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PHARMACOKINETICS AND PHARMACODYNAMICS |
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.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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40 kg/m2) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.9 kg/m2) control group. All subjects received a dose of 4 mg/kg total body weight (TBW) by intravenous infusion (30 minutes). Daptomycin plasma half-life, the fraction of the dose excreted unchanged in urine, and daptomycin absolute renal clearance (mL/h) were unchanged as a function of obesity. The absolute volume of distribution (Vz and Vss) and plasma clearance (CL) for daptomycin were higher in obese subjects as compared to nonobese matched controls. The rate of change of Vz and CL with increasing BMI was greater when these pharmacokinetic parameters were expressed in absolute terms compared to when they were normalized for TBW or ideal body weight. This suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in Vd and CL. Exposure to daptomycin in obese subjects (Cmax, AUC) was increased 25% and 30%, respectively, compared to nonobese matched controls, well within the range that was previously determined to be safe and well tolerated. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.
Key Words: Daptomycin • obesity • pharmacokinetics • drug safety • drug distribution and elimination
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In vitro, daptomycin demonstrates rapid, concentration-dependent bactericidal activity against most clinically relevant gram-positive bacteria, including methicillin-resistant staphylococci, vancomycin-intermediate susceptible Staphylococcus aureus, and vancomycin-resistant enterococci.1 The minimum inhibitory concentration of daptomycin (MIC90) is typically 
1 µg/mL for staphylococci and streptococci and 2 to 4 µg/mL for enterococcal species.2 In phase 3 trials for the treatment of cSSSI caused by aerobic gram-positive bacteria, clinical and microbiological outcomes of patients treated with daptomycin were comparable to those for patients receiving conventional antibiotic therapy.3,4
Daptomycin has been effective against clinical isolates in several different animal models of infection, including endocarditis, bacteremia, and renal and intramuscular infection. In a thigh soft tissue infection model in mice, the pharmacodynamic parameter of daptomycin that most closely correlated with bacterial eradication was the ratio of the area under the plasma concentration versus time curve to the minimum inhibitory concentration (AUC24h)/MIC.5 This characteristic is consistent with the concentration-dependent activity noted in vitro.
Daptomycin pharmacokinetics have been examined in healthy volunteers in both single-dose and repeated-dose studies up to 8 mg/kg.6,7 Daptomycin kinetics were linear, with approximately 20% accumulation following repeated once-daily doses. Daptomycin is distributed primarily to extracellular fluid, does not readily cross cell membranes, and is bound (approximately 87%-94%) to serum proteins. Elimination is primarily by renal excretion of daptomycin. Following a single dose of 14C-daptomycin, radioactivity associated with metabolites was observed only in urine. The terminal plasma half-life (t1/2) in subjects with normal renal function is approximately 9 hours. Population pharmacokinetic analysis8 has indicated that a 2-compartment model with first-order elimination provides the best fit to daptomycin plasma concentration-time data. Daptomycin plasma clearance (CL) varied linearly with estimated creatinine clearance. CL among dialysis subjects was approximately one third that of normal subjects. Renal function contributed most significantly to interindividual variability.
The pathophysiology of the obese body may affect drug distribution and elimination. Alterations in fluid volumes in obese subjects have been documented, and studies on drug kinetics have provided differing data on renal function and pharmacokinetics in obese patients.9-11 This study was designed to assess the single-dose pharmacokinetics and safety of daptomycin in moderately to morbidly obese subjects as compared with nonobese subjects who were matched for gender, age, and renal function.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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70 mL/min, as calculated by the Cockcroft and Gault equation12 using total body weight). Match by sex was 100%. Actual enrollment was 25 subjects (6 moderately obese, 7 morbidly obese, and 12 matched controls). One morbidly obese subject did not have a matched control subject. This subject was not included in the pharmacokinetic analyses but was included in the assessment of safety. All 25 enrolled subjects completed the study. Subjects were screened not more than 14 days or less than 2 days prior to study day 1, and those meeting all the inclusion/exclusion criteria were enrolled. After providing informed consent, a subject's demographic characteristics and medical/medication histories were recorded. Physical examination and vital signs assessments were performed, and blood samples were obtained for routine chemistry, hematology, and coagulation (PTT/INR) testing. Additional testing at screening included urinalysis, human immunodeficiency virus test, serum pregnancy test (if applicable), and serum creatine phosphokinase (CPK) level determination. CPK was monitored because daptomycin has been reported to have the potential for muscle toxicity.13 A 12-lead electrocardiogram (ECG) was also obtained.
General inclusion criteria for all male and female subjects included age between 18 and 65 years and estimated creatinine clearance 70 mL/min using the Cockcroft-Gault equation13 and total body weight. Female subjects of childbearing potential must have been nonpregnant, nonlacting, and willing to practice reliable birth control measures during and for at least 48 hours after treatment with daptomycin. Subjects taking concomitant medications that were not specifically excluded must have been on a stable dose for 2 weeks prior to administration of daptomycin. 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 CPK levels had to be 1.5 ULN. Additional inclusion criteria were a body mass index (BMI) from 25 to 39.9 kg/m2 for moderately obese subjects, a BMI 40 kg/m2 for morbidly obese subjects, and a BMI from 18 to 24.9 kg/m2 for nonobese matched controls. Exclusion criteria were as previously described.14
Study Design
This was an open-label, single-dose, parallel-group study of daptomycin pharmacokinetics conducted at a single center in adult subjects who were moderately obese (BMI = 25-39.9 kg/m2) or morbidly obese (BMI 40 kg/m2) and matched nonobese (BMI between 18.5 and 24.9 kg/m2) healthy subjects. The clinical portion of this study was conducted at CNS, Clinical Trials (Fort Lauderdale, Fla). Approval was received from an independent institutional review board.
All subjects received a single dose of intravenous daptomycin at 4 mg/kg total body weight in 50 mL of normal saline. Subjects were admitted to the Clinical Research Unit on the evening before daptomycin administration(day-1) and were to remain housed in the Clinical Research Unit for the duration of the study. At the time of check-in on day -1, subjects underwent a physical examination, including vital signs assessments and weight. BMI was calculated by the Clinical Research Unit using the formula BMIMALE = 50 kg + 2.3 kg per inch of height over 60 inches and BMIFEMALE = 45.5 kg + 2.3 kg per inch of height over 60 inches. Routine laboratory testing (chemistry, hematology, coagulation, and urinalysis), a serum CPK determination, a urine drug screen, and a urine pregnancy test (for women of childbearing potential) were conducted. A 12-lead ECG was also obtained. Subjects were given a standardized dinner that evening and a snack at 11:00 PM before going to bed. Subjects drank at least 8 ounces of water with each meal or snack.
On the dosing day (day 1), all subjects received a standardized breakfast at least 1 hour prior to drug administration, and intravenous catheters were placed in separate arms, one for the infusion of study drug and the other for blood sampling. Blood was drawn for the determination of CPK approximately 2 hours prior to dosing. A control urine sample (predose) was obtained within 2 hours before study drug administration. At approximately 8:00 AM on day 1, 4 mg/kg of daptomycin was administered intravenously over approximately 30 minutes. A 1.0-mL aliquot of the dosing solution was collected prior to administration and stored frozen before being sent to the laboratory for the determination of daptomycin concentration.
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), 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours from the start of the infusion. Urine samples for the determination of daptomycin concentration were collected predose (-2 hours) at 0 to 2 hours, 2 to 4 hours, 4 to 8 hours, 8 to 12 hours, 12 to 16, and 16 to 24 hours from the initiation of infusion.
Plasma and urine concentrations of daptomycin were measured by high-performance liquid chromatography (HPLC) with an ultraviolet (UV) detector. The mobile phase consisted of 90% mobile phase A (acetonitrile: 0.5% NH4H2PO4 34:66, v/v) and 10% mobile phase B (acetonitrile: 0.5% NH4H2PO4 20:80, v/v) at a flow rate of 1.5 mL/min. A Phenomenex IB-SIL 5 C8 guard column (30 x 4.6 mm) was used along with a Phenomenex IB-SIL 5 C8 column (250 x 4.6 mm). A Waters 2487 UV detector set at 214 nm was used to detect daptomycin (Rt = 15 minutes) and internal standard (Rt = 7 minutes). The total runtime was 30 minutes. The dynamic linear range was 3 to 500 µg/mL. For plasma, the method involved extraction of daptomycin and an internal standard (ethyl paraben in methanol); for urine, the method involved the direct analysis of daptomycin after the addition of an internal standard in methanol. For further details on these methods, see Dvorchik et al.7 All dosing solutions were analyzed by HPLC with UV detection.
Pharmacokinetic Analysis
All pharmacokinetic parameters were derived by noncompartmental methods using SAS (Release 6.12; SAS Institute, Cary, NC). All statistical analyses were conducted in SAS. The pharmacokinetic parameters estimated were maximum plasma concentration (Cmax, obtained directly from the experimental plasma concentration-time data without extrapolation) and time to reach Cmax (tmax, obtained directly from the experimental plasma concentration-time data without extrapolation). Area under the concentration-time curve was calculated from the linear trapezoidal rule from 0 to 24 hours (AUC0-24); area under the concentration-time curve from time 0 to infinity (AUC0-
) was calculated as the sum of AUC0-24 + Clast/Kel. Other calculated pharmacokinetic parameters were as follows: daptomycin terminal plasma half-life (t1/2 = 0.693/Kel), plasma clearance of daptomycin (CL), terminal exponential volume of distribution (Vz), mean resident time (MRT), apparent volume of distribution at steady state (Vss = CL x MRT), renal clearance of daptomycin (CLr), and fraction of the dose excreted in the urine as the parent drug, expressed as a percentage (%Fe).
Statistics
Descriptive statistics for pharmacokinetic (PK) parameters were calculated where appropriate. Comparisons of PK parameters between the 2 cohorts were analyzed by analysis of variance (ANOVA), and 90% confidence intervals using log-transformed AUC ratios were used to determine the equivalency of daptomycin AUC (using log-transformed AUC ratios), Cmax (using log-transformed Cmax ratios), plasma CL, renal CL, Vz, and %Fe. Regression plots and linear regressions of these plots were conducted using SigmaPlot 2001 (Systat Software Inc, Point Richmond, Calif).
Safety
Safety was assessed by monitoring for adverse events, physical examination, electrocardiograms, vital signs assessments, serum CPK determinations, and standard clinical laboratory evaluations before and 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. A treatment-emergent adverse event was defined as an event that was new in onset or aggravated in severity or frequency following administration of the investigational agent.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Subject demographics are presented in Table I. Most of the subjects in the study were Hispanic. The subjects in each group were within similar age and height ranges. The age of the matched controls was, on average, about 10% less than that of the 2 obese groups. Mean weight was approximately 25% lower in the control group compared to the moderately obese subjects and approximately 49% lower than the morbidly obese subjects. Ideal body weight was similar across all groups. The majority of subjects did not have any significant findings in their medical histories or upon physical examination at screening or baseline. Exceptions included 1 subject in the morbidly obese group who had type 2 diabetes and hypertension. In addition, 1 subject in the moderately obese group had a history of thalassemia minor and splenectomy, and another had enlarged and erythematous tonsils bilaterally at screening and baseline.
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Pharmacokinetics
The plasma concentration profile of daptomycin, from all groups, declined consistent with a 2-compartment model with first-order elimination (Figure 2). Analysis of all dosing solutions (data not shown) confirmed that 4-mg/kg total body weight was administered. One subject in the morbidly obese group was excluded from the pharmacokinetic analysis because a matched control could not be located.
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Daptomycin plasma half-life was invariant with BMI (Figure 3, r2 = 0.006). Tables II and III present the arithmetic mean pharmacokinetic parameters in moderately obese and morbidly obese subjects, respectively, versus matched nonobese controls. Cmax and AUC, for both groups of obese subjects, were statistically different from the respective matched controls. Table IV presents the results of paired t test and confidence intervals for least squares mean and arithmetic mean ratios of moderately obese and morbidly obese subjects, respectively, versus matched controls. For the 3 parameters Cmax, AUC0-t, and AUC0-, the lower 90% confidence interval for the ratios was greater than 1.00, indicating that obese subjects show a higher maximum concentration and extent of daptomycin exposure as compared to matched nonobese controls. In obese subjects, Cmax was 
25% higher than in matched controls; AUC values were 30% to 35% greater in obese subjects compared to the matched controls.
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Statistically significant differences in daptomycin volume of distribution (Vd) were observed between obese subjects and the respective matched controls, whether expressed as absolute values (L) or weight normalized (L/kg). Exceptions noted in moderately obese subjects were Vz/kg ideal body weight (IBW), Vss/kg IBW, and Vss/kg total body weight (TBW). P values for Vz/kg IBW and Vss/kg TBW were just outside the value for statistical significance (P = .052 and .058, respectively). Analysis of these data indicates that the average increase in absolute Vd (Vz or Vss) was 25.2% in the moderately obese subjects and 55.4% in the morbidly obese subjects compared to the respective controls.
In moderately obese subjects, daptomycin CL was statistically significantly different versus matched controls, regardless of how it was expressed. In morbidly obese subjects, statistically significant differences were noted only for TBW-normalized and absolute (non-weight-normalized) CL. Statistically significant differences in daptomycin renal clearance (CLr) between each obese group and its respective matched controls were observed only when CLr was normalized to TBW.
Table V lists the results of the regression of various PK parameters versus BMI. Although absolute values for Vz and Vss became greater with increasing BMI (slope = 0.170 and 0.180, respectively) when normalized for TBW or IBW, the changes in Vd were smaller (slopes of 10-3 to 10-4). Changes in CL were of a similar nature, with the slope decreasing from 16.28 to -0.142 and 0.241 when normalized to TBW and IBW, respectively.
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Safety
One of the 7 subjects in the morbidly obese group experienced 3 treatment-emergent adverse events, all of which occurred 8 or more hours after dosing. The 3 events were mild in severity and were not considered treatment related by the investigator. The 6 moderately obese subjects and the 12 matched control subjects did not experience any adverse events during the study. There were no deaths or serious adverse events during the study, and none of the subjects discontinued due to an adverse event.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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In obese subjects, exposure to daptomycin (Cmax, AUC) was increased 30% compared to nonobese matched controls. Comparison of the pharmacokinetic data from obese subjects to pharmacokinetic and safety data from a previous once-daily multiple-dose, dose-escalating study7 and other phase 2 studies at doses greater than 4 mg/kg15 indicates that the increased exposure to daptomycin observed in obese subjects is well within the range that is safe and well tolerated.
Human obesity, for the most part, is associated with an increase in lean body mass (LBM) in the order of 20% to 40% of excess body weight.16 This is the most plausible explanation for the observed increase in daptomycin Vd (L) observed in obese subjects. That the absolute values of Vd and CL were greater than when these parameters were normalized to either TBW or IBW suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in Vd and CL. This is consistent with the physiochemical characteristics of daptomycin (high polarity, high molecular mass, low lipid solubility) and the high plasma protein binding of daptomycin, both of which limit its overall distribution. We explain the lack of any difference in daptomycin CLr (mL/h) between each obese group and its respective matched controls as due to all volunteer subjects having an estimated creatinine clearance 70 mL/min (ie, normal renal function); in addition, obese subjects are reported to have larger kidneys than nonobese subjects.17
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Given the above, we examined the relationship between Vd and LBM as well as CL and LBM; r2 was 0.29 and 0.2, respectively (data not shown), indicating that LBM does not provide a stronger foundation on which to base dose than any of the other parameters examined. The simplicity of using TBW, as well as the fact that the increased Cmax and AUC do not pose a safety issue and err on the side of efficacy, causes us to conclude that, in obese subjects, daptomycin may be dosed based on total body weight. No adjustment in daptomycin dose or dose regimen should be required based solely on obesity.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication April 4, 2004; Revised version accepted July 26, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Fuchs PC, Barry AL, Brown SD. In vitro bactericidal activity of daptomycin against staphylococci. J Antimicrob Chemother. 2002;49: 467-470.
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3. Wesson KM, Lerner DS, Silverberg NB, Weinberg JM. Linezolid, quinupristin/dalfopristin, and daptomycin in dermatology. Clin Dermatol. 2003;21: 64-69.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI, and 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. 2004;38: 1673-1681.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. 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.
6. 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.
7. 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.
8. Dvorchik B, Arbeit R, Chung J, Liu S, Knebel W, Kastrissios H. Population pharmacokinetic analysis of daptomycin. Antimicrob Agents Chemother. 2004;48: 2799-2807.
9. Cheymol G. Effects of obesity on pharmacokinetics: implications for drug therapy. Clin Pharmacokinet. 2000;39: 215-231.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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12. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1978;16: 31-41.
13. 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.
14. Dvorchik B, Damphousse D. Single-dose pharmacokinetics of daptomycin in young and geriatric volunteers. J Clin Pharmacol. 2004;44: 612-620.
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