Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antiinfectives and antiseptics, excl. combinations with corticosteroids, antibiotics, 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.

Clindamycin, like most protein synthesis inhibitors, is predominantly bacteriostatic and efficacy is associated with the length of time during which the concentration of active ingredient remains above the MIC of the infecting microorganism.

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.

In vitro 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.


Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis and Mobiluncus spp. has not been defined. Clindamycin susceptibility breakpoints for Gram-negative and Gram-positive anaerobes bacteria have been published by EUCAST. Clinical isolates that test susceptible to clindamycin and resistant to erythromycin should 
also be tested for inducible clindamycin resistance using the D-test. However, the breakpoints are intended to guide systemic, rather than localized, antibiotic treatment.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Systemic absorption of clindamycin was estimated following a once-a-day intravaginal dose of one clindamycin phosphate vaginal ovule (equivalent to 100 mg clindamycin) administered to 11 healthy female volunteers for 3 days. Approximately 30% (range 6% to 70%) of the administered dose was absorbed systemically on day 3 of dosing based on area under the concentration-time curve (AUC).
Systemic absorption was estimated using a sub-therapeutic 100 mg intravenous dose of clindamycin phosphate as a comparator in the same volunteers as well as a 100 mg dose of clindamycin phosphate vaginal cream. The mean AUC following day 3 of dosing with the ovule was 3.2 μg•hr/mL (range 0.42 to 11 μg•hr/mL). The Cmax observed on day 3 of dosing with the ovule averaged 0.27 μg/mL (range 0.03 to 0.67 μg/mL) and was observed about 5 hours after dosing (range 1 to 10 hours). In contrast, the AUC and Cmax after the single intravenous dose averaged 11 μg•hr/mL (range 5.1 to 26 μg•hr/mL) and 3.7 μg/mL (range 2.4 to 5.0 μg/mL), respectively. The mean apparent elimination half-life after dosing with the ovule was 11 hours (range 4 to 35 hours) and is considered to be limited by the absorption rate.

The results from this study showed that systemic exposure to clindamycin (based on AUC) from the ovule was, on average, three-fold lower than that from a single sub-therapeutic 100 mg intravenous dose of clindamycin. Relative to a comparable dose of clindamycin vaginal cream, systemic absorption of the ovule was approximately 7-fold greater than that following dosing of the vaginal cream with average values of AUC and Cmax of 0.4 µg.hr/mL (range 0.13 to 1.16 µg.hr/mL and 0.02 µg/mL (range 0.01 to 0.07 µg/mL) respectively for the clindamycin vaginal cream. In addition, the recommended daily and total doses of intravaginal clindamycin ovule are far lower than those typically administered in oral or parenteral clindamycin therapy (100 mg of clindamycin per day for 3 days equivalent to about 30 mg absorbed per day from the ovule relative to 600 to 2700 mg/day for up to 10 days or more, orally or parenterally). The overall systemic exposure to clindamycin from clindamycin vaginal ovules is substantially lower than the systemic exposure from therapeutic doses of oral clindamycin hydrochloride (two-fold to 20-fold lower) or parenteral clindamycin phosphate (40- fold to 50-fold lower).