Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122 Parma, Italy
Pharmacotherapeutic group: antibacterials for systemic use, fluoroquinolones
ATC code: J01MA12
Levofloxacin is an antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic active substance ofloxacin.
The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial DNA gyrase and topoisomerase IV enzymes.
The parameters associated with the antibacterial effects of levofloxacin are the Cmax/MIC and AUC/MIC ratios (Cmax = maximum concentration at the site of infection, AUC = area under the curve and MIC = minimal inhibitory concentration).
Resistance to levofloxacin is most often acquired through a stepwise process by target site mutations in DNA gyrase and topoisomerase IV. Reduced susceptibility to levofloxacin can also result from acquisition of plasmids encoding proteins that protect these targets from inhibition. Reduced bacterial permeability (common in P. aeruginosa) and efflux mechanisms may also confer or contribute to resistance.
Cross-resistance between levofloxacin and other fluoroquinolones is observed.
Established susceptibility breakpoints for systemic (oral or intravenous) administration of levofloxacin are not applicable to delivery by inhalation.
Clinical efficacy was demonstrated in two placebo-controlled studies and one active-comparator study in 448 patients randomised to receive Quinsair 240 mg twice daily.
Two randomised, double-blind, single-cycle, placebo-controlled clinical trials (Studies 204 and 207) in patients with CF chronically infected with P. aeruginosa were conducted. Adult and adolescent (≥12 to <18 years old and weighing ≥30 kg) patients who had a FEV1 percent predicted between 25% and 85% were enrolled. All patients had also received a minimum of 3 courses of inhaled anti-pseudomonal antimicrobial therapy in the 12 months (Study 204) or 18 months (Study 207) prior to entry into the study, but none in the 28 days immediately preceding study entry. In addition to study drug, patients remained on standard of care treatment for chronic pulmonary infection. A total of 259 patients were randomised to Quinsair 240 mg twice daily for 28 days (≥18 years, n=226; ≥12 to <18 years old, n=33) and 147 were randomised to placebo (≥18 years, n=127; ≥12 to <18 years old, n=20). These two placebo-controlled studies showed that 28 days of treatment with Quinsair 240 mg twice daily resulted in significant improvement in relative change from baseline in FEV1 percent predicted compared to placebo (see Table 1).
Table 1. FEV1 Percent predicted relative change from baseline to Day 28 in placebo-controlled efficacy and safety studies of Quinsair in patients with CF:
| FEV1 percent predicted | Supportive studies | |||
|---|---|---|---|---|
| Study 207 (ITT) | Study 204 (ITT)a | |||
| Placebo | Quinsair 240 mg BID | Placebo | Quinsair 240 mg BID | |
| N=110 | N=220 | N=37 | N=39 | |
| ≥12 to <18 years, n (%) | 16 (14.5) | 30 (13.6) | 4 (10.8) | 3 (7.7) |
| ≥18 years, n (%) | 94 (85.5) | 190 (86.4) | 33 (89.2) | 36 (92.3) |
| Baseline mean (SD) | 56.32 (15.906) | 56.53 (15.748) | 52.4 (13.42) | 48.8 (15.15) |
| Relative change from Baseline to Day 28 LS Mean (SE) | 1.24 (1.041) | 3.66 (0.866) | -3.46 (2.828) | 6.11 (2.929) |
| Treatment Difference at Day 28 [95% CI]b | 2.42 [0.53, 4.31]; P=0.012c | 9.57 [3.39, 15.75]; P=0.0026c | ||
CI = Confidence interval; FEV 1 = forced expiratory volume in 1 second; ITT = intent to treat (all patients randomised); P = P value; SD = standard deviation; SE = standard error; ANCOVA = analysis of covariance.
a ANCOVA with terms for treatment, region, age (16 to 18 years, >18 years), and baseline FEV percent
1 predicted as quartiles. (Note: In Study 204, an additional 38 patients were randomised to Quinsair 120 mg once daily (≥18 years, n=35; ≥16 to <18 years old, n=3) and an additional 37patients were randomised to Quinsair 240 mg once daily (≥18 years, n=34; ≥16 to <18 years old, n=3).)
b LS Mean difference for Quinsair minus placebo.
c Tested using alpha of 0.05.
Study 209 (Core Phase) was a randomised, open-label, parallel group, active-controlled, non-inferiority study comparing Quinsair to tobramycin inhalation solution (TIS) over 3 treatment cycles. Each treatment cycle included 28 days of treatment with Quinsair 240 mg twice daily or TIS 300 mg twice daily followed by 28 days without inhaled antibiotics. Adult and adolescent (≥12 to <18 years old and weighing ≥30 kg) patients who had a FEV1 percent predicted between 25% and 85% were enrolled. All patients had also received at least 3 courses of TIS in the 12 months prior to entry into the study, but none in the 28 days immediately preceding study entry. In addition to study drug, patients remained on standard of care treatment for chronic pulmonary infection. A total of 189 patients were randomised to Quinsair 240 mg twice daily (≥18 years, n=170; ≥12 to <18 years old, n=19) and 93 were randomised to TIS (≥18 years, n=84; ≥12 to <18 years old, n=9). Results obtained for the primary and key secondary endpoints are provided in Table 2.
Table 2. Results for the primary and key secondary endpoints in the active-controlled efficacy and safety study of Quinsair in patients with CF:
| Parameter | Pivotal Study – Study 209 (Core Phase; ITT) | ||
|---|---|---|---|
| TIS 300 mg BID N=93 | Quinsair 240 mg BID N=189 | Treatment Differencea | |
| ≥12 to <18 years, n (%) | 9 (9.7) | 19 (10.1)* | |
| ≥18 years, n (%) | 84 (90.3) | 170 (89.9) | |
| FEV1 Percent predicted Baseline mean (SD) | 53.20 (15.700) | 54.78 (17.022) | |
| Primary endpoint: | |||
| FEV1 Relative change from Baseline to Day 28 of Cycle 1 | N=93 0.38 (1.262)b | N=189 2.24 (1.019)b | LS mean [95% CI]: 1.86 [-0.66, 4.39]c |
| Secondary endpoints: | |||
| FEV1 Relative change from Baseline to Day 28 of Cycle 2 | N=84 -0.62 (1.352)b | N=170 2.35 (1.025)b | LS mean [95% CI]: 2.96 [-0.03, 5.95] |
| FEV1 Relative change from Baseline to Day 28 of Cycle 3 | N=83 -0.09 (1.385)b | N=166 1.98 (1.049)b | LS mean [95% CI]: 2.07 [-1.01, 5.15] |
| Respiratory domain of Cystic Fibrosis Questionnaire – Revised (CFQ-R) Change from Baseline to Day 28 of Cycle 1 | N=91 -1.31 (1.576)b | N = 186 1.88 (1.278)b | LS mean [95% CI]: 3.19 [0.05, 6.32] P=0.046e |
| Median time to administration of anti-pseudomonal antimicrobials | N=93 110 days | N=189 141 days | Hazard ratio [95% CI]d: 0.73 [0.53, 1.01] P=0.040e |
| Median time to pulmonary exacerbation | N=93 90.5 days | N=189 131 days | Hazard ratio [95% CI]d: 0.78 [0.57, 1.07] P=0.154e |
CI = Confidence interval; FEV 1 = forced expiratory volume in 1 second; ITT = intent-to-treat (all patients randomised); P = P-value; SD = standard deviation; SE = standard error; TIS = tobramycin inhalation solution.
* Note: One adolescent randomised to Quinsair 240 mg twice daily did not receive study drug.
a Treatment difference for Quinsair minus TIS, or Hazard ratio for Quinsair/TIS.
b LS Mean (SE).
c Non-inferiority was tested using a pre-specified, fixed non-inferiority margin of 4% at Day 28 of Cycle 1.
d Estimates were obtained from a Cox proportional hazards regression model.
e P-value determined using a log-rank test.
Patients who completed Study 209 (Core Phase) could continue in an optional Extension Phase for 3 additional cycles (i.e. 28 days of treatment with Quinsair 240 mg twice daily followed by 28 days off treatment). A total of 88 patients received at least 1 dose of Quinsair in Study 209 (Extension Phase), 32 of these had received TIS and 56 of these had received Quinsair in the Core Phase. During the Extension Phase, the LS Mean change for FEV1 percent predicted ranged between 4.83% to 1.46% across the 3 additional treatment cycles. For the subgroup of patients who received TIS during the Core Phase and switched to Quinsair in the Extension Phase, the improvement in FEV1 percent predicted was more marked on Quinsair than on TIS (LS Mean change in FEV1 percent predicted on TIS ranged between 0.97% to 3.60% across Cycles 1 to 3 and between 4.00% to 6.91% across Cycles 4 to 6 on Quinsair). For the subgroup of patients who received Quinsair throughout the Core and Extension Phases (i.e. Cycles 1 to 6), the LS Mean change in FEV1 percent predicted ranged between 3.6% to 4.6% except in Cycle 6, where it was close to baseline (-0.15%). The proportion of patients who received Quinsair throughout Study 209 Core and Extension Phases (with a highest levofloxacin MIC P. aeruginosa isolate exceeding 1 μg/ml) was similar at the end of treatment during Cycles 1 and 3 in the Core Phase (76.6% to 83.3%) and at the end of treatment during Cycles 4 to 6 in the Extension Phase (77.8% to 87.5%).
In Studies 204, 207 and 209, the relative change in FEV1 percent predicted from baseline to the end of treatment in Cycle 1 was of similar magnitude in the 51 adolescents with CF (≥12 to <18 years old and weighing ≥30 kg) receiving Quinsair 240 mg twice daily to that in adults. Efficacy was not evaluated in the 14 children with CF (≥6 to <12 years old) and 13 adolescents with CF (≥12 to <17 years old) who participated in Study 206.
The European Medicines Agency has deferred the obligation to submit the results of studies with Quinsair in one or more subsets of the paediatric population in cystic fibrosis patients with P. aeruginosa pulmonary infection/colonisation (see section 4.2 for information on paediatric use).
The maximal plasma concentration (Cmax) of levofloxacin following administration by inhalation occurred at approximately 0.5-1 hour post-dose.
Multiple dose administration of Quinsair 240 mg twice daily by inhalation results in levofloxacin systemic exposure approximately 50% lower than that observed following systemic administration of comparable doses (see Table 3). However, there is variability in the systemic exposures observed which means that serum levels of levofloxacin following inhalation of Quinsair may sometimes fall within the range of levels observed following systemic administration of comparable doses.
Table 3. Comparison of mean (SD) multiple dose levofloxacin pharmacokinetic parameters following Quinsair administration by inhalation to patients with CF and following oral and intravenous administration of levofloxacin to healthy adult volunteers:
| Pharmacokinetic parameter | Quinsair | Systemic levofloxacin | |
|---|---|---|---|
| 240 mg Inhalation BID | 500 mg Oral QD* | 500 mg IV QD* | |
| Cmax (μg/ml) | 2.4 (1.0) | 5.7 (1.4) | 6.4 (0.8) |
| AUC(0-24) (μg•h/ml) | 20.9 (12.5) | 47.5 (6.7) | 54.6 (11.1) |
IV = intravenous; QD = quaque die (once a day); BID = bis in die (twice a day)
* Predicted value from population PK analysis in CF patients
** Healthy males 18-53 years old
High levofloxacin concentrations were observed in sputum following Quinsair 240 mg twice daily dosing in patients with CF. The mean post-dose sputum concentrations were approximately 500-1900 μg/ml and were approximately 400-1700 times higher than those observed in serum.
Approximately 30 to 40% of levofloxacin is bound to serum protein. The mean apparent volume of distribution of levofloxacin in serum is approximately 250 L following inhalation of Quinsair 240 mg twice daily.
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for ˂5% of the dose following systemic administration and are excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Levofloxacin is systemically absorbed following inhalation of Quinsair and eliminated similarly to levofloxacin following systemic administration. Following oral and intravenous administration, levofloxacin is eliminated relatively slowly from the plasma (t1/2: 6 to 8 hours). The half-life of levofloxacin following inhalation of Quinsair is approximately 5 to 7 hours. Elimination is primarily by the renal route (>85% of the dose following oral or intravenous administration). The mean apparent total body clearance of levofloxacin following systemic administration of a 500 mg single dose was 175 +/- 29.2 ml/min. The apparent clearance (CL/F) of levofloxacin following inhalation of Quinsair 240 mg twice daily is 31.8 +/- 22.4 L/hour.
Following systemic administration, levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.
The effects of renal impairment on the pharmacokinetics of levofloxacin administered by inhalation have not been studied. However, dose adjustments were not employed in clinical studies of Quinsair which allowed for the inclusion of patients with mild to moderate renal impairment (estimated creatinine clearance ≥20 ml/min using the Cockcroft-Gault formula in adult patients and ≥20 ml/min/1.73 m² using the Bedside Schwartz formula in patients <18 years old). Studies using systemic administration of levofloxacin show that the pharmacokinetics of levofloxacin are affected by renal impairment; with decreasing renal function (estimated creatinine clearance <50 ml/min), renal elimination and clearance are decreased, and elimination half-life increased.
Therefore, doses of Quinsair do not need to be adjusted in patients with mild to moderate renal impairment. However, Quinsair is not recommended for use in patients with severe renal impairment (creatinine clearance ˂20 ml/min, see section 4.2).
Pharmacokinetic studies with Quinsair in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism in the liver, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.
The safety and efficacy of Quinsair in children aged ˂18 years old have not yet been established (see section 4.2).
The pharmacokinetics of levofloxacin following inhalation of Quinsair 240 mg twice daily were investigated in paediatric patients with CF aged 12 years and older and weighing ≥30 kg. A population PK model based on sparse sampling determined that levofloxacin serum concentrations were comparable between paediatric and adult patients following 28 days of treatment. Higher sputum concentrations were observed in adults compared to paediatric patients in Study 207; similar sputum concentrations were observed in adult and paediatric patients in Study 209.
In addition, the pharmacokinetics of weight-based doses of levofloxacin administered by inhalation once daily for 14 days in paediatric patients with CF (≥6 to <12 years old, n=14 and ≥12 to <17 years old, n=13) were evaluated in Study 206. Patients weighing 22 to 30 kg received 180 mg levofloxacin/day and patients weighing ˃30 kg received 240 mg levofloxacin/day. The weight-based dosing scheme resulted in consistent serum and sputum PK exposure across the range of ages (7 to 16 years old) and weights (22 to 61 kg) observed in the study. Serum PK exposures were similar when comparing children receiving the weight-based regimen and adults receiving Quinsair 240 mg once daily. Sputum PK exposure in children aged 7 to 16 years old was approximately one-third of adult exposure.
The pharmacokinetics of levofloxacin administered by inhalation have not been studied in the elderly. Following systemic administration, there were no significant differences in levofloxacin pharmacokinetics between young and elderly subjects except those associated with age-related decreases in creatinine clearance.
Population pharmacokinetic analysis results showed no differences in systemic exposure of levofloxacin due to gender following administration of Quinsair.
The effects of race on the pharmacokinetics of levofloxacin administered by inhalation have not been studied. Following systemic administration, the effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.
Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.
Fluoroquinolones have been shown to cause arthropathy in weight-bearing joints of immature animals. In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs. These findings were more marked in young animals.
Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster lung cells in vitro. These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential. Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses. Levofloxacin did not show any genotoxic potential in a photomutagenicity assay. It reduced tumour development in a photocarcinogenicity study.
Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on foetuses was delayed maturation as a result of maternal toxicity.
Non-clinical studies conducted with levofloxacin using the inhalation route revealed no special hazard for humans based on conventional studies of safety pharmacology (respiratory), single dose toxicity and repeated dose toxicity.
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