Daptomycin (Page 5 of 9)

8.6 Patients with Renal Impairment

Daptomycin is eliminated primarily by the kidneys; therefore, a modification of Daptomycin for Injection dosage interval is recommended for adult patients with CLCR <30 mL/min, including patients receiving hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In adult patients with renal impairment, both renal function and creatine phosphokinase (CPK) should be monitored more frequently than once weekly [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.8), and Clinical Pharmacology (12.3)].

The dosage regimen for Daptomycin for Injection in pediatric patients with renal impairment has not been established.

10 OVERDOSAGE

In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is cleared slowly from the body by hemodialysis (approximately 15% of the administered dose is removed over 4 hours) and by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with that removed by low-flux membranes.

11 DESCRIPTION

Daptomycin for Injection contains daptomycin, a cyclic lipopeptide antibacterial agent derived from the fermentation of Streptomyces roseosporus. The chemical name is N -decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo -3-methyl-L-glutamyl-3-anthraniloyl-L-alanine ε1 -lactone. The chemical structure is:

structure
(click image for full-size original)

The empirical formula is C72 H101 N17 O26 ; the molecular weight is 1620.67. Daptomycin for Injection is supplied in a single-dose vial as a sterile, preservative-free, pale yellow to light brown, lyophilized cake containing approximately 350 mg of daptomycin for intravenous (IV) use following reconstitution with 0.9% sodium chloride injection [see Dosage and Administration (2.5)]. The only inactive ingredient is sodium hydroxide, which is used for pH adjustment. Freshly reconstituted solutions of Daptomycin for Injection range in color from pale yellow to light brown.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Daptomycin is an antibacterial drug [see Clinical Pharmacology(12.4)].

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 daptomycin for injection.

12.3 Pharmacokinetics

Daptomycin for injection 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 daptomycin for injection over a 30-minute period at 4 to 12 mg/kg q24h to healthy young adults are summarized in Table 7.

Table 7: Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State
*
Daptomycin for injection was administered by IV infusion over a 30-minute period.
Doses of daptomycin for injection 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; Cmax , maximum plasma concentration.

Dose *

(mg/kg)

Pharmacokinetic Parameters

AUC0-24

(mcg·h/mL)

t1/2

(h)

Vss

(L/kg)

CLT

(mL/h/kg)

Cmax

(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)

Daptomycin pharmacokinetics were generally linear and time-independent at daptomycin for injection doses of 4 to 12 mg/kg q24h 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 q24h 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.

Daptomycin for injection Administered over a 2-Minute Period in Adults

Following IV administration of daptomycin for injection 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 daptomycin for injection 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state Cmax values were simulated for daptomycin for injection 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 14 C-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 daptomycin for injection at 6 mg/kg to adult subjects. Minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism 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

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 daptomycin for injection 4 mg/kg q24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR 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 Cmax for patients with CLCR <30 mL/min ranged from 41 to 58 mcg/mL. After administration of daptomycin for injection 6 mg/kg q24h by IV infusion over a 30-minute period, the mean Cma x 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 daptomycin for injection 4 mg/kg or 6 mg/kg to Infected Adult Patients and Noninfected Adult Subjects with Various Degrees of Renal Function
Note: Daptomycin for injection was administred 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; AUCss , 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.

Renal Function

Pharmacokinetic Parameters *

t1/2

(h) 4 mg/kg

Vss

(L/kg) 4 mg/kg

CLT

(mL/h/kg) 4 mg/kg

AUC0-∞

(mcg·h/mL) 4 mg/kg

AUCss

(mcg·h/mL) 6 mg/kg

Cmin,ss

(mcg/mL) 6 mg/kg

Normal

(CLCR >80 mL/min)

9.39 (4.74)

N=165

0.13 (0.05)

N=165

10.9 (4.0)

N=165

417 (155)

N=165

545 (296)

N=62

6.9 (3.5)

N=61

Mild Renal Impairment

(CLCR 50-80 mL/min)

10.75 (8.36)

N=64

0.12 (0.05)

N=64

9.9 (4.0)

N=64

466 (177)

N=64

637 (215)

N=29

12.4 (5.6)

N=29

Moderate Renal Impairment

(CLCR 30-<50 mL/min)

14.70 (10.50)

N=24

0.15 (0.06)

N=24

8.5 (3.4)

N=24

560 (258)

N=24

868 (349)

N=15

19.0 (9.0)

N=14

Severe Renal Impairment

(CLCR <30 mL/min)

27.83 (14.85)

N=8

0.20 (0.15)

N=8

5.9 (3.9)

N=8

925 (467)

N=8

1050 (892)

N=2

24.4 (21.4)

N=2

Hemodialysis

30.51 (6.51)

N=16

0.16 (0.04)

N=16

3.9 (2.1)

N=16

1193 (399)

N=16

NA

NA

CAPD

27.56 (4.53)

N=5

0.11 (0.02)

N=5

2.9 (0.4)

N=5

1409 (238)

N=5

NA

NA

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

Hepati c 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 Daptomycin for Injection 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 Daptomycin for Injection is administered.

Geriatric

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 daptomycin for injection 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 Cmax [see Use in Specific Populations (8.5)].

Obesity

The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index [BMI] 25 to 39.9 kg/m2) and 6 extremely obese (BMI ≥40 kg/m2) adult subjects and controls matched for age, gender, and renal function. Following administration of daptomycin for injection 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 Daptomycin for Injection dosage is warranted in obese patients.

Pediatric use information is approved for Merck & Co., Inc.’s Cubicin (daptomycin for injection). However, due to Merck & Co., Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Drug-Drug Interactions

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 daptomycin for injection 6 mg/kg IV and a combination dose of daptomycin for injection 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 daptomycin for injection 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 daptomycin for injection was coadministered with tobramycin. The mean Cmax and AUC0-∞ of tobramycin were 10.7% and 6.6% lower, respectively, when tobramycin was coadministered with daptomycin for injection. These differences were not statistically significant. The interaction between daptomycin and tobramycin with a clinical dose of Daptomycin for Injection is unknown.

Warfarin

In 16 healthy adult subjects, administration of daptomycin for injection 6 mg/kg q24h 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).

Si m v astatin

In 20 healthy adult subjects on a stable daily dose of simvastatin 40 mg, administration of daptomycin for injection 4 mg/kg q24h 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)].

Probene c id

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

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