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PHARMACOKINETICS |
From the Department of Pharmaceutics, College of Pharmacy, (Dr Schuck, Dr Derendorf), and the Department of Pharmacology and Therapeutics (Dr Grant), University of Florida, Gainesville.
Address for reprints: Hartmut Derendorf, PhD, Department of Pharmaceutics, PO Box 100494, College of Pharmacy, University of Florida, Gainesville, FL 32610.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Key Words: Pharmacokinetics • microgravity • ciprofloxacin • tissue penetration • microdialysis
One of the biggest concerns related to long-term space flights is the increased risk of infections due to the confinement of the spacecraft and the impairment of the immune system.7-9 These factors both predispose astronauts to becoming infected and compromise the ability of the body to fight the infecting agent. In addition, physiological changes induced by microgravity may affect the antibiotic's PK, resulting in altered infection-site concentrations.8,10 These alterations may significantly affect the way antibiotics are given in space.
Ciprofloxacin is a broad-spectrum anti-infective agent of the fluoroquinolone class.11-13 It is available as 100-, 250-, 500-, or 750-mg tablets for oral administration and as an injection in 20- or 40-mL vials containing 400-mg ciprofloxacin for intravenous administration. In addition, a new extended-release dosage form of ciprofloxacin has been recently approved for treatment of acute uncomplicated and complicated urinary tract infections and uncomplicated pyelonephritis. The extended-release oral dosage form is available in 500-mg and 1000-mg tablets and is administered once daily, which vastly improves compliance. Ciprofloxacin is an excellent antibiotic candidate to be used for the treatment of bacterial infections acquired during space flight. It has reliable and good bioavailability from an oral dose11,14; a broad spectrum of activity, with particular efficacy in infections that are likely to occur during space flight (eg, upper respiratory infection, urinary tract infections, skin infections)15; infrequent dosing regimen; intravenous availability for situations in which oral administration is not possible; and lack of metabolic drug-drug interactions with compounds typically taken in space. In addition, preliminary studies have shown a good stability profile after short-term exposure to the microgravity environment of space flight.16
The aim of this study was to examine the disposition of ciprofloxacin in humans after 3 days of simulated microgravity (sµG) and compare it to that in normal gravity (1G). It was also the goal of this study to determine and compare the unbound soft tissue concentrations of ciprofloxacin by microdialysis in 1G and sµG and relate them to plasma concentrations.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Antiorthostatic Bed Rest Model
The antiorthostatic bed rest (ABR) model is widely used for ground-based sµG. The subjects are made to rest in a 6° to 12° head-down tilt for an extended time. This causes body fluids to redistribute from the lower extremities toward the upper torso and neck regions, similar to what happens during space flight. The validity of the ABR model has been demonstrated in the literature.17-25 It has been shown to be superior to the horizontal bed rest model in simulating microgravity.17,19
Subjects
Six healthy volunteers (5 men and 1 woman; 1 Asian, 1 Hispanic, 1 African American, and 3 Caucasians; ages 21-38 years; weight 54.8-96.9 kg; height 162-178 cm) participated in a randomized, open-label crossover clinical study to evaluate and compare the PK and tissue penetration of ciprofloxacin after a single oral dose in sµG and in 1G. This study was conducted in the General Clinical Research Center at Shands Hospital, University of Florida, and was approved by Shands' Hospital Institutional Review Board (IRB-01). All subjects were briefed on the study details, and a written informed consent was obtained prior to the beginning of the study. Each candidate was subjected to a screening examination including medical history and physical examination, complete blood count with differential, clinical blood chemistry, and urine pregnancy tests (for female subjects). Subjects were selected if they were nonsmokers; were nonobese; had no history of migraine, recurrent headaches, clotting disorders, or drug allergies; and were in good general health as accessed by the physical examination and laboratory results. Tolerance to ABR was also tested during a 4-hour screening trial prior to the study, in which subjects were asked to eat and urinate while in 6° ABR.
The selected subjects were randomized to receive a single 250-mg oral dose of ciprofloxacin, after an 8- to 10-hour overnight fasting, in 2 different occasions: once during an ambulatory phase (1G) and once during ABR (sµG). Each phase was separated by a 15-day washout period. The ambulatory phase consisted of 12 hours of sample and data collection, and the ABR phase consisted of 48 hours of ABR prior to drug administration and 12 hours of data collection thereafter. The 48 hours of ABR prior to the drug administration was selected based on results from earlier studies that suggested that the majority of the physiological changes due to ABR equilibrate by this time.24 Subjects remained in bed for the entire 3-day ABR period, being allowed to rest on an elbow for a maximum of 20 minutes during meals. All treatments were administered in the morning to avoid variability due to circadian rhythms. Uniform bed times and meal times were maintained during the experimental period. Physiological (blood pressure, heart and respiratory rate) were monitored every 4 hours during wake hours. Labs (cell counts, differential, electrolytes, liver enzymes, etc) were measured once at admission and once immediately at the end of the ABR phase.
Sample Collection
Blood samples (5 mL) were collected via an indwelling catheter (Intracath) placed in the antecubital vein at times 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 12 hours after the administration of the dose. Plasma was immediately separated by centrifugation at 3000 rpm for 15 minutes and stored at -70°C until analysis.
Urine samples were collected into plastic containers at times 0, 3, 6, 8, and 12 hours after dose. Additional voids between predetermined time points were also collected. The volume of each void was measured, and 30-mL aliquots were separated and stored at -70°C until analysis.
Unbound tissue concentrations of ciprofloxacin were obtained from the thigh muscle of the subjects by microdialysis.26,27 The skin at the site of the probe insertion was first cleaned and disinfected. One microdialysis probe (CMA/60 cutoff value 20 kD; CMA/Microdialysis, Stockholm, Sweden) was inserted into the medial vastus muscle by puncturing the surface of the skin with a guide needle carrying the probe. After the insertion of the needle, the microdialysis probe was secured in place by holding the plastic flap at the base of the probe while the needle was removed. The microdialysis system was flushed with lactated Ringer's solution and then connected to a microinfusion pump (Harvard Apparatus 22, model 55-4150). The flow rate was set to 1.5 µL/min.
In vivo probe calibration was performed according to the retrodialysis method 30 minutes after the equilibration period.28-30 A 0.1-mg/L solution of ciprofloxacin was perfused through the probe, and the drug concentration was measured in the dialysate. The disappearance rate through the membrane was determined and the in vivo recovery value was thus calculated as
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The in vivo calibration period lasted for 60 minutes, and 2 samples were collected (at 30 and 60 minutes). Concentrations in both retrodialysis samples were averaged and used to calculate the in vivo recovery according to the equation above. The principle of this method relies on the assumption that the diffusion process is quantitatively equal in both directions through the semipermeable membrane. After the calibration period was completed, a 30-minute washout period was observed, and the drug was administered according to the PK protocol outlined previously. Microdialysis sampling was performed at 30-minute intervals up to 12 hours postdose.
Sample Preparation and Analysis
All samples were analyzed by a sensitive high-performance liquid chromatography method with fluorescence detection at 
= 458 nm and = 300 nm for excitation. The method was modified from Zotou and Miltiadou.31
Preparation of plasma samples consisted of transferring a 200-µL aliquot into a clean Eppendorf tube and spiking with 4 µL of a 200-µg/mL solution of anthranilic acid (internal standard). Proteins were precipitated with 4 volumes of acetonitrile. Samples were vortex mixed and centrifuged at 10 000 rpm for 7 minutes. A 600-µL aliquot of the supernatant was evaporated in a vacuum centrifuge and reconstituted with 300 µL of mobile phase. Fifty microliters were injected onto the column.
To measure the free plasma concentrations, plasma ultrafiltrates were obtained from each collected plasma sample as follows. After thawing the plasma samples at room temperature, a 300-µL aliquot was transferred to an ultrafiltration device (Ultrafree-MC, Millipore) and centrifuged at 10 000 rpm for 10 minutes. The volume of plasma ultrafiltrate ranged from 12% to 15% of the original volume of plasma. A 37-µL aliquot of the plasma ultrafiltrate was then taken and diluted with 35 µL of lactated Ringer's solution and vortex mixed. Fifty microliters were injected onto the column. Loss of drug due to binding to the ultrafiltration device membrane was verified by performing the steps described above with solutions of different known concentrations of CIP in lactated Ringer's solution. The concentrations in the ultrafiltrates were compared to the theoretical concentrations tested and expressed in terms of percentage of recovery. Mean recovery was 100.9% ± 6.0%, confirming no loss due to binding.
Preparation of microdialysis samples consisted of diluting a 37-µL aliquot of the dialysate with 35 µL of a 50-ng/mL solution of the internal standard. Samples were vortex mixed, and 50 µL were injected onto the column.
The method showed excellent linearity (R2 > 0.995), sensitivity (lower limit of quantification < 10 ng/mL), and selectivity for ciprofloxacin in all matrices tested. The concentrations in all samples were detected with good precision (coefficient of variation < 12%) and accuracy (% error < 20%).
Data Analysis
Mean ciprofloxacin concentration versus time curves were generated in Microsoft Excel for plasma (total and free), urine, and muscle (free interstitial concentrations) in both 1G and sµG. PK parameters were determined by standard estimation methods32 with the software programs Kinetica (version 4.21 Innaphase, Philadelphia, Pa) and Scientist (version 2.0; MicroMath Scientific, Salt Lake City, Utah). Both noncompartmental and compartmental PK data analyses were performed.
Individual Noncompartmental PK Analysis
The following PK parameters were calculated for each subject, and the means and standard deviations were determined.
Plasma. Noncompartmental PK analysis in plasma (total and free) was performed in Kinetica. The primary noncompartmental PK parameters determined were the AUC, maximum concentration of the drug (Cmax), time for Cmax (Tmax), and the elimination rate constant (ke). AUC was calculated by the trapezoidal method (log-linear). Extrapolated AUC (AUCextra) was determined as the calculated last concentration (Clast)/ke, and AUCtot was calculated as AUClast + AUCextra, with AUClast being the AUC from zero to the last measured time point. Both Cmax and Tmax were obtained from the plots of plasma concentration versus time. The ke was obtained by linear regression of the terminal log-linear phase of the concentration-time curve. The elimination half-life (t1/2) was determined as 0.693/ke. The area under the first moment curve (AUMC) was calculated from a plot of concentration x time (C•t) versus time using the trapezoidal rule up to the last data point (Clast) at time tlast and adding the extrapolated terminal area, calculated as Clast • tlast/ke + Clast/ke2. The mean residence time was calculated as AUMC/AUC. The volume of distribution of the terminal phase (Vß) was calculated as CL/ke. The volume of distribution at steady state (Vss) was calculated as D.AUMC/AUC2. The clearance (CL) was calculated as D/AUC.
CL, Vß, and Vss were determined as CL/F, Vß/F, and Vss/F, where F represents the fraction of the dose that reaches systemic circulation.
Protein binding was determined in each sample by the ratio of the concentrations of ciprofloxacin in plasma ultrafiltrate and the total ciprofloxacin plasma concentrations. The results of all samples were averaged and expressed as means ± SD.
Muscle. Free interstitial concentrations of ciprofloxacin in the muscle were calculated from the measured concentrations in the dialysate and the measured recoveries obtained from retrodialysis. The free interstitial ciprofloxacin AUCfree,tissue was determined by the trapezoidal rule in Microsoft Excel. Since in microdialysis samples the concentrations represent the concentrations at the midpoint of collection, the equation used to calculate the AUCfree,tissue is different than that for plasma.33 The AUC up to the last measured time point is calculated as
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where Cd is the concentration of ciprofloxacin in the dialysate and 
t represents the duration of the collection interval. The AUCextra in muscle is calculated as
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where Cmt is the calculated concentration of ciprofloxacin in the muscle at the time of the last collection and kem is the elimination rate constant in the muscle. The total free tissue AUC (AUCfree,tissue) is calculated as the sum of AUCmuscle0-t and AUCmuscle,extra.
The penetration of ciprofloxacin into muscle tissue (f) was determined as the ratio of the AUCfree,tissue and the AUCtot of free ciprofloxacin in plasma (AUCtissue,free/AUCplasma,free).
Analysis of Urinary Data
Urinary data were analyzed with the software program Kinetica. Parameters estimated from urinary data included the elimination rate constant ke, which was obtained by the excretion rate method, and renal clearance (CLR), which was obtained by plotting the urinary excretion rate (dU/dt) versus the plasma concentration of ciprofloxacin at the midpoint of urine collection. The total amount excreted in urine during the 12-hour sampling period (Xu12) and the percentage of the administered dose recovered in urine were also determined. These parameters were calculated for each subject and expressed as means ± SD for each phase.
Compartmental PK Analysis
Compartmental analysis was performed with the non-linear regression software program Scientist. The mean plasma and free interstitial ciprofloxacin concentrations were simultaneously fitted to a 1-compartment body model with first-order elimination and lag time according to the following equations.
Plasma:
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Free interstitial:
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where F is the fraction of the dose that is absorbed, ka is the first-order absorption rate constant, V is the volume of distribution, ke is the first-order elimination rate constant, fu is the unbound fraction in plasma, f is the tissue penetration factor, and tlag1 and tlag2 are the lag times of the absorption in plasma and muscle, respectively.
An additional exponential term (1 - e-zt) was included in the model to describe the distribution of ciprofloxacin into muscle tissue in 1G. This term has no physiological meaning and has been included only for the purpose of improving the fit.
Goodness of fit was determined by the coefficient of determination and the model selection criteria (MSC). The closer the coefficient of determination is to 1, the better the correlation between observed and predicted values. The higher the MSC, the more appropriate the selected model.
Statistical Considerations
All PK data generated during each phase were analyzed separately and together to compare and contrast the PK of ciprofloxacin during 1G and sµG phases. Differences in the PK parameters between the 2 phases were evaluated by the 2-sample t test, at a level of significance of 95%. The main objective of this study is to determine the differences in the main PK parameters of ciprofloxacin, clearance, and volume of distribution and the tissue penetration between the 1G and sµG phases. Based on values extracted from the literature,28,34 we anticipate means and standard deviations of about 50 ± 2.5 L/h for CL/F and 200 ± 14 L for V/F and 1.23 ± 0.24 for the tissue penetration factor f.Given that the number of subjects was 6, the study will have at least 80% power to detect a difference of 3.6 L/h for CL/F, 20.1 L for V/F, and 0.34 for f.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Free interstitial concentrations. Mean probe recoveries were 15.1% ± 12.4% and 26.9% ± 15.6% in 1G and sµG, respectively. Free interstitial ciprofloxacin concentration versus time profiles in 1G and sµGare presented in Figure 2. Results of the non-compartmental PK analysis of free interstitial ciprofloxacin concentrations are presented in Table II. One subject (subject H) failed to have the microdialysis probe properly inserted in the muscle during the 1G phase; therefore, the comparison between AUCfree,tissue, and f in 1G and sµG was based on only 5 subjects (Table III).
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No significant differences were observed between the PK parameters in muscle in both phases of the study. Mean f in 1G (0.92 ± 0.63) was slightly higher than the one obtained in sµG (0.61 ± 0.36), suggesting that tissue penetration may be impaired in microgravity. However, the differences were not statistically significant (
= 0.05).
Urinary Data
Results of the analysis of urinary data are presented in Table IV. No statistically significant differences were observed between the parameters obtained in 1G and sµG. Approximately 24.0% and 17.7% of the oral dose was recovered in the 1G and sµG, respectively, urine after 12 hours. The estimates of ke from urinary data were 0.22 ± 0.09 h-1 and 0.27 ± 0.1 h-1 in 1G and sµG, respectively. Although the value of ke in sµG is slightly higher than the value estimated from plasma data, the difference is not statistically significant. Values for renal clearance (CLR) were 22.9 ± 8.3 L/h in 1G and 17.4L/h in sµG, which are in good agreement with previously reported values.14
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Compartmental PK Analysis
Figure 3 shows the simultaneously fitted plasma and free interstitial concentrations versus time profiles with the 1-compartment body model. It can be seen that the model describes both the plasma and muscle data very well, except for the initial points during the absorption phase, which gives a poor estimation of ka. The MSC in 1G was 4.16, with a correlation coefficient R2 > 0.99, representing an excellent fit. In sµG, the MSC was 1.97 and the correlation coefficient R2 > 0.95, representing an acceptable curve fit. Similarly, the initial points during the absorption phase are not properly estimated. The PK parameters obtained by fitting the mean concentration versus time profiles in plasma and muscle are presented in Table V.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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As space flights become longer, the likelihood that astronauts will face the same medical problems we have on Earth increases. For example, activities related to the construction of the International Space Station might lead to injuries that might require medical treatment. Because the immune system is compromised, infections might occur and be easily spread among the crewmembers if proper treatment is not enforced. Currently, astronauts take drugs in space according to dosing regimens optimized to 1G, assuming that they will produce the same effects. However, this assumption is not valid because, until now, it could not be supported by any study and based on what is known about space physiology, there are reasons to suspect otherwise.8,10
The results of our study suggest that the disposition of ciprofloxacin is not affected after 3 days of 6° ABR. The concentration versus time profiles of ciprofloxacin in plasma were almost identical in both phases of the study. Consequently, the results of both noncompartmental and compartmental PK analysis show the same mean PK parameters in both phases. Plasma protein binding was also not affected during 3 days of 6° ABR. Based on plasma concentrations alone (not considering possible changes in antimicrobial activity in microgravity), this study would suggest that no changes in dose or dosing regimens of CIP are necessary in sµG.
However, plasma concentrations of antibiotics are poor predictors of the antimicrobial effect in vivo. Most infections do not occur in plasma but in the interstitial space of the peripheral tissues.29,35,36 Therefore, using total plasma concentrations may overestimate the therapeutic outcome because only the unbound fraction in plasma is able to cross the capillary membrane and reach the interstitial space where the infection is. This may be the reason why some antibiotic treatments fail despite good activity in vitro.36
Free interstitial concentrations are much better predictors of antimicrobial activity in vivo. In our study, we observed that the free interstitial ciprofloxacin concentrations measured by microdialysis in the medial vastus muscle (AUCfree,tissue) were slightly lower during sµG than during 1G. Since the free plasma concentrations were not different in sµG than in 1G, a slightly lower value of f was obtained in sµG, suggesting that tissue penetration could be altered in microgravity. However, the differences were not statistically significant, probably due to the small number of subjects in our study. Nonetheless, it is not unreasonable to expect such an outcome during space flight. In space, tissue perfusion is not favored because of the lack of the mechanical pressure over the tissues and organs caused by gravity37 and the decrease in the volume of plasma.38-40 Conditions that cause impaired tissue perfusion have been shown to affect the target site concentrations of antibiotics.36
The clinical relevance of these differences still needs to be evaluated. Larger studies, and studies during real space flights, need to be performed to confirm the results observed in our study. In addition, antibiotic therapy in space is very complex, and dosing decisions cannot be made based on PK alone. The pharmacodynamics of the drug in space also needs to be studied. During space flight, bacteria are exposed to microgravity as well and may exhibit physiological changes that significantly compromise the ability of the drug to kill the bacteria41-44 or significantly increase their virulence.45
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CONCLUSIONS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Results of this work were presented in part during the 33rd annual meeting of the American College of Clinical Pharmacology, Phoenix, Arizona, October 3-5, 2004; the 44th International Conference of Antimicrobial Chemotherapy, Washington, DC, October 29-November 2, 2004; and the 2004 annual meeting and exposition of the American Association of Pharmaceutical Scientists, Baltimore, Maryland, November 6-11, 2004.
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REFERENCES |
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) and sµG (
). Points represent the means of 6 subjects. Vertical bars represent the standard deviation of the means.
