CLINICAL PHARMACOLOGY
General
In cystic fibrosis (CF) patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection (2,3).
Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection (4). In vitro, Pulmozyme hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity (1).
Pharmacokinetics
When 2.5 mg Pulmozyme was administered by inhalation to eighteen CF patients, mean sputum concentrations of 3 µg/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 µg/mL two hours following inhalation. Inhalation of up to 10 mg TID of Pulmozyme by 4 CF patients for six consecutive days, did not result in a significant elevation of serum concentrations of DNase above normal endogenous levels (5,6). After administration of up to 2.5 mg of Pulmozyme twice daily for six months to 321 CF patients, no accumulation of serum DNase was noted.
Pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/mL. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.3 ± 1.3 ng/mL for the 3 months to <5 year age group and by 0.8 ± 1.2 ng/mL for the 5 to ≤10 year age group. The relationship between BAL or serum DNase concentration and adverse experiences and clinical outcomes is unknown.
Clinical Experience
Pulmozyme has been evaluated in a randomized, placebo-controlled trial of clinically stable cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis (7). Patients were treated with placebo (325 patients), 2.5 mg of Pulmozyme once a day (322 patients), or 2.5 mg of Pulmozyme twice a day (321 patients) for six months administered via a Hudson T Up-draft II® nebulizer with a Pulmo-Aide® compressor.
Both doses of Pulmozyme resulted in significant reductions when compared with the placebo group in the number of patients experiencing respiratory tract infections requiring use of parenteral antibiotics. Administration of Pulmozyme reduced the relative risk of developing a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice daily dose, respectively (see Table 1). The data suggest that the effects of Pulmozyme on respiratory tract infections in older patients (>21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. Patients with baseline FVC >85% may also benefit from twice a day dosing (see Table 1). The reduced risk of respiratory infection observed in Pulmozyme treated patients did not directly correlate with improvement in FEV1 during the initial two weeks of therapy.
Within 8 days of the start of treatment with Pulmozyme, mean FEV1 increased 7.9% in those treated once a day and 9.0% in those treated twice a day compared to the baseline values. The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo recipients did not show significant mean changes in pulmonary function testing (see Figure 1).
For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of Pulmozyme decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or baseline FVC.
Table 1: Incidence of First Respiratory Tract Infection Requiring Parenteral Antibiotics in Patients with FVC ≥40% of Predicted
| |
Placebo
N=325 |
2.5 mg QD
N=322 |
2.5 mg BID
N=321 |
|
Percent of Patients Infected
|
43% |
34% |
33% |
| Relative Risk (vs placebo) |
|
0.73 |
0.71 |
| p-value (vs placebo) |
|
0.015 |
0.007 |
|
Subgroup by Age and Baseline FVC
|
Placebo
(N) |
2.5 mg QD
(N) |
2.5 mg BID
(N) |
|
Age
|
|
|
|
| 5-20 years |
42% (201) |
25% (199) |
28% (184) |
| 21 years and older |
44% (124) |
48% (123) |
39% (137) |
|
Baseline FVC
|
|
|
|
| 40-85% Predicted |
54% (194) |
41% (201) |
44% (203) |
| >85% Predicted |
27% (131) |
21% (121) |
14% (118) |
Figure 1 Mean Percent Change from Baseline FEV1 in Patients with FVC ≥40% of Predicted
Pulmozyme has also been evaluated in a second randomized, placebo-controlled study in clinically stable patients with baseline FVC <40% of predicted (8). Patients were enrolled and treated with placebo (162 patients) or Pulmozyme 2.5 mg QD (158 patients) for twelve weeks. In patients who received Pulmozyme, there was an increase in mean change (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p <0.001) and in FVC (12.4% vs. 7.3%, p <0.01). Pulmozyme did not significantly reduce the risk of developing a respiratory tract infection requiring parenteral antibiotics (54% of Pulmozyme patients vs. 55% of placebo patients had experienced a respiratory tract infection by 12 weeks, relative risk =.93, p=0.62).
The effect of Pulmozyme on exercise tolerance has not been established in adults and children.
Other Studies
Clinical trials have indicated that Pulmozyme therapy can be continued or initiated during an acute respiratory exacerbation.
Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not provide further improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of Pulmozyme 10 mg BID for 14 days, followed by a 14 day wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a return to baseline with each Pulmozyme withdrawal.
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