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Background: Portable spirometers are increasingly used to measure lung function at home, but doubts about the accuracy of these devices persist. These doubts stand in the way of the digital transition of chronic respiratory disease care, hence there is a need to address the accuracy of home spirometry in routine care across multiple settings and ages., Objective: This study aimed to assess the accuracy, reproducibility, and responsiveness to the treatment of home spirometry in long-term pediatric and adult cystic fibrosis care., Methods: This retrospective observational study was carried out in 5 Dutch cystic fibrosis centers. Home spirometry outcomes (forced expiratory volume in one second [FEV 1 ], and forced vital capacity [FVC]) for 601 anonymized users were collected during 3 years. For 81 users, data on clinic spirometry and elexacaftor/tezacaftor/ivacaftor (ETI) use were available. Accuracy was assessed using Bland-Altman plots for paired clinic-home measurements on the same day and within 7 days of each other (nearest neighbor). Intratest reproducibility was assessed using the American Thoracic Society/European Respiratory Society repeatability criteria, the coefficient of variation, and spirometry quality grades. Responsiveness was measured by the percentage change in home spirometry outcomes after the start of ETI., Results: Bland-Altman analysis was performed for 86 same-day clinic-home spirometry pairs and for 263 nearest neighbor clinic-home spirometry pairs (n=81). For both sets and for both FEV 1 and FVC, no heteroscedasticity was present and hence the mean bias was expressed as an absolute value. Overall, home spirometry was significantly lower than clinic spirometry (mean ΔFEV 1clinic-home 0.13 L, 95% CI 0.10 to 0.19; mean ΔFVC clinic-home 0.20 L, 95% CI 0.14 to 0.25) and remained lower than clinic spirometry independent of age and experience. One-way ANOVA with post hoc comparisons showed significantly lower differences in clinic-home spirometry in adults than in children (Δmean 0.11, 95% CI -0.20 to -0.01) and teenagers (Δmean 0.14, 95% CI -0.25 to -0.02). For reproducibility analyses, 2669 unique measurement days of 311 individuals were included. Overall, 87.3% (2331/2669) of FEV 1 measurements and 74.3% (1985/2669) of FVC measurements met reproducibility criteria. Kruskal-Wallis with pairwise comparison demonstrated that for both FVC and FEV 1 , coefficient of variation was significantly lower in adults than in children and teenagers. A total of 5104 unique home measurements were graded. Grade E was given to 2435 tests as only one home measurement was performed. Of the remaining 2669 tests, 43.8% (1168/2669) and 43.6% (1163/2669) received grade A and B, respectively. The median percentage change in FEV 1 from baseline after initiation of ETI was 19.2% after 7-14 days and remained stable thereafter (n=33)., Conclusions: Home spirometry is feasible but not equal to clinic spirometry. Home spirometry can confirm whether lung functions remain stable, but the context of measurement and personal trends are more relevant than absolute outcomes., (©Martinus C Oppelaar, Hanneke AC van Helvoort, Michiel AGE Bannier, Monique HE Reijers, Hester van der Vaart, Renske van der Meer, Josje Altenburg, Lennart Conemans, Bart L Rottier, Marianne Nuijsink, Lara S van den Wijngaart, Peter JFM Merkus, Jolt Roukema. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 03.12.2024.)

Background: The current literature inadequately addresses the extent to which remote monitoring should be integrated into care models for chronic respiratory diseases (CRDs)., Objective: This study examined a remote monitoring program (RMP) in cystic fibrosis (CF) by exploring experiences, future perspectives, and use behavior over 3 years, with the aim of developing future directions for remote monitoring in CRDs., Methods: This was a mixed methods, multicenter, observational study in 5 Dutch CF centers following a sequential explanatory design. Self-designed questionnaires using the technology acceptance model were sent out to people with CF who had a minimum of 12 months of experience with the RMP and local health care professionals (HCPs). Questionnaire outcomes were used to inform semistructured interviews with HCPs and people with CF. Qualitative findings were reported following the COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist. Anonymous data on use frequency of all people with CF were analyzed., Results: Between the second quarter of 2020 and the end of 2022, a total of 608 people with CF were enrolled in the program, and a total of 9418 lung function tests and 2631 symptom surveys were conducted. In total, 65% (24/37) of HCPs and 89% (72/81) of people with CF responded to the questionnaire, and 7 HCPs and 12 people with CF participated in semistructured interviews. Both people with CF and HCPs were positive about remote monitoring in CF care and found the RMP a good addition to daily care (people with CF: 44/72, 61%; HCPs: 21/24, 88%). Benefits ranged from supporting individual patients to reducing health care consumption. The most valued monitoring tool was home spirometry by both people with CF (66/72, 92%) and HCPs (22/24, 92%). Downsides included the potential to lose sight of patients and negative psychosocial effects, as 17% (12/72) of people with CF experienced some form of stress due to the RMP. A large majority of people with CF (59/72, 82%) and HCPs (22/24, 92%) wanted to keep using the RMP in future, with 79% (19/24) of HCPs and 75% (54/72) of people with CF looking forward to more replacement of in-person care with digital care during periods of well-being. Future perspectives for the RMP were centered on creating hybrid care models, personalizing remote care, and balancing individual benefits with monitoring burden., Conclusions: Remote monitoring has considerable potential in supporting people with CF and HCPs within the CF care model. We identified 4 practice-based future directions for remote monitoring in CF and CRD care. The strategies, ranging from patient driven to prediction driven, can help clinicians, researchers, and policy makers navigate the rapidly changing digital health field, integrate remote monitoring into local care models, and align remote care with patient and clinician needs., (©Martinus C Oppelaar, Yvette Emond, Michiel A G E Bannier, Monique H E Reijers, Hester van der Vaart, Renske van der Meer, Josje Altenburg, Lennart Conemans, Bart L Rottier, Marianne Nuijsink, Lara S van den Wijngaart, Peter J F M Merkus, Maud Heinen, Jolt Roukema. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.08.2024.)

Background: The use of elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCF) after solid organ transplantation is controversial because of potential drug-drug interactions (DDI) with tacrolimus. We aimed to improve insight into the safety and clinical benefits of co-administration of ETI and tacrolimus in liver or kidney transplanted adult pwCF., Methods: In 5 pwCF, tacrolimus concentrations were monitored during 2 weeks before and 4 weeks after starting ETI treatment. Trough levels, area under the curve (AUC) and clinical effect of ETI were investigated. During the study (6 weeks in total) adverse events were monitored., Results: The DDI between tacrolimus and ETI resulted in an increased exposure of tacrolimus in all subjects, the dose adjusted AUC 0-24h was 1.79 (median) times higher at the end of the study. Five dose adjustments were performed in 4 subjects in order to attain tacrolimus target range. No adverse events were reported and all subjects showed clinical improvement during ETI treatment., Conclusion: The clinical value of ETI treatment in kidney and liver transplanted pwCF is clear. The use of ETI may increase tacrolimus levels moderately. Therefore, we recommend close monitoring of tacrolimus trough levels in patients who start ETI., Competing Interests: Declaration of competing interest We hereby declare that none of the authors have received any financial support or other benefits from commercial sources for the work reported in this manuscript; neither do they have any financial interest which could create a potential conflict of interest., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and show robust treatment effects at group level. The individual effect however, is variable which might be (partially) related to differences in drug exposure. The profound influence of fat containing food compared to fasting on drug exposure gives need to investigate if the exocrine pancreatic function changes the degree and rate of absorption of ivacaftor and thereby may contribute to differences in drug exposure., Methods: Pharmacokinetic parameters of ivacaftor were measured in 10 pancreatic sufficient (PS) and 10 pancreatic insufficient (PI) patients with CF on current treatment with tezacaftor/ivacaftor and compared between both groups. In PI patients pharmacokinetic parameters were investigated with and without the use pancreatic enzymes and compared in each individual., Results: We demonstrated that the pharmacokinetic parameters of ivacaftor did not differ significantly between PS and PI people with CF (pwCF). Pancreatic enzymes did not significantly change the absorption or exposure to ivacaftor in PI pwCF using tezacaftor/ivacaftor., Conclusion: The exocrine pancreatic function of pwCF does not significantly influence the absorption and exposure of ivacaftor. The use of pancreatic enzymes in PI pwCF does not change the absorption and exposure of ivacaftor. Therefore, the dosing advice as mentioned in the SmPC for ivacaftor can be maintained independent of the exocrine pancreatic function., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022. Published by Elsevier B.V.)

Background: Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF., Methods: We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators., Results: In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy., Conclusion: This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies., One-Sentence Summary: We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes., Competing Interests: Declaration of Competing Interest J.M.B. reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos, outside the submitted work; In addition, J.M.B. has a patent(s) related to the FIS-assay with royalties paid. C.K.v.d.E. reports grants from GSK, grants from Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV and Eloxx outside the submitted work; In addition, C.K.v.d.E. has a patent 10006904 with royalties paid. G.H.K. reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, ZON-MW (Vici-grant), European Union (H2020), outside the submitted work; and he has participated in advisory boards meetings to GSK and PURE-IMS outside the submitted work (Money to institution). All other authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Rationale: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC)., Methods: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV 1 pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC., Results: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV 1 pp decline of 0.32% (95% CI 0.11-0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07-0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC., Conclusion: This study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences., Competing Interests: Conflict of interest: J.M. Beekman reports personal fees from Vertex Pharmaceuticals, Proteostasis Therapeutics, Eloxx Pharmaceuticals, Teva Pharmaceutical Industries and Galapagos, outside the submitted work; in addition, J.M. Beekman has a patent related to the FIS-assay with royalties paid. C.K. van der Ent reports grants from GSK, Nutricia, TEVA, Gilead, Vertex, ProQR, Proteostasis, Galapagos NV and Eloxx, outside the submitted work; in addition, C.K. van der Ent has a patent 10006904 with royalties paid. G.H. Koppelman reports grants from Lung Foundation of the Netherlands, Vertex Pharmaceuticals, UBBO EMMIUS foundation, GSK, TEVA the Netherlands, TETRI Foundation and European Union (H2020), outside the submitted work; and has participated in advisory board meetings for GSK and PURE-IMS outside the submitted work (money paid to institution). P. van Mourik reports financial compensation (money to institution) from Vertex for participation in a webinar, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Substantial progress has been made in the treatment of Cystic fibrosis due to introduction of CFTR modulators. However, little is known about the long term side effects of treatment with these drugs. We here present a 7 year old girl with CF who presented with breast development as a rare dose dependent side effect of treatment with ivacaftor and we report data on the correlation between drug plasma concentration and clinical effect, bodyweight, and BSA in 16 patients. Higher plasma concentrations did not correlate with clinical effect, as change in FEV1 and sweat chloride concentration. Patients with low bodyweight or BSA tended to have higher plasma concentrations. This might indicate that the current recommended dose of ivacaftor is at the top of the dose-response curve and that some patients can be treated with lower doses of ivacaftor with similar clinical effect., Competing Interests: Declaration of Competing Interest Dr. Jeyaratnam, Dr. van der Meer, Dr. Berkers and Dr. Heijerman have nothing to disclose. Dr. Beekman reports grants from proteostasis, personal fees from proteostasis,  outside the submitted work;  In addition, Dr. Beekman is inventor on a patent related to Intestinal Organoid swelling  and received royalties paid from Hubrecht Organoid Technology. Dr. van der Ent reports grants from GSK, grants from Nutricia, grants from TEVA, grants from Gilead, grants from Vertex, grants from ProQR, grants from Proteostasis, grants from Galapagos NV, grants from Eloxx, outside the submitted work; In addition, Dr. van der Ent has a patent 10,006,904 with royalties paid., (Copyright © 2021. Published by Elsevier B.V.)

Background: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation., Methods: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV 1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated., Results: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV 1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV 1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively., Conclusions: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV 1 ) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331)., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: JRD, ZY, and NK are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated; PA was employed by Vertex Pharmaceuticals Incorporated at the time the study was conducted; HH reports personal fees from Gilead, PTC, Teva, and Vertex Pharmaceuticals Incorporated, and clinical trials with AbbVie and Vertex Pharmaceuticals Incorporated; JMB reports grants from Eloxx and Proteostasis, travel support from Proteostasis and Vertex Pharmaceuticals Incorporated, and royalties from the Royal Netherlands Academy of Sciences and Arts; RGJV is the CEO of Hubrecht Organoid Technology, a company based on the commercial implementation of the organoid technology, and reports grants and advisory board membership from Vertex Pharmaceuticals Incorporated; CKvdE reports grants from Eloxx, Galapagos NV, Gilead, GSK, Nutricia, ProQR, Proteostasis, Teva, and Vertex Pharmaceuticals Incorporated, and a patent (10006904) with royalties paid. SFB does not have any other disclosures to report., (Copyright © 2020. Published by Elsevier B.V.)

Background: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations., Methods: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids., Results: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma., Conclusions: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed., Competing Interests: Declaration of Competing Interest J.M.B. and C.K.v.d.E are inventors on a patent application related to these findings. GHK reports research funding from the Lung Foundation of the Netherlands, GSK, Ubbo Emmius Foundation, Vertex, TEVA the Netherlands, TETRI Foundation, outside the submitted work and participation in advisory boards from GSK and PureIMS, outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Background: In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of the time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated., Methods: In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 hours. Pharmacokinetic and kidney function parameters were compared between the 2 groups., Results: Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 versus 1.43 mL/h*kg (P = 0.50) and mean volumes of distribution were 0.25 versus 0.27 L/kg (P = 0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group, indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 versus 0.2 mmol/L, P = 0.015)., Conclusions: The time of administration (8:00 versus 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

Background: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations., Methods: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV 1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function., Findings: FIS was positively correlated with FEV 1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089)., Interpretation: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression., (Copyright © 2019. Published by Elsevier B.V.)

Purpose of Review: Due to continuous development of new drugs and better treatment strategies, survival of patients with cystic fibrosis has changed dramatically. Recently, targeted therapy of cystic fibrosis transmembrane conductance regulator (CFTR) modulators have become available. Despite these promising developments, treatment of this complex multiorgan disease constitutes a high and variable amount of other drugs. Complications of pharmacotherapeutic treatment are, therefore, expected to become more prevalent. This gives cause to review drug-related side effects in this new era in cystic fibrosis treatment., Recent Findings: We will discuss cystic fibrosis-related pharmacotherapies with a focus on indication of treatment, side effects and their complications, drug--drug interactions, and options to monitor and prevent drug-induced toxicity. Many recent publications about pharmacotherapy in cystic fibrosis, focus on antifungal therapy and CFTR modulators. We will give an overview of the most important studies., Summary: With increased life expectancy which is, in part, because of better treatment options, the burden of pharmacotherapy in cystic fibrosis patients will increase. This has a high impact on quality of life as pharmacotherapy is time consuming and may cause side effects. Therefore, it is very important to be aware of possible pharmacotherapy-related side effects and their complications, drug--drug interactions, and options to monitor and prevent drug-induced toxicity.

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects. The in vitro organoid responses correlated with both change in pulmonary response and change in sweat chloride concentration. Receiver operating characteristic curves indicated good-to-excellent accuracy of the organoid-based test for defining clinical responses. This study indicates that an in vitro assay using stem cell cultures can prospectively select efficacious treatments for patients and suggests that biobanked stem cell resources can be used to tailor individual treatments in a cost-effective and patient-friendly manner., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)