Publications
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Dobra RA, Davies JC, Elborn JS, et al., 2022, A DISCRETE CHOICE EXPERIMENT (DCE) TO QUANTIFY THE INFLUENCE OF TRIAL FEATURES ON THE DECISION TO PARTICIPATE IN CYSTIC FIBROSIS (CF) TRIALS, Winter Meeting of the British-Thoracic-Society (BTS), Publisher: BMJ PUBLISHING GROUP, Pages: A114-A115, ISSN: 0040-6376
Drevinek P, Canton R, Johansen HK, et al., 2022, New concepts in antimicrobial resistance in cystic fibrosis respiratory infections, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 937-945, ISSN: 1569-1993
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- Citations: 4
Mahenthiralingam E, Weiser R, Floto RA, et al., 2022, Selection of relevant bacterial strains for novel therapeutic testing: a guidance document for priority cystic fibrosis lung pathogens, Current Clinical Microbiology Reports, Vol: 9, Pages: 33-45, ISSN: 2196-5471
Purpose of ReviewPeople with cystic fibrosis (CF) suffer chronic lung infections with a range of antimicrobial-resistant bacterial pathogens. There is an urgent need for researchers to develop novel anti-infectives to treat these problematic infections, but how can we select bacterial strains which are relevant for robust testing and comparative research?Recent FindingsPseudomonas aeruginosa, Burkholderia cepacia complex and Burkholderia gladioli, Mycobacterium abscessus complex, Staphylococcus aureus, Haemophilus influenza, and several multidrug-resistant Gram-negative species were selected as key CF infections that urgently require new therapeutics. Reference isolates and strain panels were identified, and a summary of the known genotypic diversity of each pathogen was provided.SummaryHere, we summarise the current strain resources available for priority CF bacterial pathogens and highlight systematic selection criteria that researchers can use to select strains for use in therapeutic testing.
Short C, Abkir M, Pinnell S, et al., 2022, Migration is not the perfect answer: How the cross-talk error correction for multiple breath nitrogen washout (MBWN2) parameters differs on directly collected vs. legacy data, Pediatric Pulmonology, Vol: 58, Pages: 328-331, ISSN: 1099-0496
Recently, a cross-talk error with commercial multiple breath nitrogen washout (MBWN2) software was discovered, which produced an absolute over-reading of N2 of approximately 1%, i.e., 2% N2 read as 3%. This caused an extended tail to the washout, and over-estimated lung clearance index (LCI2.5) values. Subsequently an updated and corrected software version has been released. Within the field there have been discussions on how to correct legacy data, whether to migrate or completely “rerun” raw data A-files from the old software into the new corrected software. To our knowledge, no research has been published assessing whether either method is equivalent to directly collecting data in the new corrected software. We prospectively recruited 19 participants, 10 adult healthy controls and 9 people with cystic fibrosis (CF). MBWN2 was performed using the Exhalyzer® D first on the old 3.1.6 software and next, directly on corrected 3.3.1 software. Multiple breath washout (MBW) data directly collected in 3.3.1 was significantly different from both migrated and rerun data. A total of 7 of the 19 participants (37%; 4 CF) had a relative difference in LCI2.5 > 10% for both migrated and rerun data compared to 3.3.1 collected data. Our findings have implications for the Global Lung Initiative MBW project, which is accepting a combination of directly collected, A-file reruns and migrated data to establish normative values. Further, caution must be used in clinical practice when comparing corrected legacy data versus 3.3.1 collected data for clinical interpretation. We recommend that a new baseline is collected directly on 3.3.1. before clinical interpretation and decisions are determined when comparing consecutive MBW tests.
Stanford GE, Jones M, Charman SC, et al., 2022, Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review, Therapeutic Advances in Respiratory Disease, Vol: 16, Pages: 1-12, ISSN: 1753-4666
Background:Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.Objectives:To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.Design and Methods:A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.Results:No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.Discussion and conclusion:This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essenti
McLachlan G, Alton EWFW, Boyd AC, et al., 2022, Progress in Respiratory Gene Therapy, HUMAN GENE THERAPY, Vol: 33, Pages: 893-912, ISSN: 1043-0342
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- Citations: 2
Hine C, Desai M, Davies J, et al., 2022, A systematic review of lung clearance index in non-cystic fibrosis, non-primary ciliary dyskinesia bronchiectasis, Respiratory Medicine, Vol: 201, Pages: 1-8, ISSN: 0954-6111
BackgroundNon cystic fibrosis, non primary ciliary dyskinesia bronchiectasis (nCFnPCD-BE) results in significant morbidity with few evidence-based treatments.Objectiveassessments are required to assess severity and evaluate treatment. Lung clearance index (LCI) measures ventilation inhomogeneity and is a sensitive test of disease in CF; its use in nCFnPCD-BE is unclear.MethodsA systematic review of LCI in nCFnPCD-BE was performed using standard methodology (protocol registered on PROSPERO, University of York).ResultsOf 276 records identified, 12 articles, describing 519 adult and paediatric patients in cross-sectional studies were included, addressing several domains.1: What is the utility of LCI in detecting disease and severity?LCI detected disease in adults, differentiating bronchiectasis from controls (AUC 0.90 to 0.96) and mild from moderate/severe bronchiectasis on CT (AUC 0.73).2: Does LCI correlate with spirometry and imaging?LCI correlated with spirometry in adult (r = −0.37 to −0.61) and paediatric (r = −0.6) groups, signs of bronchiectasis on CT, and CT scoring systems (modified Reiff).3: Does LCI relate to subjective scores of severity?In adults, LCI correlated with St. George's Respiratory Questionnaire (r = 0.18) and Bronchiectasis Severity Index (r = 0.45).4: Does LCI identify response to intervention?LCI did not change in studies examining LCI pre-post intervention (adults treated for exacerbation and undergoing physiotherapy).Overall study quality was variable.ConclusionContrary to data in CF, the review did not identify good quality studies defining the role of LCI in children with bronchiectasis. In adults, LCI was a sensitive measure of disease severity and correlated with clinical assessment tools.
Murphy R, Coates M, Thrane S, et al., 2022, Synergistic activity of repurposed peptide drug glatiramer acetate with tobramycin against cystic fibrosis Pseudomonas aeruginosa, Microbiology Spectrum, Vol: 10, ISSN: 2165-0497
Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P = 0.002) and the MIC90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms.
Dobra R, Bentley S, Edmondson C, et al., 2022, Going the extra mile: why clinical research in cystic fibrosis must include children, Children, Vol: 9, ISSN: 2227-9067
This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, “Children are not just little adults” been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.
King JA, Nichols A-L, Bentley S, et al., 2022, An Update on CFTR Modulators as New Therapies for Cystic Fibrosis., Paediatr Drugs, Vol: 24, Pages: 321-333
Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.
Sawicki GS, Chilvers M, McNamara J, et al., 2022, A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for <i>F508del</i> or heterozygous for <i>F508del</i> and a residual function <i>CFTR</i> variant, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 675-683, ISSN: 1569-1993
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- Citations: 5
Davies J, Horsley A, Brightling C, et al., 2022, Early-phase clinical trials in a pandemic: learning from the response to COVID-19, The Lancet Respiratory Medicine, Vol: 10, Pages: 625-627, ISSN: 2213-2600
Horsley AR, Pearmain L, Knight S, et al., 2022, Large scale clinical trials: lessons from the COVID-19 pandemic, BMJ Open Respiratory Research, Vol: 9, ISSN: 2052-4439
Background The COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response to COVID-19 in order to identify these challenges as well as solutions for future pandemic planning.Methods We conducted a survey of diverse research staff involved in delivery of COVID-19 clinical trials across the UK. This was delivered online across centres linked to the NIHR Respiratory Translational Research Collaboration. Responses were analysed using a formal thematic analysis approach to identify common themes and recommendations.Results 83 survey participants from ten teaching hospitals provided 922 individual question responses. Respondents were involved in a range of research delivery roles but the largest cohort (60%) was study investigators. A wide range of research experiences were captured, including early and late phase trials. Responses were coded into overarching themes. Among common observations, complex protocols without adaptation to a pandemic were noted to have hampered recruitment. Recommendations included the need to develop and test pandemic-specific protocols, and make use of innovations in information technology. Research competition needs to be avoided and drug selection processes should be explicitly transparent.Conclusions Delivery of clinical trials, particularly earlier phase trials, in a pandemic clinical environment is highly challenging, and was reactive rather than anticipatory. Future pandemic studies should be designed and tested in advance, making use of pragmatic study designs as far as possible and planning for integration between early and later phase trials and regulatory frameworks.
Dixon E, Dick K, Ollosson S, et al., 2022, Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 23-28, ISSN: 1526-0542
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- Citations: 20
Balfour-Lynn IM, Puckey M, Simmonds NJ, et al., 2022, Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 29-34, ISSN: 1526-0542
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- Citations: 2
King J, Nichols A, Bentley S, et al., 2022, An update on CFTR modulators as new therapies for Cystic Fibrosis, Paediatric Drugs, Vol: 24, Pages: 321-333, ISSN: 1174-5878
Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug–drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.
Robinson PD, Jensen R, Seeto RA, et al., 2022, Impact of cross-sensitivity error correction on representative nitrogen-based multiple breath washout data from clinical trials, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: E204-E207, ISSN: 1569-1993
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- Citations: 13
Irving S, Bayfield K, Davies JC, et al., 2022, Curvilinearity provides additional information to lung clearance index only in a minority of children with early cystic fibrosis lung disease, ERJ Open Research, Vol: 8, ISSN: 2312-0541
Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4.
Davies J, Goss C, Fajac I, et al., 2022, Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE–CF™ 1 – a randomised, Phase II study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936
Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.Objective: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.Results: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.Conclusion: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.
Edmondson C, Westrupp N, Seddon P, et al., 2022, The feasibility of home monitoring of young people with cystic fibrosis: results from CLIMB-CF, Journal of Cystic Fibrosis, Vol: 21, Pages: 70-77, ISSN: 1569-1993
BACKGROUND: CF is traditionally assessed in clinic. It is unclear if home monitoring of young people with CF is feasible or acceptable. The COVID-19 pandemic has made home monitoring more of a necessity. We report the results of CLIMB-CF, exploring home monitoring's feasibility and potential obstacles. METHODS: We designed a mobile app and enrolled participants with CF aged 2-17 years and their parents for six months. They were asked to complete a variety of measures either daily or twice a week. During the study, participants and their parents completed questionnaires exploring depression, anxiety and quality of life. At the end of the study parents and participants completed acceptability questionnaires. RESULTS: 148 participants were recruited, 4 withdrew prior to starting the study. 82 participants were female with median (IQR) age 7.9 (5.2-12 years). Median data completeness was 40.1% (13.6-69.9%) for the whole cohort; when assessed by age participants aged ≥ 12 years contributed significantly less (15.6% [9.8-30%]). Data completeness decreased over time. There was no significant difference between parental depression and anxiety scores at the start and the end of the study nor in CFQ-R respiratory domain scores for participants ≥ 14 years. The majority of participants did not feel the introduction of home monitoring impacted their daily lives. CONCLUSIONS: Most participants felt home monitoring did not negatively impact their lives and it did not increase depression, anxiety or decrease quality of life. However, uptake was variable, and not well sustained. The teenage years pose a particular challenge and further work is required.
Short C, Semple T, Saunders C, et al., 2022, A Short extension to multiple breath washout provides additional signal of distal airway disease in people with CF: A pilot study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 146-154, ISSN: 1569-1993
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Thursfield RM, Shafi N, Davies JC, 2022, COUNTERPOINT: In the Era of Cystic Fibrosis Transmembrane Regulator Protein Modulator Therapy, Are the Treatment Goals for Adults Now Different From Those for Children With Cystic Fibrosis? No, CHEST, Vol: 161, Pages: 21-24, ISSN: 0012-3692
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Thursfield RM, Shafi N, Davies JC, 2022, Rebuttal From Dr Thursfield et, CHEST, Vol: 161, Pages: 25-25, ISSN: 0012-3692
Hughes DA, Archangelidi O, Coates M, et al., 2022, Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 129-135, ISSN: 1569-1993
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- Citations: 3
Davies J, Kos R, Brinkman P, et al., 2022, Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients, Journal of Cystic Fibrosis, Vol: 21, Pages: e28-e34, ISSN: 1569-1993
BackgroundPseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively.MethodsThis study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture.Results241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71–1.0) and 0.87 (CI 0.72–1.0) for adults and children, respectively.ConclusionsTargeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.
King J, Murphy R, Davies JC, 2022, <i>Pseudomonas aeruginosa</i> in the Cystic Fibrosis Lung, PSEUDOMONAS AERUGINOSA, Vol: 1386, Pages: 347-369, ISSN: 0065-2598
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- Citations: 4
Ahmed B, Cox MJ, Cuthbertson L, et al., 2021, Comparison of the airway microbiota in children with chronic suppurative lung disease, BMJ Open Respiratory Research, Vol: 8, Pages: 1-10, ISSN: 2052-4439
Rationale:The airway microbiota is important in chronic suppurative lung diseases (CSLD), such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). This comparison has not previously been described but is important because difference between the two diseases may relate to the differing prognoses and lead to pathological insights and potentially, new treatments. Objectives:To compare the longitudinal development of the airway microbiota in children with PCD to that of CF and relate this to age and clinical status. Methods:Sixty-two age-matched children (age range 0.5–17 years) with PCD or CF (n=31 in each group) were recruited prospectively and followed for 1.1 years. Throat swabs or sputum as well as clinical information were collected at routine clinical appointments. 16S rRNA gene sequencing was performed. Measurements and Main Results:The microbiota was highly individual and more diverse in PCD and differed in community composition when compared with CF. Whilst Streptococcus was the most abundant genus in both conditions, Pseudomonas was more abundant in CF with Haemophilus more abundant in PCD (Padj=0.0005). In PCD only, an inverse relationship was seen in the relative abundance of Streptococcus and Haemophilus with age. Conclusions:Bacterial community composition differs between children with PCD and those with CF. Pseudomonas is more prevalent in CF and Haemophilus in PCD, at least until infection with Pseudomonas supervenes. Interactions between organisms, particularly members of Haemophilus, Streptococcus, and Pseudomonas genera appear important. Study of the interactions between these organisms may lead to new therapies or risk stratification.
Bentley S, Davies J, Gastine S, et al., 2021, Clinical pharmacokinetics and dose recommendations for posaconazole gastro-resistant tablets in children with Cystic Fibrosis, Journal of Antimicrobial Chemotherapy, Vol: 76, Pages: 3247-3254, ISSN: 0305-7453
ObjectivesTo investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses.Patients and methodsChildren from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function.Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients.ConclusionsA starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L.
Bayfield KJ, Douglas TA, Rosenow T, et al., 2021, Time to get serious about the detection and monitoring of early lung disease in cystic fibrosis, THORAX, Vol: 76, Pages: 1255-1265, ISSN: 0040-6376
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Davies JC, 2021, The life rafts sailed; Now let's take stock and set the course ahead (Commentary), JOURNAL OF CYSTIC FIBROSIS, Vol: 20, Pages: S29-S30, ISSN: 1569-1993
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