Synercid (Quinupristin / Dalfopristin Injection) - Description and Clinical Pharmacology

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DESCRIPTION

Synercid^® (quinupristin and dalfopristin powder for injection) I.V., a streptogramin antibacterial agent for intravenous administration, is a sterile lyophilized formulation of two semisynthetic pristinamycin derivatives, quinupristin (derived from pristinamycin I) and dalfopristin (derived from pristinamycin IIA) in the ratio of 30:70 (w/w).

Quinupristin is a white to very slightly yellow, hygroscopic powder. It is a combination of three peptide macrolactones. The main component of quinupristin (>88.0%) has the following chemical name: N-[(6 R,9 S,10 R,13 S,15 aS,18 R,22 S,24 aS)-22-[ p -(dimethylamino)benzyl]-6-ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(3 S)-3-quinuclidinylthio] methyl]-12 H -pyrido[2,1- f ]pyrrolo-[2,1- l ][1,4,7,10,13,16] oxapentaazacyclononadecin-9-yl]-3-hydroxypicolinamide.

The main component of quinupristin has an empirical formula of C₅₃H₆₇N₉O₁₀S, a molecular weight of 1022.24 and the following structural formula:

Dalfopristin is a slightly yellow to yellow, hygroscopic, powder. The chemical name for dalfopristin is: (3 R,4 R,5 E,10 E,12 E,14 S,26 R,26a S)-26-[[2-(diethylamino)ethyl]sulfonyl]-8,9,14,15,24,25,26,26a-octahydro-14-hydroxy-3-isopropyl-4,12-dimethyl-3 H -21,18-nitrilo-1 H,22 H -pyrrolo[2,1- c ][1,8,4,19]-dioxadiazacyclotetracosine-1,7,16,22(4 H,17 H)-tetrone.

Dalfopristin has an empirical formula of C₃₄H₅₀N₄O₉S, a molecular weight of 690.85 and the following structural formula:

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 the following table:

Mean Steady-State Pharmacokinetic Parameters of Quinupristin and Dalfopristin in Combination with their Metabolites (± SD¹) (dose = 7.5 mg/kg q8h; n=10)

	C max2 (μg/mL)	AUC 3 (μg.h/mL)	t 1/24 (hr)
1 SD= Standard Deviation
2 Cmax = Maximum drug plasma concentration
3 AUC = Area under the drug plasma concentration-time curve
4 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 protein binding of Synercid is moderate.

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 μg/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 C_max 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.

Synercid is bacteriostatic against Enterococcus faecium and bactericidal against strains of methicillin-susceptible and methicillin-resistant staphylococci.

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.

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.

The mode of action differs from that of other classes of antibacterial agents such as β-lactams, aminoglycosides, glycopeptides, quinolones, macrolides, lincosamides and tetracyclines. There is no cross resistance between Synercid and these agents when tested by the minimum inhibitory concentration (MIC) method.

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

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

Aerobic gram-positive microorganisms
Enterococcus faecium (Vancomycin-resistant and multi-drug resistant strains only)
Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pyogenes

NOTE: Synercid is not active against Enterococcus faecalis. Differentiation of enterococcal species is important to avoid misidentification of Enterococcus faecalis as Enterococcus faecium.

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

The combination of quinupristin and dalfopristin (Synercid) exhibits in vitro minimum inhibitory concentrations (MIC's) of ≤1.0 μg/mL against most (≥90%) isolates of the following microorganisms; however, the safety and effectiveness of Synercid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms
Corynebacterium jeikeium
Staphylococcus aureus (methicillin-resistant strains)
Staphylococcus epidermidis (including methicillin-resistant strains)
Streptococcus agalactiae

SUSCEPTIBILITY TESTING

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of microorganisms to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution¹ method (broth or agar) or equivalent using standardized inoculum concentrations, and standardized concentrations of quinupristin/dalfopristin (Synercid) in a 30:70 ratio made from powder of known potency. The MIC values should be interpreted according to the following criteria:

For Susceptibility Testing of Enterococcus faecium, Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)^a.

MIC (μg/mL)	Interpretation
a.The interpretive values for Streptococcus spp. are applicable only to broth microdilution susceptibility testing using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
≤1.0	Susceptible (S)
2.0	Intermediate (I)
≥4.0	Resistant (R)

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the concentration of the antimicrobial compound in the blood reaches usually achievable levels. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Quality Control

A standardized susceptibility test procedure requires the use of laboratory control organisms to control the technical aspects of the laboratory procedures. Standard quinupristin/dalfopristin powder in a 30:70 ratio should provide the following MIC values with the indicated quality control strains:

Microorganisms (ATCC®   #)	MIC (μg/mL)
Enterococcus faecalis (29212)	2.0 to 8.0
Staphylococcus aureus (29213)	0.25 to 1.0

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15 μg quinupristin/dalfopristin in a ratio of 30:70 (Synercid) to test the susceptibility of microorganisms to quinupristin/dalfopristin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg quinupristin/dalfopristin disk should be interpreted according to the following criteria:

For Susceptibility Testing of Enterococcus faecium, Staphylococcus spp., and Streptococcus spp. (excluding Streptococcus pneumoniae)^b.

Zone Diameter (mm)	Interpretation
b.The zone diameter for Streptococcus spp. are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood when incubated in 5% CO2.
≥19	Susceptible (S)
16 to 18	Intermediate (I)
≤15	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for quinupristin/dalfopristin.

Quality Control

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15 μg quinupristin/dalfopristin (30:70 ratio) disk should provide the following zone diameter with the quality control strain listed below:

Microorganism (ATCC®   #)	Zone Diameter Range (mm)
Staphylococcus aureus (25923)	21 to 28

ATCC ^® is a registered trademark of the American Type Culture Collection

CLINICAL STUDIES

NON-COMPARATIVE TRIALS

In the non-comparative trials, patients often presented with multiple co-morbidities and/or physiologic impairments, and may have been intolerant to or failed other antibacterial therapies.

Vancomycin-Resistant Enterococcus faecium

Results are available from four non-comparative studies of Synercid (7.5 mg/kg q8h) for the treatment of vancomycin-resistant Enterococcus faecium (VREF) (N=1222). Three of these studies were prospective, the fourth consisted of a collection of individual emergency-use requests.

Of the 1222 patients, 27% did not have a specific site of infection identified, but presented with pure growth of VREF in two or more blood cultures. Ninety percent (90%) of these patients had clearance of their VREF bacteremia within the first 48 to 72 hours of therapy.

Because of the emergency use nature of the VREF trials and the variability in data collection in these severely ill patients, the percentage of patients found to be evaluable was 24.4%. The overall efficacy rate (defined as clinical success and eradication of the initial pathogen) in the evaluable patients (n=298) was 52.3%. The most common sites of infection included intra-abdominal, skin and skin structure, and the urinary tract. In these subgroups, the efficacy rates for the evaluable patients having the most complete documentation were 46.3% (n=67), 66.7% (n=15), and 73.9% (n=23), respectively.

The most common adverse reactions considered related to Synercid use were myalgias and arthralgias. (See ADVERSE REACTIONS.) All-cause mortality in the 4 studies ranged from 49.5% to 54.0%.

COMPARATIVE TRIALS

Complicated Skin and Skin Structure Infections

Two randomized, open-label, controlled clinical trials of Synercid (7.5 mg/kg q12h intravenously [iv]) in the treatment of complicated skin and skin structure infections were performed. The comparator drug was oxacillin (2g q6h iv) in the first study (JRV 304) and cefazolin (1g q8h iv) in the second study (JRV 305); however, in both studies vancomycin (1g q12h iv) could be substituted for the specified comparator if the causative pathogen was suspected or confirmed methicillin-resistant staphylococcus or if the patient was allergic to penicillins, cephalosporins or carbapenems. Study JRV 304 enrolled 450 patients (n = 229 Synercid; n= 221 Comparator) and Study JRV 305 enrolled 443 patients (n = 221 Synercid; n = 222 Comparator).

In the first study, 105 patients (45.9%) and 106 patients (48.0%) in the Synercid and Comparator arms, respectively, were found to be clinically evaluable. For the second study, these values were 113 (51.1%) and 120 (54.1%) patients in the Synercid and Comparator arms, respectively. Patients were found not to be clinically evaluable for reasons such as: wrong diagnosis, lower extremity infection in patients with diabetes or peripheral vascular disease since these infections were assumed to include aerobic gram-negative and anaerobic organisms, no specimen for culture obtained, insufficient therapy, no test of cure assessment, etc.

For the patients found to be clinically evaluable, in Study JRV 304 the success rate was 49.5% in the Synercid arm and 51.9% in the Comparator arm. In Study JRV 305, the success rates were 66.4% and 64.2% in the Synercid and Comparator arms, respectively.

The following table shows the clinical success rate (combined results from two clinical trials) in the clinically evaluable population. Due to the small numbers of patients in the subsets, statistical conclusions could not be reached.

	Cured or Improved
Infection Type	Synercid		Comparator
	(n/N)	(%)	(n/N)	(%)
Erysipelas (cellulitis)	52/82	(63.4)	43/77	(55.8)
Post-operative infections	14/38	(36.8)	24/42	(57.1)
Traumatic wound infection	33/55	(60.0)	33/55	(60.0)

SAFETY

Discontinuations of therapy because of adverse reactions which were probably or possibly due to drug therapy occurred more than four times as often in the Synercid group than in the comparator group. Approximately half of the discontinuations in the Synercid arm were due to venous adverse events. (See ADVERSE REACTIONS: Clinical Reactions: Skin and Skin Structure Studies.)

Keep out of the reach of children.