INTERACTION BETWEEN DIET AND SUNLIGHT EXPOSURE ON VITAMIN D STATUS IN WOMEN LIVING IN SOUTHERN ENGLAND: MULTILEVEL MODELLING ANALYSIS OF THE D-FINES STUDY

The relative contribution of UVB sunlight exposure and dietary vitamin D intake to 25-hydroxyvitamin D (25(OH)D) remains to be fully determined. The aim of this study was to examine these factors in combination using a repeated measures multilevel modelling approach. The D-FINES study investigated 373 Surrey Caucasian and Asian women in four seasons of the year for 25(0H)D, dietary vitamin D and UVB exposure. To capitalise on the clustered nature of the repeated seasonal measurements within individuals, multilevel modelling was undertaken using MLwiN v.2.1software. Thus seasonal data (dietary vitamin D (DietaryVitD), UV exposure (UVdosi), vitamin D status (VitDstatus)) were included at level one (ij) and individual level data (ethnicity, menopausal status (0=Caucasian, 1=Asian; 0=Premenopausal, 1=Postmenopausal)) at level two (j). Using a random intercept model, the following equation was constructed, which was significantly different from an intercept only model (Log likelihood test- Chi square X2= 2216.51, df=5, p<0.001): 25(OH)Dij= 0j-0.130(0.283)DietaryVitDij + 1.199(0.201)UVdosiij -27.559(2.637) Ethnicity_j: -6.082(2.051)Menopause_1j – 0.020(0.008)UVdosi2ij+ e ij0j=56.650(1.825) + u0j This model showed no effect of diet on 25(OH)D, but did show a significant interaction between Standard Erythema Dose (SED)UV and 25(OH)D. Being of Caucasian ethnicity was associated with a 27.6 nmol/l higher 25(OH)D than Asian ethnicity, and being of premenopausal status was associated with a 6.1 nmol/l higher 25(OH)D than postmenopausal status. Total body fat mass and seasonal dietary calcium had initially been included in the model but were removed as they were not significant parameters. Dietary vitamin D was retained, even though not a significant parameter as it was of high theoretical and practical importance. The implications of this model are that UV exposure has an effect on vitamin D status but dietary vitamin D does not. Ethnicity has a greater influence than menopausal status. This work is funded by the FSA (Project No. NO5064). This work was funded by the UK Foods Standards Agency (NO5064). The views expressed are those of the authors alone. Disclosure o

INTERACTION BETWEEN DIET AND SUNLIGHT EXPOSURE ON VITAMIN D STATUS IN WOMEN LIVING IN SOUTHERN ENGLAND: MULTILEVEL MODELLING ANALYSIS OF THE D-FINES STUDY

A.L.Darling1, A.R.Kang’ombe2, A.Dragen1, B.Diffey3, D.P.Lovell1, D.J.Torgerson2, P.A. Lee1, W.T.K. Lee1, J.L. Berry4 and S.A. Lanham-New

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: − 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug