Pharmacokinetics and Inflammatory Fluid Penetration of Intravenous Daptomycin in Volunteers

The lipopeptide antimicrobial daptomycin was administered intravenouslyat a dose of 4 mg/kg of body weight to seven healthy male volunteers.The concentrations of daptomycin in plasma, cantharidin-inducedinflammatory fluid, and urine were measured by a microbiologicalassay. The mean ± standard deviation peak concentrationsin plasma and inflammatory fluid were 77.5 ± 8.3 and27.6 ± 9.5 µg/ml, respectively; the mean terminalelimination half-lives were 7.74 and 13.2 h, respectively. Theoverall penetration of total drug into the inflammatory fluid(measured by ratio of the area under the concentration-timecurve from 0 to 24 h for inflammatory fluid compared with thatfor plasma) was 68.4%. The mean urinary recovery over 24 h was59.7%.

INTRODUCTION

Top

Introduction

Daptomycin is a cyclic lipopeptide antimicrobial with in vitroactivity against gram-positive organisms including vancomycin-resistantenterococci, methicillin-resistant staphylococci, and "heterodrug-resistant"glycopeptide-resistant Staphylococcus aureus (M. D. Applemanand D. M. Citron, Abstr. 40th Intersci. Conf. Antimicrob. AgentsChemother., abstr. 2291, p. 183, 2000; E. J. C. Goldstein andD. M. Citron, Abstr. 40th Intersci. Conf. Antimicrob. AgentsChemother., abstr. 2293, p. 183, 2000). In vitro studies todate have shown that daptomycin is rapidly bactericidal, withtreatment with daptomycin resulting in greater than 3 log reductionsin 8 h for methicillin-resistant S. aureus, vancomycin-resistantenterococci, and glycopeptide-resistant S. aureus (1). Daptomycinis being investigated against complicated skin and skin structureinfections in two large phase III trials by use of a dose of4 mg/kg of body weight every 24 h. There is little recent publishedinformation on the pharmacokinetics of this compound; hence,the aim of the present study was to investigate the pharmacokineticsof daptomycin following the administration of a single intravenousdose of 4 mg/kg. In addition, a cantharidin-induced inflammatoryblister technique was used to assess the penetration of thiscompound into an inflammatory exudate (2).

MATERIALS AND METHODS

Top

Materials and Methods

Seven healthy male volunteers (age range, 21 to 28 years; meanweight, 78.5 kg; weight range, 70.1 to 95.2 kg; mean height,179.8 cm; height range, 173 to 195 cm) gave written informedconsent following hospital ethical committee approval of theprotocol. Exclusion criteria included atopy, liver and renaldisease, and significant central nervous system pathology.

All volunteers underwent a full medical history examinationand routine hematological and biochemical investigations. Onthe evening prior to the study two 0.2% cantharidin-impregnatedplasters (1 by 1 cm) were placed on each subject’s forearmto induce inflammatory blister formation. The volunteers receivedonly clear fluids in the 8 h prior to administration of theplasters.

The volunteers received daptomycin at a dose of 4 mg/kg of bodyweight administered in 50 ml of normal saline over 30 min. Forthe next 2 h only clear fluids were taken by mouth, after whicha light diet was allowed. Blood samples were obtained at timezero (at the beginning of infusion), 0.25 h (halfway throughthe infusion), 0.5 h (at the end of the infusion), and 0.58,0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 h after the infusion. Blisterfluid was sampled with a fine needle at 0.5, 1, 1.5, 2, 4, 6,8, 12, and 24 h. The blister was then resealed by spraying itwith a plastic dressing aerosol. Urine was collected over 0to 4, 4 to 8, 8 to 12, and 12 to 24 h after the initiation ofthe infusion.

Drug analysis. The blood samples were centrifuged, and the plasma was collectedand assayed, in triplicate, within 1 h. Plasma, inflammatoryfluid, and urine daptomycin concentrations were measured bya microbiological assay with Isotonic Sensitivity Test agar(Mast, Merseyside, United Kingdom) supplemented with 50 mg ofCa²⁺ per liter. The indicator organism was S. aureus F1445 (fromthe organism collection of the Department of Microbiology, CityHospital NHS Trust, Birmingham, United Kingdom), which was incorporatedinto the agar in order to achieve semiconfluent growth. Thedaptomycin standard concentration range was 2 to 32 mg/liter,and the lower limit of sensitivity of the assay was 1 mg/liter.Calibrators were prepared in human serum, 70% serum (in bufferat pH 7), and phosphate buffer (pH 7) for the plasma, inflammatoryfluid, and urine samples, respectively. Incubation was for 24h, after which the assay plates were read with an image analyzer(Image Associates, Teme, United Kingdom). The interassay coefficientsof variation (for the internal controls) were 6.3, 7.8, and7.2% for plasma, inflammatory fluid, and urine, respectively;and the intra-assay regression analysis of quality assurancesamples yielded r² values of 0.959, 0.82, and 0.99 for the threetypes of samples, respectively. All samples were processed within1 h of collection.

Pharmacokinetic analysis. Plasma daptomycin concentration data were analyzed by compartmentaland model-independent methods with WinNonLin software (version3.0; Pharsight Corp., Mountain View, Calif.), and the inflammatoryfluid daptomycin concentration data were analyzed by model-independentmeans. Determination of the area under the concentration-timecurve (AUC) for inflammatory fluid used a log-linear method;for the AUC for plasma the linear trapezoidal rule was applied.The following were calculated: the maximum concentration (C_max)in plasma or inflammatory fluid and the time to C_max (T_max),the AUCs for plasma and inflammatory fluid over the dosing intervalof 0 to 24 h (AUC_0–24), the AUC extrapolated to infinity(AUC_0–), the terminal linear elimination half-life (t_1/2),the clearance from plasma (CL_plasma), the volume of distributionof daptomycin in the central compartment (V₁), the volume ofdistribution based on the terminal phase (V_z), the volume ofdistribution at steady state (V_ss), the mean residence timein plasma (MRT), the percent excreted unchanged in urine over24 h (A_e), and the percent penetration into inflammatory fluid(which is the ratio of the AUC_0–24 for inflammatory fluidcompared with that for plasma).

RESULTS

Top

Results

The mean concentrations of daptomycin in plasma and the inflammatoryfluid following administration of the drug at 4 mg/kg are shownin Fig. 1, and the derived pharmacokinetic parameters are shownin Tables 1 and 2. These data were obtained for six of the sevenvolunteers, with one volunteer having to be excluded due toan adverse event (see below). There was good agreement betweenthe data generated by compartmental and noncompartmental analyses.V₁, normalized to body weight, corresponds to the volume ofdistribution for plasma (mean ± standard deviation [SD],0.043 ± 0.011 liter/kg); V_ss did not differ significantlyfrom V_z. When these values were normalized to body weight, theyreflected the V_ss and V_z values for plasma and interstitialfluid (0.082 ± 0.013 liter/kg).

View larger version (16K):
[in this window]
[in a new window]
FIG. 1. Mean concentrations in plasma ( ${lozenge}$ ) and inflammatory fluid ( ${circ}$ ) following intravenous administration of a 4-mg/kg dose of daptomycin over 30 min (vertical bars indicate SDs).

View this table:
[in this window]
[in a new window]
TABLE 1. Daptomycin pharmacokinetic parameters following intravenous infusion of a 4-mg/kg dose over 30 min

View this table:
[in this window]
[in a new window]
TABLE 2. Daptomycin pharmacokinetics in inflammatory fluid following administration of a 4-mg/kg dose

The mean plasma daptomycin C_max was 77.5 µg/ml at theend of the infusion period. The mean t_1/2 from plasma was 7.74h, with relatively little individual variation (SD, 0.63 h).The mean AUC_0–24 was 468.0 µg · h/ml. Themean AUC_0–24 was equal to 88% of the AUC_0–.

Daptomycin penetrated the inflammatory exudate moderately rapidly,with the mean concentrations at 1 and 2 h being 9.4 and 14.5µg/ml, respectively. The mean T_max was 3.7 h when themean C_max in inflammatory fluid was 27.6 µg/ml. The t_1/2of daptomycin from the inflammatory exudate was highly variable,ranging from 6.3 to 32 h, with the mean being 17.3 h. The meanAUC_0–24 for this fluid was 318.2 µg · h/ml.When the penetration is compared by determination of the ratioof the AUC_0–24 for inflammatory fluid compared with thatfor plasma, a mean value of 68.4% (coefficient of variation,29.1%) was obtained.

The mean ± SD urinary elimination of the drug from fiveof the six volunteers was 59.7% ± 10.2%; the set of datafor one volunteer was not included as no urine was said to havebeen collected from 0 to 12 h postadministration. The biochemicaland hematological parameters studied showed no drug-relatedabnormalities.

Two volunteers experienced adverse events. One volunteer waswithdrawn from the study because of serious diarrhea followedby vomiting starting approximately 1.5 h after the end of theintravenous infusion. He required intravenous metoclopramideand fluids; the symptoms subsided within the following 5 to6 h. The second volunteer experienced a milder incident of asimilar nature but continued in the study.

The severity of the gastrointestinal symptoms observed in thetwo volunteers mentioned above was unexpected and has not beenseen in other studies in patients or healthy volunteers withdaptomycin at doses up to 8 mg/kg/day for 14 days. Gastrointestinaladverse effects, while observed, have not been common, occurringat rates similar to those for comparative antibacterial agents(Barry Dvorchik, personal communication).

DISCUSSION

Top

Discussion

There are limited published data on the pharmacokinetics ofdaptomycin. A linear dose-response has been demonstrated for1 to 6 mg/kg given intravenously (3), with a mean t_1/2 fromplasma of 8.56 h, close to the value of 7.74 h found in thepresent study. The earlier study demonstrated a AUC_0–for plasma of 382 µg · h/ml, whereas our valuewas higher (537 µg · h/ml). This difference canprobably be accounted for by our observation of a higher C_max(77.5 µg/ml), whereas the value in the earlier study was52.3 µg/ml. This may well be related to differences inthe preparation of the daptomycin solution.

Daptomycin penetrated into the inflammatory fluid fairly rapidly;the T_max for inflammatory fluid was about 3 h later than thatfor plasma. The mean penetration into this inflammatory exudatewas 68.4%. The level of binding of daptomycin to serum proteinsis 90% (mean). The protein content of inflammatory exudate isabout 70% of that of plasma. Thus, the penetration of daptomycininto this inflammatory exudate most likely reflects these twofactors, and differences in the protein content of the inflammatoryexudate compared with that of plasma may explain differencesin the observed penetration. The high level of protein bindingof daptomycin and the lack of protein in the interstitial fluidwere probably the most likely explanations for the fact thatthe apparent volumes of distribution of daptomycin (V_z or V_ss)were lower than the estimates of the extracellular fluid volume(0.157 to 0.187 liter/kg).

FOOTNOTES

* Corresponding author. Mailing address: Department of Microbiology, City Hospital NHS Trust, Dudley Rd., Birmingham B18 7QH, United Kingdom. Phone: (0121) 507 4255. Fax: (0121) 551 7763. E-mail: r.wise{at}bham.ac.uk.

REFERENCES

Top