Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2   Pharmacodynamics

Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus. The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with CUBICIN.

Pharmacokinetic Properties

12.3   Pharmacokinetics

CUBICIN Administered over a 30-Minute Period in Adults
The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of CUBICIN over a 30-minute period at 4 to 12 mg/kg every 24h to healthy young adults are summarized in Table 7.


Table 7: Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State
Pharmacokinetic Parameters‡
Dose*†
AUC0-24         t1/2              Vss         CLT             Cmax
(mg/kg)
(mcg•h/mL)        (h)             (L/kg)     (mL/h/kg)       (mcg/mL) 4 (N=6)               494 (75)              8.1 (1.0)          0.096 (0.009)           8.3 (1.3)              57.8 (3.0)
6 (N=6)               632 (78)              7.9 (1.0)          0.101 (0.007)           9.1 (1.5)              93.9 (6.0) 8 (N=6)             858 (213)               8.3 (2.2)          0.101 (0.013)           9.0 (3.0)            123.3 (16.0) 10 (N=9)             1039 (178)              7.9 (0.6)          0.098 (0.017)           8.8 (2.2)            141.1 (24.0) 12 (N=9)             1277 (253)              7.7 (1.1)          0.097 (0.018)           9.0 (2.8)            183.7 (25.0) *CUBICIN was administered by IV infusion over a 30-minute period.
†Doses of CUBICIN in excess of 6 mg/kg have not been approved.
‡AUC0-24, area under the concentration-time curve from 0 to 24 hours; t1/2, elimination half-life; Vss, volume of distribution at steady-state; CLT, total plasma clearance; C max, maximum plasma concentration.


Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN doses of 4 to 12 mg/kg every 24h administered by IV infusion over a 30-minute period for up to 14 days. Steady- state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg every 24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively.

CUBICIN Administered over a 2-Minute Period in Adults

Following IV administration of CUBICIN over a 2-minute period to healthy adult volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were
475 (71) and 701 (82) mcg•h/mL, respectively. Values for maximum plasma concentration (Cmax) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy adult volunteers who received a single dose of CUBICIN 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for CUBICIN 4 and 6 mg/kg IV administered over a 2-minute period. The simulated mean (SD) steady-state Cmax values were 77.7 (8.1) and 116.6 (12.2) mcg/mL, respectively.

Distribution

Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner. The overall mean binding ranges from 90 to 93%.

In clinical studies, mean serum protein binding in adult subjects with creatinine clearance (CLCR) ≥30 mL/min was comparable to that observed in healthy adult subjects with normal renal function.
However, there was a trend toward decreasing serum protein binding among subjects with CLCR <30 mL/min (88%), including those receiving hemodialysis (86%) and continuous ambulatory peritoneal dialysis (CAPD) (84%). The protein binding of daptomycin in adult subjects with moderate hepatic impairment (Child-Pugh Class B) was similar to that in healthy adult subjects.

The volume of distribution at steady-state (Vss) of daptomycin in healthy adult subjects was approximately 0.1 L/kg and was independent of dose.

Metabolism

In in vitro studies, daptomycin was not metabolized by human liver microsomes.

In 5 healthy adults after infusion of radiolabeled 14C-daptomycin, the plasma total radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference between total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma on Day 1 following the administration of CUBICIN at 6 mg/kg to adult subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of m etabolism has not been identified.

Excretion

Daptomycin is excreted primarily by the kidneys. In a mass balance study of 5 healthy adult subjects using radiolabeled daptomycin, approximately 78% of the administered dose was recovered from urine based on total radioactivity (approximately 52% of the dose based on microbiologically active concentrations), and 5.7% of the administered dose was recovered from feces (collected for up to 9 days) based on total radioactivity.

Specific Populations

Patients with Renal Impairment
Population-derived pharmacokinetic parameters were determined for infected adult patients (complicated skin and skin structure infections [cSSSI] and S. aureus bacteremia) and noninfected adult subjects with various degrees of renal function (Table 8). Total plasma clearance (CLT), elimination half-life (t1/2), and volume of distribution at steady-state (Vss) in patients with cSSSI were similar to those in patients with S. aureus bacteremia. Following administration of CUBICIN 4 mg/kg every 24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CL CR 50–80 mL/min), moderate (CLCR 30–<50 mL/min), and severe (CLCR <30 mL/min) renal impairment, respectively, than in those with normal renal function (CLCR >80 mL/min). The mean steady-state systemic exposure (AUC), t1/2, and Vss increased with decreasing renal function, although the mean AUC for patients with CLCR 30–80 mL/min was not markedly different from the mean AUC for patients with normal renal function. The mean AUC for patients with CLCR <30 mL/min and for patients on dialysis (CAPD and hemodialysis dosed post-dialysis) was approximately 2 and 3 times higher, respectively, than for patients with normal renal function. The mean Cmax ranged from 60 to 70 mcg/mL in patients with CLCR ≥30 mL/min, while the mean C max for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of CUBICIN 6 mg/kg every 24h by IV infusion over a 30-minute period, the mean Cmax ranged from 80 to 114 mcg/mL in patients with mild to moderate renal impairment and was similar to that of patients with normal renal function.


Table 8: Mean (SD) Daptomycin Population Pharmacokinetic Parameters Following Infusion of CUBICIN 4 mg/kg or 6 mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal Function
Pharmacokinetic Parameters* t1/2†       Vss†       CLT†        AUC0-∞†      AUCss‡       Cmin,ss‡ Renal Function
(h)      (L/kg)    (mL/h/kg) (mcg•h/mL)     (mcg•h/mL) (mcg/mL)
4 mg/kg    4 mg/kg     4 mg/kg      4 mg/kg      6 mg/kg      6 mg/kg
Normal               9.39        0.13    10.9 (4.0)    417 (155)    545 (296)    6.9 (3.5) (CLCR               (4.74)      (0.05)     N=165        N=165         N=62        N=61 >80 mL/min)         N=165      N=165
Mild Renal          10.75        0.12     9.9 (4.0)    466 (177)    637 (215)   12.4 (5.6) Impairment          (8.36)      (0.05)     N=64          N=64         N=29        N=29 (CLCR 50–           N=64        N=64
80 mL/min)
Moderate Renal               14.70           0.15         8.5 (3.4)        560 (258)          868 (349)        19.0 (9.0) Impairment                  (10.50)         (0.06)         N=24              N=24               N=15             N=14 (CLCR 30–                    N=24           N=24
<50 mL/min)
Severe Renal                 27.83           0.20         5.9 (3.9)        925 (467)         1050 (892)           24.4 Impairment                  (14.85)         (0.15)          N=8              N=8                N=2              (21.4) (CLCR                         N=8            N=8                                                                  N=2 <30 mL/min)
Hemodialysis                30.51            0.16         3.9 (2.1)       1193 (399)              NA               NA (6.51)          (0.04)         N=16             N=16
N=16            N=16
CAPD                        27.56            0.11         2.9 (0.4)       1409 (238)              NA               NA (4.53)          (0.02)          N=5              N=5
N=5             N=5
Note: CUBICIN was administered over a 30-minute period.
*CLCR, creatinine clearance estimated using the Cockcroft-Gault equation with actual body weight; CAPD, continuous ambulatory peritoneal dialysis; AUC0-∞, area under the concentration-time curve extrapolated to infinity; AUC ss, area under the concentration-time curve calculated over the 24-hour dosing interval at steady-state; Cmin,ss, trough concentration at steady-state; NA, not applicable.
†Parameters obtained following a single dose from patients with complicated skin and skin structure infections and healthy subjects.
‡Parameters obtained at steady-state from patients with S. aureus bacteremia.

Because renal excretion is the primary route of elimination, adjustment of CUBICIN dosage interval is necessary in adult patients with severe renal impairment (CL CR <30 mL/min) [see Dosage and Administration (2.4)].

Patients with Hepatic Impairment

The pharmacokinetics of daptomycin were evaluated in 10 adult subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy adult volunteers (N=9) matched for gender, age, and weight. The pharmacokinetics of daptomycin were not altered in subjects with moderate hepatic impairment. No dosage adjustment is warranted when CUBICIN is administered to patients with mild to moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh Class C) have not been evaluated.

Gender

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed. No dosage adjustment is warranted based on gender when CUBICIN is administered.

Geriatric Patients

The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (≥75 years of age) and 11 healthy young adult controls (18 to 30 years of age). Following administration of a single 4 mg/kg dose of CUBICIN by IV infusion over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0- was approximately 58% higher in elderly subjects than in healthy young adult subjects. There were no differences in C max [see Use in Specific Populations (8.5)].

Obese Patients

The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m 2) and 6 extremely obese (BMI ≥40 kg/m 2) adult subjects and controls matched for age,
gender, and renal function. Following administration of CUBICIN by IV infusion over a 30-minute period as a single 4 mg/kg dose based on total body weight, the total plasma clearance of daptomycin normalized to total body weight was approximately 15% lower in moderately obese subjects and 23% lower in extremely obese subjects than in nonobese controls. The AUC0- of daptomycin was approximately 30% higher in moderately obese subjects and 31% higher in extremely obese subjects than in nonobese controls. The differences were most likely due to differences in the renal clearance of daptomycin. No adjustment of CUBICIN dosage is warranted in obese patients.

Drug Interaction Studies

In Vitro Studies
In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.
It is unlikely that daptomycin will inhibit or induce the metabolism of drugs metabolized by the P450 system.

Aztreonam

In a study in which 15 healthy adult subjects received a single dose of CUBICIN 6 mg/kg IV and a combination dose of CUBICIN 6 mg/kg IV and aztreonam 1 g IV, administered over a 30-minute period, the Cmax and AUC0- of daptomycin were not significantly altered by aztreonam.

Tobramycin

In a study in which 6 healthy adult males received a single dose of CUBICIN 2 mg/kg IV, tobramycin 1 mg/kg IV, and both in combination, administered over a 30-minute period, the mean Cmax and AUC0- of daptomycin were 12.7% and 8.7% higher, respectively, when CUBICIN was coadministered with tobramycin. The mean Cmax and AUC0- of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with CUBICIN. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of CUBICIN is unknown.

Warfarin

In 16 healthy adult subjects, administration of CUBICIN 6 mg/kg every 24h by IV infusion over a 30- minute period for 5 days, with coadministration of a single oral dose of warfarin (25 mg) on the 5th day, had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR (International Normalized Ratio).

Simvastatin

In 20 healthy adult subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 4 mg/kg every 24h by IV infusion over a 30-minute period for 14 days (N=10) had no effect on plasma trough concentrations of simvastatin and was not associated with a higher incidence of adverse events, including skeletal myopathy, than in subjects receiving placebo once daily (N=10) [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Probenecid

Concomitant administration of probenecid (500 mg 4 times daily) and a single dose of CUBICIN 4 mg/kg by IV infusion over a 30-minute period in adults did not significantly alter the C max or AUC0- of daptomycin.


12.4   Microbiology

Daptomycin belongs to the cyclic lipopeptide class of antibacterials. Daptomycin has clinical utility in the treatment of infections caused by aerobic, Gram-positive bacteria. The in vitro spectrum of activity of daptomycin encompasses most clinically relevant Gram-positive pathogenic bacteria.

Daptomycin exhibits rapid, concentration-dependent bactericidal activity against Gram-positive bacteria in vitro. This has been demonstrated both by time-kill curves and by MBC/MIC (minimum bactericidal concentration/minimum inhibitory concentration) ratios using broth dilution methodology. Daptomycin maintained bactericidal activity in vitro against stationary phase S. aureus in simulated endocardial vegetations. The clinical significance of this is not known.

Mechanism of Action

Daptomycin binds to bacterial cell membranes and causes a rapid depolarization of membrane potential. This loss of membrane potential causes inhibition of DNA, RNA, and protein synthesis, which results in bacterial cell death.

Resistance

The mechanism(s) of daptomycin resistance is not fully understood. Currently, there are no known transferable elements that confer resistance to daptomycin.


Interactions with Other Antibacterials
In vitro studies have investigated daptomycin interactions with other antibacterials. Antagonism, as determined by kill curve studies, has not been observed. In vitro synergistic interactions of daptomycin with aminoglycosides, β-lactam antibacterials, and rifampin have been shown against some isolates of staphylococci (including some methicillin-resistant isolates) and enterococci (including some vancomycin-resistant isolates).


Complicated Skin and Skin Structure Infection (cSSSI) Trials in Adults 
The emergence of daptomycin non-susceptible isolates occurred in 2 infected patients across the set of Phase 2 and pivotal Phase 3 clinical trials of cSSSI in adult patients. In one case, a non-susceptible S. aureus was isolated from a patient in a Phase 2 trial who received CUBICIN at less than the protocol-specified dose for the initial 5 days of therapy. In the second case, a non-susceptible Enterococcus faecalis was isolated from a patient with an infected chronic decubitus ulcer who was enrolled in a salvage trial.

S. aureus Bacteremia/Endocarditis and Other Post-Approval Trials in Adults 
In subsequent clinical trials in adult patients, non-susceptible isolates were recovered. S. aureus was isolated from a patient in a compassionate-use trial and from 7 patients in the S. aureus bacteremia/endocarditis trial [see Clinical Studies (14.2)]. An E. faecium was isolated from a patient in a vancomycin-resistant enterococci trial.

Antimicrobial Activity

Daptomycin has been shown to be active against most isolates of the following microorganisms both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-Positive Bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)
Staphylococcus aureus (including methicillin-resistant isolates)
Streptococcus agalactiae
Streptococcus dysgalactiae subsp. equisimilis
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 daptomycin against isolates of similar genus or organism group.
However, the efficacy of daptomycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-Positive Bacteria

Corynebacterium jeikeium
Enterococcus faecalis (vancomycin-resistant isolates)
Enterococcus faecium (including vancomycin-resistant isolates)
Staphylococcus epidermidis (including methicillin-resistant isolates) Staphylococcus haemolyticus

Susceptibility Testing

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