerative disease with an average survival time of 2 to 5 years. Percutaneous endoscopic gastrotomy (PEG) and bi-level intermittent positive pressure (BIPAP) ventilation may be the major interventions leading to longer survival of patients with ALS. Riluzole has been shown to have modest effects on survival (as opposed to functional) gains and is currently the only drug approved for the treatment of ALS. There is conflicting evidence with regard to the ability of recombinant human insulin-like growth factor (rhIGF-I) to retard ALS progression. Mechanical ventilation (via a tracheostomy tube) is expensive, but is widely used in later stage patients with ALS in the US. A review of nine cost-effectiveness studies of riluzole and one of rhIGF-I found the following: drug costs and survival gains are the major drivers of cost effectiveness; survival gains are estimated from truncated databases with a high degree of uncertainty; more accurate stage-specific utility weights based on patients who agreed to treatment are needed; case incidence-based evaluations should be carried out; cost-effectiveness ratios are insensitive to discount rates; employment and caregiver issues or externalities have been widely ignored; threshold acceptance cost-effectiveness values are ill-defined and evaluations are not generalisable to other countries because of cost and treatment style differences. On account of the high degree of uncertainty pertaining to survival gains and the relatively high costs per life years or quality-adjusted life-years gained, and while acknowledging that not every therapy has to be cost effective (e.g. orphan drugs), it is still inconclusive as to whether or not riluzole or rhIGF-1 can be considered as cost-effective therapies for ALS.

Measurement of health-related quality of life in patients with amyotrophic lateral sclerosis in clinical trials of new therapies.

OBJECTIVES: Recent trials of amyotrophic lateral sclerosis (ALS) therapies have included the Sickness Impact Profile (SIP) to evaluate health-related quality of life (HQL). The purpose of this study was to assess the feasibility, psychometric properties, and interpretation of the Sickness Impact Profile in this setting. METHODS: The Sickness Impact Profile was administered at baseline, 3, 6, and 9 months during a double-blind, placebo-controlled study of recombinant human insulin-like growth factor I. The frequency of missing Sickness Impact Profile data and administration time were recorded. Patients' scores on the Appel ALS (AALS) Rating Scale were used to identify a stable subgroup for reliability testing and clinically distinct groups for validity testing. Internal consistency reliability and reproducibility were evaluated using Cronbach's alpha and intraclass correlation coefficients, respectively. Analysis of variance (ANOVA) models and t tests were used to assess validity. Effect sizes and the responsiveness index were used to assess responsiveness. RESULTS: At baseline, 259 (97%) patients completed a 30-minute Sickness Impact Profile interview. At subsequent assessments, response rates ranged from 92% to 97% and mean administration times ranged from 25 to 27 minutes. The overall Sickness Impact Profile score demonstrated alpha reliability and 3-month stability coefficients of 0.94 and 0.80, respectively. Baseline overall Sickness Impact Profile scores discriminated between patients in the two AALS-defined groups with a mean of 13.0+/-7.8 and 24.0+/-11.7 in the better and worse AALS groups, respectively. Similarly, mean overall SIP change scores discriminated patients progressing at different rates (slow to moderate = 4.00+/-7.97; rapid = 10.74+/-8.76). With few exceptions, dimension and category scores met similar criteria. Responsiveness statistics for the physical and overall Sickness Impact Profile scores were lower at 3 months and higher at 6 and 9 months. CONCLUSIONS: The feasibility, psychometric, and interpretive findings support the validity of the Sickness Impact Profile for assessing outcomes of amyotrophic lateral sclerosis and its treatment. Based on these findings, we recommend including the Sickness Impact Profile in future amyotrophic lateral sclerosis clinical trials.

Cost effectiveness of recombinant human insulin-like growth factor I therapy in patients with ALS.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterised by a progressive loss of voluntary motor activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown to be useful in treating ALS. The purpose of this study was to examine the cost effectiveness of rhIGF-I therapy in patients who have ALS. DESIGN: We performed a cost-effectiveness analysis from the societal perspective on 177 patients who received treatment with rhIGF-I or placebo in a North American randomised clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I using resource utilisation and functional status measurements from the clinical trial. Costs were estimated from 1996 US Medicare reimbursement schedules. Utility weights were elicited from ALS healthcare providers using the standard gamble technique. MAIN OUTCOME MEASURES AND RESULTS: The overall cost per quality-adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was $US67,440. For the subgroups of patients who were progressing rapidly or were in earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per QALY gained, respectively. CONCLUSIONS: Treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favourably with treatments for other chronic progressive diseases.

Effects of recombinant growth factors on energy expenditure in maintenance hemodialysis patients.

We compared the metabolic effects of recombinant human (rh) insulin-like growth factor (IGF)-1 or a combination of rhIGF-1 + rh growth hormone (GH) on resting energy expenditure (REE) in 8 maintenance hemodialysis (MHD) patients. Seven males and 1 female (aged 41.6 +/- (SD) 12.4) with no evidence of malnutrition (BMI 21.6 +/- 2.2 kg/m2, serum albumin 45 +/- 2 g/l, serum IGF-1 359 +/- 165 microg/l) received either rhIGF-1 (80 microg/kg/day) or rhIGF-1 (80 microg/kg/day) + rhGH (50 microg/kg/day) for 3 days in a random crossover design. REE and the respiratory quotient (RQ) were measured at rest before and after the 3-day treatment. The results confirmed that MHD patients have a REE not different from normal individuals. REE was strongly correlated with lean body mass but not with fat mass. rhIGF-1 treatment did not modify REE despite doubling serum IGF-1 values, whereas a combined rhIGF1 + rhGH treatment significantly increased REE by 11% (p < 0.001). There was no change in RQ under both treatments, in response to a proportionate increase in VCO2 and VO2. These results show that energy expenditure is mainly dependent upon lean body mass in well-nourished MHD patients. The metabolic effects of rhIGF-1 and rhGH on energy expenditure may differ in response to their opposite effects on lipid oxidation and insulin regulation.