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SYNERCID® (quinupristin, dalfopristin) Clinical Pharmacology

CLINICAL PHARMACOLOGY

Pharmacokinetics

Quinupristin and dalfopristin are the main active components circulating in plasma in human subjects. Quinupristin and dalfopristin are converted to several active major metabolites: two conjugated metabolites for quinupristin (one with glutathione and one with cysteine) and one non-conjugated metabolite for dalfopristin (formed by drug hydrolysis).

Pharmacokinetic profiles of quinupristin and dalfopristin in combination with their metabolites were determined using a bioassay following multiple 60-minute infusions of Synercid in two groups of healthy young adult male volunteers. Each group received 7.5 mg/kg of Synercid intravenously q12h or q8h for a total of 9 or 10 doses, respectively. The pharmacokinetic parameters were proportional with q12h and q8h dosing; those of the q8h regimen are shown in Table 1:

Table 1: Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD*) (dose = 7.5 mg/kg q8h; n=10)
Cmax
(mcg/mL)
AUC
(mcg.h/mL)
t 1/2§(hr)
*
SD= Standard Deviation
Cmax = Maximum drug plasma concentration
AUC = Area under the drug plasma concentration-time curve
§
t 1/2 = Half-life
Quinupristin and metabolites 3.20 ± 0.67 7.20 ± 1.24 3.07 ± 0.51
Dalfopristin and metabolite 7.96 ± 1.30 10.57 ± 2.24 1.04 ± 0.20

The clearances of unchanged quinupristin and dalfopristin are similar (0.72 L/h/kg), and the steady-state volume of distribution for quinupristin is 0.45 L/kg and for dalfopristin is 0.24 L/kg. The elimination half-life of quinupristin and dalfopristin is approximately 0.85 and 0.70 hours, respectively.

The total protein binding of quinupristin is higher than that of dalfopristin. Synercid does not alter the in vitro binding of warfarin to proteins in human serum.

Penetration of unchanged quinupristin and dalfopristin in noninflammatory blister fluid corresponds to about 19% and 11% of that estimated in plasma, respectively. The penetration into blister fluid of quinupristin and dalfopristin in combination with their major metabolites was in total approximately 40% compared to that in plasma.

In vitro, the transformation of the parent drugs into their major active metabolites occurs by non-enzymatic reactions and is not dependent on cytochrome-P450 or glutathione-transferase enzyme activities.

Synercid has been shown to be a major inhibitor (in vitro inhibits 70% cyclosporin A biotransformation at 10 mcg/mL of Synercid) of the activity of cytochrome P450 3A4 isoenzyme. (See WARNINGS.)

Synercid can interfere with the metabolism of other drug products that are associated with QTc prolongation. However, electrophysiologic studies confirm that Synercid does not itself induce QTc prolongation. (See WARNINGS.)

Fecal excretion constitutes the main elimination route for both parent drugs and their metabolites (75 to 77% of dose). Urinary excretion accounts for approximately 15% of the quinupristin and 19% of the dalfopristin dose. Preclinical data in rats have demonstrated that approximately 80% of the dose is excreted in the bile and suggest that in man, biliary excretion is probably the principal route for fecal elimination.

Special Populations

Elderly

The pharmacokinetics of quinupristin and dalfopristin were studied in a population of elderly individuals (range 69 to 74 years). The pharmacokinetics of the drug products were not modified in these subjects.

Gender

The pharmacokinetics of quinupristin and dalfopristin are not modified by gender.

Renal Insufficiency

In patients with creatinine clearance 6 to 28 mL/min, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 40% and 30%, respectively.

In patients undergoing Continuous Ambulatory Peritoneal Dialysis, dialysis clearance for quinupristin, dalfopristin and their metabolites is negligible. The plasma AUC of unchanged quinupristin and dalfopristin increased about 20% and 30%, respectively. The high molecular weight of both components of Synercid suggests that it is unlikely to be removed by hemodialysis.

Hepatic Insufficiency

In patients with hepatic dysfunction (Child-Pugh scores A and B), the terminal half-life of quinupristin and dalfopristin was not modified. However, the AUC of quinupristin and dalfopristin in combination with their major metabolites increased about 180% and 50%, respectively. (See DOSAGE AND ADMINISTRATION and PRECAUTIONS.)

Obesity (body mass index ≥30): In obese patients the Cmax and AUC of quinupristin increased about 30% and those of dalfopristin about 40%.

Pediatric Patients

The pharmacokinetics of Synercid in patients less than 16 years of age have not been studied.

Microbiology

The streptogramin components of Synercid, quinupristin and dalfopristin, are present in a ratio of 30 parts quinupristin to 70 parts dalfopristin. These two components act synergistically so that Synercid's microbiologic in vitro activity is greater than that of the components individually. Quinupristin's and dalfopristin's metabolites also contribute to the antimicrobial activity of Synercid. In vitro synergism of the major metabolites with the complementary parent compound has been demonstrated.

Mechanism of Action

The site of action of quinupristin and dalfopristin is the bacterial ribosome. Dalfopristin has been shown to inhibit the early phase of protein synthesis while quinupristin inhibits the late phase of protein synthesis. Synercid is bactericidal against isolates of methicillin-susceptible and methicillin-resistant staphylococci. The mode of action of Synercid differs from that of other classes of antibacterial agents such as ß-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. Therefore, there is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.

Resistance

Resistance to Synercid is associated with resistance to both components (i.e., quinupristin and dalfopristin). In non-comparative studies, emerging resistance to Synercid has occurred.

Interaction with other Antibacterials

In vitro combination testing of Synercid with aztreonam, cefotaxime, ciprofloxacin, and gentamicin against Enterobacteriaceae and Pseudomonas aeruginosa did not show antagonism.

In vitro combination testing of Synercid with prototype drugs of the following classes: aminoglycosides (gentamicin), β-lactams (cefepime, ampicillin, and amoxicillin), glycopeptides (vancomycin), quinolones (ciprofloxacin), tetracyclines (doxycycline) and also chloramphenicol against enterococci and staphylococci did not show antagonism.

Antimicrobial Activity

Synercid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section.

Gram-positive bacteria
Staphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus pyogenes

The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for quinupristin and dalfopristin (Synercid) against isolates of similar genus or organism group. However, the efficacy of Synercid in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria
Corynebacterium jeikeium
Staphylococcus aureus
(methicillin-resistant isolates)
Staphylococcus epidermidis
(including methicillin-resistant isolates)
Streptococcus agalactiae

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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