Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Teva B.V., Swensweg 5, 2031 GA Haarlem, The Netherland
Pharmacotherapeutic group: antibacterials for systemic use, other antibacterials.
ATC Code: J01XB01
Colistimethate sodium (CMS) is a cyclic polypeptide antibacterial active substance that is derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. Polymyxins work by damaging the cell membrane and the resulting physiological effects are lethal to the bacterium. Polymyxins are selective for Gram-negative bacteria that have a hydrophobic outer membrane.
Resistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharide, which become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.
Cross resistance between colistimethate sodium and polymyxin B is expected. Since the mechanism of action of the polymyxins is different from that of other antibacterial agents, resistance to colistin and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.
The epidemiological cut off value for colistimethate sodium for Pseudomonas aeruginosa, distinguishing the wild type population from isolates with acquired resistance traits, is 4 mg/l.
The Phase 3 clinical study was a randomised, open-label active comparator study comparing the efficacy of colistimethate sodium 1,662,500 IU dry powder for inhalation to tobramycin nebuliser solution for inhalation, 300 mg/5 ml, in 380 subjects with documented cystic fibrosis complicated by chronic pulmonary infection with Pseudomonas aeruginosa. The subjects were aged 6 years and above and had an FEV1% predicted of 25-75%. All subjects were also required to have successfully completed a minimum of two cycles of nebulised tobramycin solution run-in prior to randomisation. Subjects were randomised to receive either one 1,662,500 IU capsule of colistimethate sodium twice daily, or 300 mg of tobramycin, twice daily. It should be noted that treatment was not interrupted when patients received concomitant parenteral antibacterial active substances.
Efficacy was measured by the change in FEV1 % predicted compared to baseline after a 24-week treatment period.
The results of the Intent-To-Treat (ITT) population for the primary efficacy outcome are shown below:
Change in FEV1 (% predicted) from baseline at Week 24 (ITT Population):
| Patient group | Colobreathe (Mean) | Tobramycin (Mean) | Adjusted Treatment difference | 95% CI |
|---|---|---|---|---|
| All patients using LOCF | -0.90 (n=183) | 0.35 (n=190) | -0.97 | -2.74, 0.86 |
| Completed patients | 0.39 (n=153) | 0.78 (n=171) | -0.29 | -2.21, 1.71 |
The data from the primary outcome parameter, change in FEV1 % predicted, are not normally distributed. The adjusted treatment difference and 95% confidence interval have been back transformed from log transformed data. The ITT population excluded patients who had been treated but demonstrated no evidence of chronic infection.
The European Medicines Agency has deferred the obligation to submit the results of studies with Colobreathe in one or more subsets of the paediatric population in Pseudomonas aeruginosa pulmonary infection/colonisation in patients with cystic fibrosis (see section 4.2 for information on paediatric use).
Colistimethate is not significantly absorbed from the lung after inhalation of Colobreathe. After administration of 1,662, 500IU twice daily for 7 days in adult, adolescent and paediatric cystic fibrosis patients mean Cmax values of total colistimethate of up to 455ng/ml (adult mean) were observed. Tmax for total colistimethate occurred between 0.5 and 1 hour post-dose. Although the population PK analysis showed that age is a statistically significant covariate, the AUC0-6 and dose adjusted AUC0-6 (AUC0-6/D) for total CMS and total free colistin were similar between children and adolescents, while higher AUC0-6 was observed in the adult group. When AUC0-6 was adjusted by dose and body weight, a slightly higher AUC0-6/D/W for total CMS and total free colistin was observed in children. High PK variability was observed in all three groups. Therefore, dose adjustment in low age groups is considered not necessary.
High concentrations of total free colistin (mean 23.5mg/L) and total colistimethate (mean 178mg/L) were observed in sputum at 1 hour post-dose on Day 8 following BID dosing for 7 days across all age groups.
Absorption of colistimethate from the gastro-intestinal tract does not occur to any appreciable extent in the normal individual.
Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. One study in cystic fibrosis patients gives the steady-state volume of distribution as 0.09 l/kg.
Colistimethate sodium is converted to the base in vivo. As 80% of a parenteral dose can be recovered unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism is unknown.
A systemic absorption study showed minimal urinary excretion with less than 3% of the dose of Colobreathe excreted in the urine as colistimethate sodium and colistin. Therefore, dose adjustment in patients with renal impairment is not considered necessary. The estimated mean terminal half-lives for total CMS and total free colistin were 3.0 and 6.4 h, respectively.
Nonclinical data reveal no special hazard for humans based on conventional studies of genotoxicity. Animal studies of safety pharmacology, repeated dose toxicity or toxicity to reproduction, employing routes assuring systemic exposure, showed no particular hazard. There were no notable effects on fertility or general reproductive performance in male or female rats or mice. In embryo-fetal development studies in mice, resorptions and reduced ossification were seen, and in rats reduced fetal weights, reduced ossification and at the high dose of 10 mg colistin base per day, reduced post-natal survival. An embryo-fetal study in rabbits reported no effects at intravenous doses up to 80 mg/kg colistimethate sodium (32 mg colistin base/kg).
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