197 Influence of inhalation mode on aerosol lung deposition in patients with cystic fibrosis PART 1: Pharmacokinetic data as representative of lung deposition

Objectives: To investigate the impact of two different inhalation flow maneuvers (TIM = slow and deep inhalation and TBM = normal tidal breathing) on aerosol lung deposition in patients with CF using pharmacokinetic parameters as a representation of lung deposition. Methods: Randomized, open-label, cross-over study. The study group consisted of 18 adult patients with a confirmed diagnosis of CF (genetic analysis). Each patient inhaled a tobramycin solution twice during separate study visits: once in TIM and the other time in TBM mode. Blood samples were collected in order to model tobramycin pharmacokinetics. Outcome measurements: Relative bioavailability (Frel) of tobramycin is defined as the ratio of AUCTIM to AUCTBM, in which the AUC represents the plasma concentration area under the curves. A ratio greater than 1 indicates higher lung deposition for TIM compared to TBM. Individual pharmacokinetic parameters were calculated and assimilated with patient tobramycin serum values using a computerized CF-based Bayesian population model (MW-Pharm, Mediware). Results: Frel was 1 or greater for all patients (mean = 1.55, sd = 0.39, 95%CI = 1.37-1.73). In addition, mean Frel was significant higher than the value of 1 (mean difference = 0.55,

Effect of nebulized colistin sulphate and colistin sulphomethate on lung function in patients with cystic fibrosis:A pilot study

Background: Pulmonary administration of colistin is one of the antimicrobial treatments used in Cystic Fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. Dry powder inhalation of colistin may be an attractive alternative to nebulization of colistin. However, nebulized colistin can cause bronchoconstriction in CF patients. Therefore, in the progress of developing a dry powder formula, the choice of the inhaler and its contents should be guided by optimal efficacy and the least possible side effects. To investigate the side effects, a study was initiated to compare the tolerability of colistin sulphate to colistin sulphomethate per nebulization in CF-patients. Methods: Nine CF-patients chronically infected with P. aeruginosa participated in a double blind, randomized cross over study. On two visits to the outpatient clinic, patients were submitted to either nebulized colistin sulphate or colistin sulphomethate solution. Lung function tests were performed immediately before and 15 and 30 min after nebulization. Results: Nebulization of colistin sulphate caused a significant larger mean decrease in lung function compared to nebulized colistin sulphomethate. A significant decrease in mean changes (SD) in FEV1 at 30 min and FVC at 15 and 30 min after nebulization compared to baseline of -7.3% (8.6%), -5.7% (7.3%) and -8.4% (7.5%) respectively was seen after colistin sulphate nebulization compared to colistin sulphomethate (

41 Pharmacokinetics of nasally administered tobramycin, colistin sulphomethate sodium and a combination of tobramycin and colistin sulphomethate sodium

The paranasal sinuses can constitute a niche for bacteria which can migrate to the lungs. Nasal administration of antibiotics may be effective, but safety of this treatment has to be established first. Objectives: Investigation of the pharmacokinetics (PK) of nasally administered tobramycin (T), colistin sulphomethate sodium (CSS) and a combination of both drugs using systemic absorption, expressed as % absorbed, as surrogate for safety. In addition, tolerability of the nasal irrigations was examined. Methods: Ten adult CF patients performed three different nasal irrigations: 300 mg of T, 2 million IU of CSS and 300 mg of T combined with 2 million IU of CSS. Serum concentrations T and CSS were analysed using a validated assay. Individual PK parameters were calculated and assimilated with T and colistin serum values using a computerized CF-based population model. Maximum serum level (Cmax), trough serum level (Ctrough ) and bioavailability (F) were calculated. T Cmax >30 mg/L and Ctrough >0.5 mg/L were considered to be toxic. For colistin toxic levels are not known. Tolerability was measured using a Visual Analog Scale (VAS). Results: Following the T and the combined irrigation only 2 patients had detectable tobramycin serum levels with a Cma

WS14.5 Influence of breathing pattern on pulmonary aerosol deposition in patients with cystic fibrosis (CF): a pharmacokinetic approach

The therapeutic effect of inhaled antibiotics on lung infection in CF patients is dependent on the aerosol deposition achieved in the lungs. Objectives: To evaluate the influence of two breathing patterns on pulmonary aerosol deposition using pharmacokinetic parameters as surrogate for deposition. Methods: In a randomized, open-label, crossover study pulmonary deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. According to their lung function, patients were categorized in subgroup 1, 2 or 3 corresponding to FEV1 predicted ≤59%, 60-79% or ≥80%. Blood samples were collected in order to model tobramycin pharmacokinetics. Results: Mean Cmax and AUC0-24hr were significantly increased for TIM compared to TBM. Inhalation in TIM also resulted in higher mean Cmax and AUC0-24hr for each subgroup. Mean bioavailability of TIM relative to TBM breathing pattern (Frel) was 1.53±0.41 and mean Frel in each subgroup was also significantly higher than 1. Subgroup category did not affect the results. Conclusion: Slow and deep inhalation of aerosolized tobramycin with the I-neb nebulizer resulted in an estimated 53% higher lung deposition compared to tidal breathing. This result was independent from lung function category, which suggests that regardless the disease state, slow and deep inhalation always results in higher pulmonary aerosol deposition compared to tidal breathing

71 Pharmacokinetics of nasal administered tobramycin in patients with cystic fibrosis

Recent studies showed that the paranasal sinuses can constitute a niche for bacteria. To date no effective treatment for these bacteria is available. Off label administration of nasal antibiotics may be an option. However, first safety of this treatment has to be established. Objectives: With this pilot study in two patients the pharmacokinetic parameters of nasal administered tobramycin were investigated. Methods: In two hospitalised CF-patients, treated with intravenous tobramycin, after a wash-out period, 320 mg of tobramycin, dissolved in 200 ml isotonic saline, was administered to the nose using nasal lavage. Eleven venous blood samples were collected and with a Liquid Chromatography Tandem Mass Spectometer (LCMSMS) method, serum tobramycin concentrations were determined. Tobramycin pharmacokinetic parameters were calculated using the MW\Pharm software package. Systemic absorption was calculated by dividing AUC after nasal administration by AUC after intravenous administration corrected for the administered dose. Results: In patient 1, a female of 32 years old, the maximum concentration (Cmax) of tobramycin was 0.027 mg/L. This Cmax was reached 30 minutes after the nasal lavage with tobramycin (tmax). In total 0.20% (0.62 mg) of the tobramycin was systemically absorbed. In patient 2, a male of 36 years old, the Cmax was 0.029 mg/L. The tmax was 45 minutes and in total 0.16% (0.51 mg) of tobramycin was absorbed. Conclusion: Nasal lavage with 320 mg tobramycin did not result in toxic serum levels. The results of two patients showed a fast absorption of tobramycin and a slow elimination. Approximately 0.20% of the tobramycin was absorbed by the sinonasal mucosa

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study

Aims: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. Methods: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. Results: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. Conclusions: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis

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 forskolininduced 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-toexcellent 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

Pharmacotherapy of cystic fibrosis

Cystic fibrosis (CF) is the most common potentially fatal inherited disease in the white population. In patients with CF, abnormal chloride transport across the apical membrane of epithelial cells has been identified, causing inspissated secretions in the airways, pancreas and other organs. Clinical manifestations result from obstruction in ducts or organs followed by tissue destruction and inflammatory response due to viscid secretions. Most morbidity and mortality arises from pulmonary disease. Pulmonary infection usually occurs with Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa. Pharmacotherapeutic treatment modalities have been focused on substituting pancras enzymes and suppression of the chronic pulmonary infection. However, in case Burkholderia cepacia is isolated from the airways, this is associated with an increased deterioration of the pulmonary function and a high mortality. There is an urgent need for antibiotics with sufficient activity against B. cepacia. New therapeutic modalities are directed towards the normalization of the ion transport across the membranes and the suppression of the pulmonary inflammatory response. If the pulmonary ion transport could be normalized, it should be possible to treat the pulmonary manifestations of the disease

Farmacotherapie bij adolescente en volwassen patienten met cystische fibrose

Cystic fibrosis (CF) is the most common potentially fatal inherited disease in the white population. In patients with CF, abnormal chloride transport across the apical membrane of epithelial cells has been identified, causing inspissated secretions in the airways, pancreas and other organs. Clinical manifestations result from obstruction in ducts or organs followed by tissue destruction and inflammatory response due to viscid secretions. Most morbidity and mortality arises from pulmonary disease. Pulmonary infection usually occurs with Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa. Pharmacotherapeutic treatment modalities have been focused on substituting pancras enzymes and suppression of the chronic pulmonary infection. However, in case Burkholderia cepacia is isolated from the airways, this is associated with an increased deterioration of the pulmonary function and a high mortality. There is an urgent need for antibiotics with sufficient activity against B. cepacia. New therapeutic modalities are directed towards the normalization of the ion transport across the membranes and the suppression of the pulmonary inflammatory response. If the pulmonary ion transport could be normalized, it should be possible to treat the pulmonary manifestations of the disease