Effect of high-dose ibuprofen in patients with cystic fibrosis. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects.
Since the inflammatory response to chronic infection contributes to lung destruction in patients with cystic fibrosis, we hypothesized that anti-inflammatory therapy might slow the progression of lung disease.
                In a double-blind trial, 85 patients, 5 to 39 years of age, with mild lung disease (forced expiratory volume in one second [FEV1], > or = 60 percent of the predicted value) were randomly assigned to receive ibuprofen or placebo orally twice daily for four years. Doses were adjusted individually to achieve peak plasma concentrations of 50 to 100 micrograms per milliliter. Changes in pulmonary function, the percentage of ideal body weight, the chest-radiograph score, and the frequency of hospitalization were assessed.
                Patients randomly assigned to ibuprofen had a slower annual rate of change in FEV1 than the patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was better maintained in the former group (P = 0.02). Among the patients who took ibuprofen for four years and had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), and this group of patients also had a significantly slower rate of decline in forced vital capacity, the percentage of ideal body weight, and the chest-radiograph score. There was no significant difference between the ibuprofen and placebo groups in the frequency of hospitalization. One patient was withdrawn from the study because of conjunctivitis, and one because of epistaxis related to ibuprofen.
                In patients with cystic fibrosis and mild lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lung disease without serious adverse effects. To assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with cystic fibrosis (CF).
                In this multicenter, double-blinded, placebo-controlled trial, a total of 142 patients age 6 to 18 years with mild lung disease (forced expiratory volume in 1 minute [FEV1] > 60 predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 mug/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annualized rate of change in FEV1% predicted.
                The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 +/- 0.51 vs -1.62 +/- 0.52; P = .03), but not FEV1%. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events.
                High-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated. Antiinflammatory therapy with ibuprofen has been proposed to retard the progression of lund disease in cystic fibrosis (CF). The pharmacokinetics and toxicity of ibuprofen were investigated in a randomized, double-blind, placebo-controlled, 3-month dose-escalation study in 19 children with CF, 6 to 12 years of age. The subjects received orally and twice daily 300 mg of drug during the first month, 400 mg in the second month, and 600 mg in the third month. Ibuprofen pharmacokinetics and evaluation for adverse effects were performed at the beginning and end of each month. The dose of ibuprofen was increased if peak plasma concentration (Cmax) was less than 50 micrograms/ml. To preserve the blind nature of the study, the dose in matched subjects taking placebo was also increased. The subjects randomly assigned to receive ibuprofen (n = 13) completed 26 months of treatment; placebo subjects (n = 5) completed 12 months. With dose escalation, Cmax and the area under the concentration-time curve from zero to infinity significantly increased (p less than 0.01). The pharmacokinetics of ibuprofen in 13 children with CF who received 13.4 +/- 4.1 mg/kg (mean +/- SD) were compared with those in four healthy children who received a similar dose. Peak plasma concentration (48 +/- 17 micrograms/ml) was decreased by 27% (p = 0.06), the area under the concentration-time curve (6.1 +/- 1.7 mg.min/ml) was decreased by 46% (p less than 0.001), apparent total clearance (2.3 +/- 0.6 ml/min.kg-1) was increased by 77% (p less than 0.01), and apparent volume of distribution during terminal phase (291 +/- 91 ml/kg) was increased by 84% (p = 0.01) in the children with CF. Time to Cmax (66 +/- 20 minutes) and elimination half-life (92 +/- 27 minutes) were not significantly different. No subjects were withdrawn from the study because of side effects. No adverse effects could be attributed to ibuprofen. Thus ibuprofen administration has no significant toxic effects, but Cmax will need to be monitored for effective dosing in patients with CF.
High-dose ibuprofen can slow the progression of lung disease in people with CF, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with CF.