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Moderate Liver Impairment Has No Influence on Daptomycin Pharmacokinetics

From Cubist Pharmaceuticals, Inc., Lexington, Massachusetts. Dr. Dvorchik's current affiliation is Barry Dvorchik and Associates, Inc., Tampa, Florida.

Address for reprints: Megan Robertson, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Daptomycin (N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanine-lactone) is a novel cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus. Daptomycin was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram-positive bacteria, including those caused by methicillin-resistant and methicillin-susceptible Staphylococcus aureus. This single-dose, parallel-design, matched-controlled study was designed to evaluate the pharmacokinetics of daptomycin in subjects between ages 18 and 80 years with moderately impaired hepatic function (Child-Pugh Class B, n = 10). Subjects were administered a single intravenous dose (6 mg/kg total body weight) over 30 minutes using a syringe pump. A normal volunteer control group matched by weight (±25 lb/11 kg), age (±10 years), and sex was included in this study for comparison to the hepatic-impaired group. The pharmacokinetic parameters of daptomycin were similar in both groups. Adverse events occurred only in the hepatic-impaired patients and were consistent with the subjects' disease state. In conclusion, subjects with moderate hepatic impairment receiving daptomycin do not require an adjustment in daptomycin dose or dose regimen.

Key Words: Daptomycin • liver impairment • hepatic function • pharmacokinetics • complicated skin and skin structure infections

Daptomycin is extensively ( 90%) bound to serum proteins, has a plasma half-life (in subjects with normal renal function) of 8 hours, and is characterized by a low steady-state volume of distribution, averaging 0.06 to 0.15 L/kg.^5,6 This volume of distribution is consistent with distribution into extracellular fluid. Elimination is primarily by renal excretion of unchanged drug; in healthy adult subjects, approximately 50% of the dose is recovered as unchanged daptomycin over the first 24-hour period following dosing.⁵ Following administration of ¹⁴C-daptomycin, plasma radioactivity was equivalent to daptomycin, as determined by a validated microbiological assay, whereas radioactivity in urine was composed of daptomycin and uncharacterized inactive metabolites.⁵ Total recovery of the radiolabel was 78% over a 5-day period. Current Food and Drug Administration (FDA) guidelines require a study in subjects with hepatic impairment "if the metabolism of the drug is unknown and other information is lacking to suggest that hepatic impairment routes are minor."⁸ The primary objective of this open-label study was to evaluate the pharmacokinetics of daptomycin following a single dose in subjects with moderate hepatic impairment and to compare that with the pharmacokinetics in a control cohort matched by sex, age, and weight.

	METHODS

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Subjects
Subjects with hepatic impairment were enrolled first, allowing for the selection of healthy subjects who were individually matched with hepatic-impaired subjects by weight (±11 kg/25 lb), age (±10 years), and sex. These ranges were chosen to maintain a reasonable match while not being a significant impairment to subject recruitment. Subjects classified as hepatically impaired were graded for hepatic impairment status using the Child-Pugh classification.⁹ Subjects classified as Child-Pugh Class B and meeting all other inclusion/exclusion criteria were enrolled in the study.

General inclusion criteria for all subjects included age between 18 and 80 years, body weight within 30% of the ideal body weight (as defined in the 1996 Metropolitan height and weight tables for men and women), estimated creatinine clearance 70 mL/min using the Cockcroft-Gault equation,¹⁰ and total body weight. Female subjects of childbearing potential must have been nonpregnant, nonlactating, and willing to practice reliable birth control measures (oral contraceptives, diaphragm with spermicide, intrauterine device, condom and foam, vaginal spermicide suppository, or surgical sterilization) during and for at least 48 hours after treatment with daptomycin. Hepatic-impaired subjects taking concomitant medications that were not specifically excluded must have been on a stable dose for 2 weeks prior to administration of daptomycin. All subjects had to refrain from alcohol ingestion for the 3 days prior to admission into the clinical study and for the duration of the study. Serum creatine phosphokinase (CPK) levels had to be 1.5 ULN. Subjects were excluded from the study if, at screening, they had anemia with a hematocrit < 27%, had used an investigational drug or participated in any experimental procedure within the 30 days proceeding study entry, had used an HMG-CoA reductase inhibitor within 7 days or warfarin within 15 days of daptomycin administration, were HIV positive, had a positive drug or alcohol screen, had donated blood within the past 30 days, had a history of muscular disease or neurological disease, or had intramuscular injections or weight training within 7 days of daptomycin administration.

Subjects were screened within 21 days prior to study day 1, and those meeting all inclusion/exclusion criteria were enrolled. After providing informed consent, demographic characteristics and medical/medication histories were recorded. Physical examination and vital signs assessments were performed, and blood/urine samples were obtained for routine chemistry, hematology, coagulation (PTT/INR) testing, and urinalysis. Additional testing included a urine drug screen, HIV test, serum pregnancy test (if applicable), and serum CPK-level determination. CPK was monitored since daptomycin has been reported to have the potential for muscle toxicity.¹¹ An alcohol Breathalyzer test and a 12-lead electrocardiogram (ECG) were also administered. In the routine screening laboratory test, negative serology results were required in all subjects; however, in subjects with hepatic impairment, out-of-range serology results that were related to the subjects' underlying condition were considered acceptable.

Study Design
This was a single-dose, parallel-design, match-controlled study of daptomycin pharmacokinetics in volunteers. A minimum of 8 hepatic-impaired subjects and 8 matched healthy controls were enrolled. The clinical portion of this study was conducted at the following sites (number of subjects/site): the Medical College of Virginia/Virginia Commonwealth University (n = 1) and SFBC International (n = 18). Approval was received from the independent institutional review board used by each site, and the study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and its amendments, as well as the International Conferences of Harmonization (ICH) harmonized tripartite guidelines for good clinical practice and local laws and regulations relevant to the use of investigational therapeutic agents. A total of 10 hepatic-impaired subjects (Child-Pugh Class B) were enrolled. Only 9 control subjects were enrolled; a match for 1 of the hepatic-impaired subjects could not be found. Data from all 19 subjects enrolled in this study were included in the safety analysis. Plasma pharmacokinetic analyses were based on the data from 18 subjects. Urine parameters were based only on 17 subjects since urine was not collected completely from 1 of the 18 subjects.

Each subject received daptomycin as a single intravenous dose of 6 mg/kg total body weight in 50 mL of saline administered as a 30-minute infusion via a calibrated syringe pump at the rate of 1.67 mL/min. Subjects were required to enter the testing facility the evening prior to drug administration and to remain within the unit for 24 hours (controls) and 48 hours (hepatic-impaired subjects) after drug administration. During this time, subjects consumed standard institutional meals; consumption of grapefruit juice or beverage containing caffeine or alcohol was prohibited. Subjects were to refrain from strenuous exercise of all types.

Sampling and Bioanalysis
Plasma concentrations of daptomycin were assessed from blood samples taken predose (-0.5 h) and 0.25, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 36, and 48 hours from the start of the infusion. The 36- and 48-hour samples were not taken from matched controls as previous studies⁶ have demonstrated that the plasma concentration of daptomycin in healthy subjects was below the limit of quantification 24 hours postadministration. Serum samples for the determination of protein binding were obtained at the end of infusion (0.5 h) and 8 hours from the initiation of infusion. Urine samples were collected predose ( 2 h) and at the following intervals from the start of the infusion: 0 to 12 hours and 12 to 24 hours.

Plasma and urine concentrations of daptomycin were measured by high-performance liquid chromatography (HPLC) with a UV detector.⁶ The dynamic linear range was 3 to 500 µg/mL. For plasma, the method involved extraction of daptomycin and an internal standard; for urine, the method involved the direct analysis of daptomycin after addition of an internal standard in methanol. Quality control standards were prepared at final concentrations of 3.0, 7.50, 75.0, and 499 µg/mL. The 3.0-µg/mL pool (limit of quantitation) had an intra-assay coefficient of variation (CV) of 3.51% and a 9.21% difference from the theoretical value. The remaining quality control pools had intra-assay CVs ranging from 1.7% to 2.95% and percentages of difference within 2.12% of theoretical values. Interassay precision and accuracy for the 3.0-µg/mL pool were 4.8% and a 3.8% difference from the theoretical value. The remaining quality control pools had interassay CVs ranging from 1.86% to 2.07% and percentages of difference within 1.16% of theoretical values. Mean absolute recovery for daptomycin (7.5 µg/mL) was 92.4%, with a CV of 1.66%. For the 499-µg/mL quality control sample, the mean recovery of daptomycin was 95.0%, with a CV of 1.53%. The recovery of the internal standard was 103%, with a CV of 0.82%. For further details on these methods, see Dvorchik et al.⁶ All dosing solutions were analyzed by HPLC with UV detection. Serum protein binding was determined by equilibrium dialysis. A validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method (Cubist Pharmaceuticals, internal report) was used for the quantification of daptomycin concentrations in postdialysis sera and buffer (lower limit of quantitation = 0.1 µg/mL).

Safety
Safety was assessed by monitoring for adverse events and by conducting physical examinations, electrocardiograms, vital signs assessments, serum CPK determinations, and standard clinical laboratory evaluations before and 24 hours after study drug administration. The overall pattern and incidence of adverse events, including clinically significant abnormal laboratory values, were used to evaluate safety. Adverse events were coded using the MedDRA 3.3 Dictionary of Adverse Reaction Terms and are presented by system class and preferred term.

Pharmacokinetic Analysis
The maximum plasma concentration (C_max) and the time to reach C_max (t_max) were obtained directly from the experimental plasma concentration-time data. All other pharmacokinetic parameters were derived by noncompartmental methods using SAS (release 6.12; SAS Institute, Cary, NC). All graphs were generated using both Sigma Plot (version 5.0; SPSS, Inc., Chicago) and SAS.

The pharmacokinetic parameters estimated and method of calculation are as follows: half-life (t_1/2) = log_e(2)/K_{el 1/2}, where K_{el 1/2} is the slope of the terminal linear phase of the log_e plasma concentration-time curve, calculated from a minimum of three time points for a given set of data; AUC_t = area under the concentration versus time curve, calculated using the linear trapezoidal rule from time 0 to the last quantifiable concentration time (t = 24 h); AUC_0- = AUC_t + C_t/K_el, where C_t is the observed concentration at the last quantifiable concentration time point; K_el is the terminal elimination rate constant; plasma clearance is CL = Dose/AUC_0-; and renal clearance (CL_r) = U₂₄/AUC_t, where U₂₄ is the cumulative of amount of daptomycin excreted in urine to time t. V_z (terminal exponential volume of distribution for an IV dose based on the terminal phase) = CL/K_el; mean residence time (MRT) = (AUMC_I/AUC_0-) - (infusion time/2), where AUMC_I = AUMC_last + (t_last • C_last/K_el) + (C_last/K_el²), and AUMC_last is the area under the moment curve computed from the start of dosing to the last measurable concentration; V_ss (the volume of distribution at steady state for an IV dose) = CL x MRT; and Fe_dose (fraction of dose excreted in the urine as the parent drug, expressed as percentage) = [U_0-24/Dose] x 100.

Statistics
All statistical analyses were conducted in SAS. The sample size calculation was based on the CV of the logarithmically transformed AUCs from a previous study in healthy volunteers,⁶ estimated by a power of 80%. Descriptive statistics for pharmacokinetic parameters (mean, %CV) were calculated for all pharmacokinetic parameters. Comparisons of pharmacokinetic parameters between the two cohorts were analyzed by ANOVA, and 90% confidence intervals using log-transformed AUC ratios were used to determine equivalency of AUC, C_max, t_max, Fu, and Fe.

	RESULTS

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Subjects
Nineteen subjects were enrolled into the study, and all completed the study. A matched control for 1 hepatic-impaired subject could not be located. Thus, 10 hepatic-impaired subjects and only 9 matched controls were enrolled into the study. The baseline demographic characteristics of the groups were comparable (Table I). Most of the subjects in the study were Caucasian. In the hepatic-impaired group, 7 of 10 were male and 6 of 9 were male in the matched control group. The mean age of the subjects with hepatic impairment was 55.7 years (range: 41-73) and 52.4 years (range: 37-66) for the matched controls. All hepatic-impaired and control subjects were matched for sex, age (±10 years), and weight (±11 kg), with the exception of 1 hepatic-impaired subject for whom there was no matched control subject. All hepatic-impaired subjects were Child-Pugh Class B.

None of the matched control subjects had any significant findings in their medical histories or upon physical examination at screening. Other than hepatic disease, the hepatic-impaired subjects were, for the most part, free of any significant findings in their medical histories or upon physical examination at screening. All subjects with hepatic impairment had a history of hepatitis C, cirrhosis, and/or alcohol cirrhosis. Abdominal ascites were commonly present in hepatic-impaired subjects on physical examination.

Pharmacokinetics
Consistent with previous pharmacokinetic studies,^5,6 the plasma concentration profile of daptomycin, from both groups, declined consistent with a two-compartment model with first-order elimination (Figure 1). Analysis of all dosing solutions (data not shown) confirmed that 6 mg/kg total body weight was administered (mean ± SD, 5.96 ± 0.3 mg/kg; range: 5.55-6.98 mg/kg).

View larger version (10K): [in this window] [in a new window]   Figure 1. Mean daptomycin plasma concentration profiles (semi-log).

For the hepatic-impaired subjects, the 36-hour and 48-hour time points were excluded from Figure 1 as only 5 of 10 subjects and 1 of 10 subjects, respectively, had plasma concentrations above the lower limit of quantification. The %CV for the mean values was 114% and 316%, respectively.

There were no significant differences in the pharmacokinetic parameters of daptomycin in subjects with moderate hepatic impairment (n = 9) compared to the 9 matched healthy subjects (Table II). Statistical analysis of the log-transformed C_max and AUC_0- confirms these results as the p-value for both comparisons was greater than 0.05 (p = 0.77 for C_max and p = 0.43 for AUC_0-). Also, as shown in Table III, the confidence intervals were from the predetermined limits of 70% to 143% for C_max and 80% to 125% for AUC_0-, as per the FDA guidance for studies in hepatic-impaired subjects.⁸

Serum samples were analyzed at the end of the infusion (0.5 h) and at 8 hours following the start of infusion for plasma protein binding. A paired t-test was used to compare protein binding at 0.5 and 8 hours. The p-values observed were 0.37 for group A and 0.39 for group B, indicating that protein binding at the two time points was not statistically different. An ANOVA model with terms for treatment, time, and the treatment-by-time interaction was examined. The treatment-by-time interaction was not statistically significant (p > 0.15). Therefore, the reduced model without the interaction term was evaluated. The results indicated that the fraction of daptomycin unbound in serum (Fu) is not statistically significantly different (p = 0.06) between the two groups.

Mean fraction unbound (mean of 0.5 and 8 h) was used to calculate unbound parameters. Mean unbound clearances (total and renal) between hepatic-impaired subjects and normal matched control subjects were the same (Table II). Comparison of mean clearances indicates that renal clearance is much lower than total clearance for both groups. This is true for both bound and unbound clearances. The unbound renal clearances also appear to be lower than the glomerular filtration rate of 120 mL/min.

Figure 2 shows the renal clearance of daptomycin across the two groups. The mean values for both groups are similar. Urine was not collected completely from 1 subject, and thus urine parameters were calculated for only 8 matched subjects.

View larger version (8K): [in this window] [in a new window]   Figure 2. Scatter plot of daptomycin renal clearance by treatment.

The fraction of the dose excreted in the urine as daptomycin (%Fe) is given in Figure 3. For the hepatic-impaired group, 89.5% of the dose was recovered in urine from 1 subject; for another subject, 51.8% of the dose was recovered. All other subjects had an %Fe value below 50%. For the normal healthy controls, %Fe values were below 50% for all subjects. Statistical comparisons of the loge-transformed %Fe values gave a p-value of 0.2, indicating no statistically significant difference between the two groups.

View larger version (9K): [in this window] [in a new window]   Figure 3. Scatter plot of fraction of dose excreted in the urine (Fe) as daptomycin by treatment.

Safety
The overall treatment-emergent adverse event rate in the 19 subjects treated in this study was 21.1% (4 of 19). Treatment emergent was defined as an event that was new in onset or aggravated in severity or frequency following administration of the investigational agent. Four of the 10 subjects with hepatic impairment experienced six treatment-emergent adverse events. The 9 matched control subjects did not experience any adverse events in this study. All treatment-emergent events were mild in severity. Three of the six events were judged possibly related to study drug by the investigator; the other three events were considered not related to the study drug. There were no deaths or serious adverse events during the study, and none of the subjects discontinued due to an adverse event. Table IV presents all treatment-emergent adverse events reported during the study.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Analysis of the results of this study suggests that moderate hepatic impairment (Child-Pugh Class B) does not have a statistically significant effect on the pharmacokinetics of daptomycin. Estimates of the pharmacokinetic parameters of daptomycin in subjects with moderate hepatic impairment were similar to those obtained in healthy subjects with normal hepatic function, who were matched for sex, age, and weight with the subjects with moderate hepatic impairment. The pharmacokinetic results from this study are slightly higher than those from a previous study of daptomycin pharmacokinetics,⁶ which showed an AUC on the order of 700 µg•h/mL, peak concentrations of daptomycin of 90 µg/mL, and an apparent first-order elimination with a t_1/2 of approximately 8 hours following a single 6-mg dose of daptomycin in healthy subjects. These differences are most likely due to differences in the mode of administration; in this study, daptomycin was administered via a calibrated syringe pump at the rate of 1.67 mL/min, whereas in the earlier study,⁶ administration used standard hospital flow controllers.

In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the human cytochrome (CYP) 450 isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 (data on file, Cubist Pharmaceuticals). In a human radiolabeled ADME study,⁵ the plasma total radioactivity was equivalent to daptomycin, as determined by a validated microbiological assay, whereas urine contained both daptomycin and inactive metabolites. These data, along with daptomycin's physiochemical properties (high polarity, high molecular mass, low lipid solubility) and pharmacokinetic properties (high protein binding, low apparent volume of distribution), led these authors⁵ to conclude that daptomycin does not readily cross certain cell membranes and is not metabolized by the liver but rather by the kidney with almost immediate renal excretion. Thus, they speculated that daptomycin would not accumulate in hepatic-impaired patients.

As observed in two double-blind, comparator-controlled phase III clinical studies with daptomycin in subjects with cSSSI caused by susceptible strains of gram-positive microorganisms,¹² daptomycin appeared safe and well tolerated in the present study. The presence of moderate hepatic impairment in this study did not affect the tolerability profile of daptomycin. Aside from the underlying disease states for subjects with hepatic impairment, no consistent changes in blood chemistry, hematology, or urinalysis were observed. Vital signs and EKG results were similarly unaffected by daptomycin administration in subjects with moderate hepatic impairment, as well as in healthy subjects.

In conclusion, the pharmacokinetics and tolerability of daptomycin in subjects with moderate hepatic impairment are similar to those observed in matched healthy subjects with normal hepatic function. No adjustment in the dose or dose regimen of daptomycin is necessary in patients with moderate hepatic impairment.

	ACKNOWLEDGEMENTS

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This work was supported by and conducted under the auspices of Cubist Pharmaceuticals, Inc.

	FOOTNOTES

 
DOI: 10.1177/0091270004266619

Submitted for publication September 26, 2003; Revised version accepted April 18, 2004.

	REFERENCES

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2. Bush LM, Boscia JA, Wendeler M, Pitsakis PG, Kaye D: In vitro post antibiotic effect of daptomycin (L146032) against Enterococcus faecalis and methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 1989;33: 1198-1300.[Abstract/Free Full Text]

3. Hanbeger H, Nilsson LE, Maller R, et al: Pharmacodynamics of daptomycin and vancomycin on Enterococcus facalis and Staphylococcus aureus demonstrated by studies of initial killing and postantibiotic effect and influence of Ca2+ and albumin on these drugs. Antimicrob Agents Chemother 1991;35: 1710-1716.[Abstract/Free Full Text]

4. Silverman JA, Oliver N, Andrew T, Li T: Resistance studies with daptomycin. Antimicrob Agents Chemother 2001;45: 1799-1802.[Abstract/Free Full Text]

5. Woodworth JR, Nyhart EH, Brier GL, Wolny JD, Black HR: Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy subjects. Antimicrob Agents Chemother 1992;36: 318-325.[Abstract/Free Full Text]

6. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD: Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother 2003;47: 1318-1323.[Abstract/Free Full Text]

7. Louie A, Kaw P, Liu W, Jumbe N, Miller MH, Drusano GL: Pharmacodynamics of daptomycin in a murine thigh model of staphylococcus aureus infection. Antimicrob Agents Chemother 2001;45: 845-851.[Abstract/Free Full Text]

8. Food and Drug Administration: Guidance for Industry: Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 2003.

9. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R: Transection of the esophagus for bleeding esopheal varices. Br J Surg 1973;60: 646-649.[Web of Science][Medline] [Order article via Infotrieve]

10. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1978;16: 31-41.

11. Oleson FB Jr, Berman CL, Kirkpatrick JB, Regan KS, Lai JJ, Tally FP: Once-daily dosing in dogs optimizes daptomycin safety. Antimicrob Agents Chemother 2000;44: 2948-2953.[Abstract/Free Full Text]

12. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, and the Daptomycin 98-01 and 99-01 Investigators: The safety and efficacy of daptomycin in the treatment of complicated skin and skin structure infections. Clin Infect Dis; in press.
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Dvorchik, B. Search for Related Content PubMed PubMed Citation Articles by Dvorchik, B. Social Bookmarking                   What's this?