Daptomycin clinical pharmacology

# Mechanism of Action
Daptomycin is an antibacterial drug .

# 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.

# Pharmacokinetics
CUBICIN Administered over a 30-Minute Period
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 q24h to healthy young adults are summarized in Table 7.
Daptomycin pharmacokinetics were generally linear and time-independent at CUBICIN 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.
CUBICIN Administered over a 2-Minute Period
Following IV administration of CUBICIN over a 2-minute period to healthy 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) mcgh/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 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 subjects with creatinine clearance (CLCR) 30 mL/min was comparable to that observed in healthy 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 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 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 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 patients (complicated skin and skin structure infections  and S. aureus bacteremia) and noninfected 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 q24h by IV infusion over a 30-minute period, the mean CLT was 9%, 22%, and 46% lower among subjects and patients with mild (CLCR5080 mL/min), moderate (CLCR 3080 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 3080 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 CUBICIN 6 mg/kg q24h by IV infusion over a 30-minute period, the mean Cmaxranged 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.
Because renal excretion is the primary route of elimination, adjustment of CUBICIN dosage interval is necessary in patients with severe renal impairment (CLCR <30 mL/min) .

# Hepatic Impairment
The pharmacokinetics of daptomycin were evaluated in 10 subjects with moderate hepatic impairment (Child-Pugh Class B) and compared with those in healthy 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
The pharmacokinetics of daptomycin were evaluated in 12 healthy elderly subjects (75 years of age) and 11 healthy young 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 subjects.  There were no differences in Cmax .

# Obesity
The pharmacokinetics of daptomycin were evaluated in 6 moderately obese (Body Mass Index  25 to 39.9 kg/m2) and 6 extremely obese (BMI 40 kg/m2) 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.

# Pediatric
The pharmacokinetics of daptomycin in pediatric populations (<18 years of age) have not been established .

# 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 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 subjects, administration of CUBICIN 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).
Simvastatin
In 20 healthy subjects on a stable daily dose of simvastatin 40 mg, administration of CUBICIN 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) .
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 did not significantly alter the Cmax or AUC0- of daptomycin.