Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

General properties
Pharmacotherapeutic group: Gynaecological anti-infectives and antiseptics, ATC Code: G01AA10.

Mechanism of action
Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis at the level of the bacterial ribosome. The antibiotic binds preferentially to the 50S ribosomal subunit and affects the translation process. Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship
Similar to other protein synthesis inhibitors, efficacy is associated with the length of time the concentration of clindamycin remains above the MIC of the infecting organism.

Mechanism of resistance
Resistance to clindamycin is most often due to modification of the target site on the ribosome, usually by chemical modification of RNA bases or by point mutations in RNA or occasionally in proteins. Cross resistance has been demonstrated in vitro between lincosamides, macrolides and streptogramins B in some organisms. Cross resistance has been demonstrated between clindamycin and lincomycin.

Breakpoints
Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis, and Mobiluncus spp has not been defined. Methods for determining the susceptibility of Bacteroides spp. and Gram-positive anaerobic cocci, as well as Mycoplasma spp. have been described by the Clinical and Laboratory Standards Institute (CLSI) and clindamycin susceptibility breakpoints for Gram-negative and Gram-positive anaerobes have been published by both EUCAST and CLSI. However the breakpoints are intended to guide systemic, rather than localized, antibiotic treatment.

Microbiological susceptibility
Clindamycin is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

•      Bacteroides spp.
•      Gardnerella vaginalis
•      Mobiluncus spp.
•      Mycoplasma hominis
•      Peptostreptococcus spp.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties


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2014-0004758
Following a once a day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered to 6 healthy female volunteers for 7 days, approximately 4% (range 0.6% to
11%) of the administered dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 18 ng/mL (range 4 to 47 ng/mL) and on day 7 it averaged 25 ng/mL (range 6 to 61 ng/mL). These peak concentrations were attained approximately 10 hours post-dosing (range 4–24 hours).

Following a once a day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered for 7 consecutive days to 5 women with bacterial vaginosis, absorption was slower and less variable than that observed in healthy females. Approximately 4% (range 2% to 8%) of the dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 13 ng/mL (range 6 to 34 ng/mL) and on day 7 it averaged 16 ng/mL (range 7 to 26 ng/mL). These peak concentrations were attained approximately 14 hours post-dosing (range 4–24 hours).

There was little or no systemic accumulation of clindamycin after repeated (7 day) vaginal dosing of clindamycin phosphate vaginal cream 2%. The systemic half-life was 1.5 to 2.6 hours.

Elderly
Clinical studies for clindamycin phosphate vaginal cream 2% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.