Ceftaroline clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]
Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline[seeClinical Pharmacology (12.3)].
Mechanism of Action
Ceftaroline is an antibacterial drug[seeClinical Pharmacology (12.4)].
Pharmacodynamics
As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model withS. aureusandS. pneumoniae.
Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of Teflaro 600 mg every 12 hours by IV infusion over 1 hour. For Phase 3 CABP trials, an exposure-response relationship could not be identified due to the limited range of ceftaroline exposures in the majority of patients.
Cardiac Electrophysiology
In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of Teflaro 1500 mg, placebo, and a positive control by IV infusion over 1 hour. At the 1500 mg dose of Teflaro, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
Pharmacokinetics
The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized inTable 5. Pharmacokinetic parameters were similar for single and multiple dose administration.
The Cmaxand AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multiple IV infusions of 600 mg administered every 12 hours for up to 14 days in healthy adults with normal renal function.
Distribution
The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over 1-50 mcg/mL (14.5-28.0%). The median (range) steady-state volume of distribution of ceftaroline in healthy adult males (n=6) following a single 600 mg IV dose of radiolabeled ceftaroline fosamil was 20.3 L (18.3-21.6 L), similar to extracellular fluid volume.
Metabolism
Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1. The mean (SD) plasma ceftaroline M-1 to ceftaroline AUC0-∞ratio following a single 600 mg IV infusion of ceftaroline fosamil in healthy adults (n=6) with normal renal function is 28% (3.1%).
When incubated with pooled human liver microsomes, ceftaroline was metabolically stable (< 12% metabolic turnover), indicating that ceftaroline is not a substrate for hepatic CYP450 enzymes.
Excretion
Ceftaroline and its metabolites are primarily eliminated by the kidneys. Following administration of a single 600 mg IV dose of radiolabeled ceftaroline fosamil to healthy male adults (n=6), approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours. Of the radioactivity recovered in urine approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1. The mean (SD) renal clearance of ceftaroline was 5.56 (0.20) L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.
Specific Populations
Renal Impairment
Following administration of a single 600 mg IV dose of Teflaro, the geometric mean AUC0-∞of ceftaroline in subjects with mild (CrCl > 50 to ≤ 80 mL/min, n=6) or moderate (CrCl > 30 to ≤ 50 mL/min, n=6) renal impairment was 19% and 52% higher, respectively, compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). Following administration of a single 400 mg IV dose of Teflaro, the geometric mean AUC0-∞of ceftaroline in subjects with severe (CrCl ≥ 15 to ≤30 mL/min, n=6) renal impairment was 115% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). Dosage adjustment is recommended in patients with moderate and severe renal impairment[see Dosage and Administration (2.2)].
A single 400 mg dose of Teflaro was administered to subjects with ESRD (n=6) either 4 hours prior to or 1 hour after hemodialysis (HD). The geometric mean ceftaroline AUC0-∞following the post-HD infusion was 167% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). The mean recovery of ceftaroline in the dialysate following a 4-hour HD session was 76.5 mg, or 21.6% of the administered dose. Dosage adjustment is recommended in patients with ESRD (defined as CrCL < 15 mL/min), including patients on HD [see Dosage and Administration (2.2)].
Hepatic Impairment
The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established. As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment.
Geriatric Patients
Following administration of a single 600 mg IV dose of Teflaro to healthy elderly subjects (≥ 65 years of age, n=16), the geometric mean AUC0-∞of ceftaroline was ~33% higher compared to healthy young adult subjects (18-45 years of age, n=16). The difference in AUC0-∞was mainly attributable to age-related changes in renal function. Dosage adjustment for Teflaro in elderly patients should be based on renal function [see Dosage and Administration (2.2)].
Pediatric Patients
The pharmacokinetics of ceftaroline were evaluated in adolescent patients (ages 12 to 17, n=7) with normal renal function following administration of a single 8 mg/kg IV dose of Teflaro (or 600 mg for subjects weighing > 75 kg). The mean plasma clearance and terminal phase volume of distribution for ceftaroline in adolescent subjects were similar to healthy adults (n=6) in a separate study following administration of a single 600 mg IV dose. However, the mean Cmaxand AUC0-∞for ceftaroline in adolescent subjects who received a single 8 mg/kg dose were 10% and 23% less than in healthy adult subjects who received a single 600 mg IV dose.
Gender
Following administration of a single 600 mg IV dose of Teflaro to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean Cmaxand AUC0-∞for ceftaroline were similar between males and females, although there was a trend for higher Cmax(17%) and AUC0-∞(6-15%) in female subjects. Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC0-taubased on gender in Phase 2/3 patients with ABSSSI or CABP. No dose adjustment is recommended based on gender.
Race
A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 ABSSSI and CABP trials. No significant differences in ceftaroline AUC0-tauwas observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients. Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions. No dosage adjustment is recommended based on race.
Drug Interactions
In vitrostudies in human liver microsomes indicate that ceftaroline does not inhibit the major cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.In vitrostudies in human hepatocytes also demonstrate that ceftaroline and its inactive open-ring metabolite are not inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Therefore Teflaro is not expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.
Population pharmacokinetic analysis did not identify any clinically relevant differences in ceftaroline exposure (Cmaxand AUC0-tau) in Phase 2/3 patients with ABSSSI or CABP who were taking concomitant medications that are known inhibitors, inducers, or substrates of the cytochrome P450 system; anionic or cationic drugs known to undergo active renal secretion; and vasodilator or vasoconstrictor drugs that may alter renal blood flow.
References
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/200327s001lbl.pdf