Synercid

SYNERCID- quinupristin and dalfopristin injection, powder, lyophilized, for solution
Pfizer Laboratories Div Pfizer Inc

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Synercid and other antibacterial drugs, Synercid should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

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-[(6R ,9S ,10R ,13S ,15aS ,18R ,22S ,24aS)-22-[p -(dimethylamino)benzyl]-6-ethyldocosahydro-10,23-dimethyl-5,8,12,15,17,21,24-heptaoxo-13-phenyl-18-[[(3S)-3-quinuclidinylthio] methyl]-12H -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 C53 H67 N9 O10 S, a molecular weight of 1022.24 and the following structural formula:

Chemical Structure
(click image for full-size original)

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

Dalfopristin has an empirical formula of C34 H50 N4 O9 S, a molecular weight of 690.85 and the following structural formula:

Chemical Structure
(click image for full-size original)

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%.

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