Salomé Dumasdelage 1, Hanna Maria Öhnell 2, Ulrika Sjöbom 3, Lotta Gränse 2, John Van Den Anker 4, Ann Hellström 3,5, Verena Gotta 1
1 Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital (Basel, Switzerland), 2 Department of Clinical Sciences, Lund, Ophthalmology, Lund University, Skåne University Hospital (Lund, Sweden), 3 The Sahlgrenska Centre for Pediatric Ophthalmology Research, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg (Gothenburg, Sweden), 4 Center for Health Outcomes Research & Delivery Science, Children’s National Hospital (Washington DC, USA), 5 Department of Ophthalmology, Sahlgrenska University Hospital,Region Västra Götaland (, Sweden)
Objectives
Ocular dexamethasone is licensed as an anti-inflammatory agent for adults, while paediatric use is generally off-label and recommendations are missing. Nevertheless, its potential to prevent the progression of severe retinopathy of prematurity (ROP) requiring conventional treatment has been suggested (1). In preterm infants, systemic absorption and possible suppression of endogenous cortisol are potential safety concerns. We aimed to characterize systemic exposure and bioavailability following ocular dexamethasone administration, and to quantify its effect on endogenous cortisol using a population pharmacokinetic (PK)/pharmacodynamic (PD) modelling approach.
Methods
Clinical data originates from a prospective, open-label, two-center PK study, conducted as a pilot of a randomized controlled trial (2). Preterm infants (gestational age < 30 weeks) with type 2 ROP initiating ocular dexamethasone treatment were enrolled. The initial regimen consisted of one drop of Dexafree® 0.1% (0.036 mg) per affected eye/day. On day 1, infants were randomized to one of three PK sampling schedules, with 3-4 serum dexamethasone samples per patient collected between 0.25 and 18 hours post-dose. One predose sample was subsequently obtained on days 3, 7, 14, 21, and 28. Serum cortisol samples were collected at identical time points.
A sequential PK/PD modelling approach was implemented using Monolix and SimulX. A one-compartmental population PK model was developed to characterize systemic exposure and estimate systemic bioavailability (F), with logit-distributed inter-individual variability (IIV) and inter-occasion variability (IOV) on F. Concentrations below the limit of quantification (BLQ) were handled using the M3 method. In the absence of intravenous data, literature PK parameters from preterm neonates were used as priors (Cl = 0.140 L/h/kg, CVCL=21% ; V =1.85 L/kg, CVV = 27%) (3). Individual PK parameter estimates were then fixed to investigate the PK/PD relationship between dexamethasone concentrations and endogenous cortisol levels. Cortisol suppression was modelled using a turnover model, assuming full inhibition (Imax = 1) of cortisol production rate (kin) (4). Individual baseline cortisol concentrations (R0) were incorporated as regressor, assuming steady state conditions (R0 = kin_0/kout) with a cortisol elimination rate kout of 0.405 h-1(5). To improve model fit beyond day 1, several assumptions were evaluated, including alternative values of the inhibitory concentration leading to half-maximal suppression (IC50), sigmoidicity (γ), and long-term steady-state cortisol production (Rss). IIV was explored on all parameters. Proportional error models were applied for residual variability in both PK and PD components.
Results
A total of 73 dexamethasone and 84 cortisol samples from 11 infants were available. Body weight ranged from 1382-2550 grams and gestational age from 23 to 28 weeks. Forty-two dexamethasone serum samples (57.5%) were BLQ (<0.5 nmol/L).
PK analysis indicated fast systemic absorption, characterized by an absorption rate (ka) fixed at 4 h-1 corresponding to an absorption half-life of approximately 10 minutes. Bioavailability was estimated at 5.5% using day 1 data only, and 2.3% (95% CI: 1.5 – 3.4) when including measurements up to day 28. High IOV on F was estimated (CVIOV_F= 122.7%, range of individual occasion-specific estimates: 0.47-39%). Residual error was 37%.
In the PD analysis, IC50 was initially estimated at 0.34 nmol/L (RSE = 54.6 %), i.e. BLQ, and was subsequently fixed to the literature-reported value of 0.43 nmol/L with γ set to 2 (estimated CVIC50 = 178.84%) (5,6). This appropriately described day 1 cortisol profiles but underpredicted trough cortisol concentrations measured day 3-28. Adjusting IC50, γ or kout did not improve the model fit. Allowing variability in cortisol production over time (Rss = 63.9 nmol/L; CVRss = 61.4%) partially reduced the bias. Large residual error (63%) however remained.
Conclusions
This model-based analysis estimated generally low systemic bioavailability (<10%) of ocular dexamethasone in preterm infants, despite high variability between dosing occasions inherent to ocular administration. PK/PD modelling suggested that achieved dexamethasone concentrations are sufficient to transiently suppress endogenous cortisol, as observed from profiles during the initial treatment phase. However, the initial model inadequately captured cortisol pre-dose levels beyond day 1, possibly reflecting maturational changes in hypothalamic–pituitary–adrenal axis function, rebound phenomena, and/or limited PD information due to sparse sampling and high BLQ proportion in dexamethasone samples. Overall, ocular dexamethasone concentrations resulted in low but pharmacologically active systemic exposure in this vulnerable population. Further studies are needed to better characterize long-term adrenal effects and balance potential risks and benefits in preterm infants with ROP.
References:
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Reference: PAGE 34 (2026) Abstr 12008 [www.page-meeting.org/?abstract=12008]
Poster: Drug/Disease Modelling - Paediatrics