Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Long term results of lung transplantation for cystic fibrosis.

OBJECTIVES: We reviewed our experience with lung transplant for cystic fibrosis (CF) over a 10-year period to identify factors influencing long-term survival. METHODS: One hundred and twenty-three patients with CF have undergone 131 lung transplant procedures at our institution; 114 have had bilateral sequential lung transplants (DLTX) and nine have had bilateral lower lobe transplants from living donors. Three patients had retransplant for acute graft failure, and five had late retransplant for bronchiolitis obliterans syndrome (BOS). Kaplan-Meier survival was calculated for the entire cohort and for subsets at higher risk of death to determine factors predicting a better outcome. RESULTS: Actuarial survival for the entire group of DLTX CF patients was 81% at 1 year, 59% at 5 years, and 38% at 10 years. Lobar transplant was associated with a poorer survival (37.5% at 1 and 5 years). Among DLTX patients, colonization with Burkholderia cepacia was present in 22 patients and was associated with poorer outcome (1- and 5-year survival 60 and 36% in B. cepacia patients vs. 86 and 64% in non-cepacia patients). DLTX patients younger than age 20 (n=22) had a similar survival to patients age 20 or older (n=90). Being on a ventilator at the time of transplant was not associated with poorer survival (n=8). BOS affects increasing numbers of survivors with time. Five CF patients have been retransplanted due to BOS with one operative death and 1-year survival of 60%. CONCLUSIONS: DLTX has acceptable long term survival in CF adults and children with end stage disease. CF patients colonized with B. cepacia have a worse outcome but transplantation is still warranted.

Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis.

OBJECTIVES: To assess the serum and lower respiratory tract tobramycin concentrations (C(T)) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients with cystic fibrosis (CF) 6 months to 6 years of age. STUDY DESIGN: We performed a dose escalation study of serum C(T) measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) C(T) was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. RESULTS: A 180-mg dose of inhaled tobramycin produced a mean peak serum C(T) of 0.5 microg/mL (SD 0.4; range, <0.2 to 1.4 microg/mL). A 300-mg dose produced a mean peak serum C(T) of 0.6 microg/mL (SD 0.5; range, <0.2 to 1.2 microg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 microg/mL). The target ELF C(T) was 20 microg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 microg/mL). Mean ELF C(T) was 90 microg/mL (SD 54; range, 16 to 204 microg/mL) and exceeded the target concentration in 11 patients. CONCLUSION: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract.

Renal failure and vestibular toxicity in an adolescent with cystic fibrosis receiving gentamicin and standard-dose ibuprofen.

Gentamicin and standard-dose ibuprofen were administered to an adolescent with cystic fibrosis who developed renal failure and severe vestibulotoxicity. A contributing factor was possible suboptimal intravascular volume status. Because of the potential severity of this drug interaction, hydration status and renal and vestibular functions should be closely monitored in patients receiving ibuprofen and intravenous aminoglycosides concomitantly.

Pharmacokinetics of ibuprofen enantiomers in children with cystic fibrosis.

Chiral inversion of R(-)- to S(+)-ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2-13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean Cmax, AUC, apparent CL/F, and Varea/F of S-ibuprofen were significantly different from those of R-ibuprofen. The enantiomeric ratio of plasma AUC (S:R = 2.09:1) and of free and conjugated ibuprofen in urine (S:R = 13.9:1) of children with cystic fibrosis was not different from reported values for healthy children and adults. No significant gender difference was observed for any of the pharmacokinetic parameters determined. However, there was an inverse linear relationship between the CL/F of R-ibuprofen and age in children with cystic fibrosis. Apparent CL/F was higher in children with cystic fibrosis than previously reported for healthy children; therefore, higher doses of ibuprofen would be necessary for children with cystic fibrosis.

The pharmacokinetics of ibuprofen suspension, chewable tablets, and tablets in children with cystic fibrosis.

OBJECTIVES: The objectives of this study were to compare the pharmacokinetic parameters of ibuprofen administered as a suspension, chewable tablet, or tablet in children with cystic fibrosis and to determine the optimal blood sampling times for measuring ibuprofen peak concentrations. STUDY DESIGN: A single oral 20 mg/kg dose of ibuprofen was administered, and blood samples were obtained at 15, 30, 45, 60, 120, 240, and 360 minutes after the dose was administered. Peak plasma concentration (Cmax ), time to peak concentration (Tmax ), and other pharmacokinetic parameters were determined and compared (analysis of variance and analysis of covariance). RESULTS: Thirty-eight children were included (22, 4, and 12 in the suspension, chewable tablet, and tablet groups, respectively). Tmax was the only parameter for which statistical differences were noted (suspension vs tablet, P

Cellular localization of messenger RNAs for insulin-like growth factors (IGFs), their receptors and binding proteins during fetal rat lung development.

To gain insight into the role of the insulin-like growth factors (IGFs) in regulating lung development, we have used in situ hybridization histochemistry (ISHH) to examine the ontogeny and sites of expression of IGF-I and IGF-II, IGF binding proteins (IGFBP-1 to IGFBP-6), and IGF cell surface receptors in fetal rat lung from 15 to 21 days of gestation. Both IGF-I and IGF-II mRNAs were expressed throughout the developmental period studied with little change in apparent abundance. IGF-I mRNA localized to mesenchymal cells, especially those surrounding airway epithelium, while IGF-II mRNA, which was somewhat more abundant, localized predominantly to epithelia. The type 1 IGF receptor, the receptor that likely mediates the actions of both IGFs, was expressed widely in virtually all cells, whereas the expression of the type 2 IGF receptor, thought to be involved in IGF internalization and degradation, was confined to the mesenchyme and medial layers of intrapulmonary vessels. As with the IGFs, there was little apparent change in the abundance of IGF receptor mRNAs through fetal development, and the type 2 IGF receptor mRNA was more abundant. The expression of IGFBPs changed significantly during lung development. IGFBP-2, -3, -4, and -5 were expressed from day 15 of gestation, but their sites of expression and ontogeny differed. IGFBP-2 mRNA expression was abundant and constant throughout gestation and was confined to proximal and distal airway epithelia. IGFBP-3 and IGFBP-5 also were expressed by proximal airway epithelia, but also exhibited significant expression in interstitial mesenchyme and in mesenchyme surrounding vessels. The abundance of both increased as gestation progressed (IGFBP-5 greater than IGFBP-3). IGFBP-4 mRNA was confined to interstitial mesenchyme and its abundance peaked at days 16 to 19 of gestation. We found no evidence for expression of either IGFBP-1 or IGFBP-6. We conclude that the expression of IGF-I, IGF-II, and the type 1 IGF receptor throughout gestation in the lung supports a role for the IGFs in lung growth and development. The complex pattern of IGFBP expression (differing sites and ontogeny of expression) suggests that the IGFBPs modulate IGF actions at specific target sites. Furthermore, because there is little change in the expression of IGFs or IGF receptor mRNAs during fetal lung development, regulation of IGFBP expression may be essential to the control of IGF actions during lung development.

Insulin-like growth factor-I (IGF-I) antisense oligodeoxynucleotide mediated inhibition of DNA synthesis by WI-38 cells: evidence for autocrine actions of IGF-I.

Insulin-like growth factor-I (IGF-I) is elaborated into culture medium by WI-38 cells, a human embryonic lung fibroblast cell line, and may participate in the autocrine stimulation of DNA synthesis. We have confirmed the expression of IGF-I by these cells and documented that they express the type 1 IGF receptor and a number of IGF-binding proteins. In situ hybridization histochemistry demonstrated relatively uniform expression of IGF-I and type 1 IGF receptor transcripts among WI-38 cells. To determine whether WI-38-synthesized IGF-I exerted mitogenic effects, a 15-base oligodeoxynucleotide complementary to the 5'IGF-I mRNA sequence (IGF-I AS-Oligo), including the translation start site, was incubated with cultured cells in an attempt to inhibit IGF-I synthesis. The IGF-I AS-Oligo was stable in cell culture, formed intracellular duplexes with IGF-I mRNA, and at 2 microM reduced IGF-I in conditioned medium by 83%. The IGF-I AS-Oligo also inhibited [3H]thymidine incorporation into DNA in a dose-dependent fashion (by 77% at 2 microM and by 95% at 20 microM). This reduction in DNA synthesis was prevented when the medium was supplemented with 100 ng/ml IGF-I. The oligomer also decreased the abundance of IGF-binding proteins in conditioned medium. The IGF-I AS-Oligo appears to exert its effects by blocking IGF-I mRNA translation, rather than blocking transcription or initiating RNase-H activity, because the abundance of IGF-I transcripts was not decreased in its presence. These findings confirm an essential role for IGF-I in WI-38 cell DNA synthesis and are consistent with autocrine actions by WI-38 cell IGF-I.

Canine tracheal epithelial cells express the type 1 insulin-like growth factor receptor and proliferate in response to insulin-like growth factor I.

Disaggregated airway epithelial cells replicate in serum-free media containing supraphysiologic concentrations of insulin. To examine the hypothesis that the type 1 insulin-like growth factor (IGF) receptor mediates the mitogenic action of insulin on these cells, we studied the mitogenic effects of IGF-I and insulin, and the expression of type 1 IGF receptors in primary cultures of adult canine tracheal epithelial cells. Isolated tracheal epithelial cells were grown in varying concentrations of IGF-I or insulin in Ham's F12 medium supplemented with transferrin, cholera toxin, and endothelial cell growth supplement. Both IGF-I and insulin increased DNA synthesis (measured as [3H]thymidine incorporation into DNA) and cell number in a concentration-dependent fashion, but IGF-I was at least 20 to 60 times more potent than insulin in its mitogenic effects. No additive or synergistic effect was observed with the simultaneous addition of IGF-I and insulin in maximally effective doses. A monoclonal antibody directed against the type 1 IGF receptor (alpha IR3) blocked the mitogenic activity of both IGF-I and insulin. Affinity labeling of type 1 IGF receptors by covalent cross-linking with disuccinimidyl suberate demonstrated the tracheal epithelial cell IGF-I binding moiety to have a relative molecular weight of 130,000 D. Binding of [125I]IGF-I to this protein was inhibited by low concentrations of IGF-I, relative to insulin, and by alpha IR3. An 11-kb transcript characteristic of mRNA for the type 1 IGF receptor was recognized in poly(A+) RNA derived from cultured canine tracheal epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)