1 Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, CRTC-1-575, Bethesda, MD 20892, USA; 2 Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany; 3 Surgery Service, Veterinary Resources Program, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
Received 17 March 2005; returned 3 June 2005; revised 14 July 2005; accepted 24 July 2005
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Abstract |
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Methods: Normal catheterized rabbits received the prodrug at 1.25, 2.5, 5, 10, 20 and 40 mg/kg once daily as 5 min iv bolus for 8 days. Serial plasma levels were collected at days 1 and 7, and tissues were obtained 30 min after the eighth dose. Concentrations of ravuconazole were determined by a validated HPLC method. Plasma concentration data were fitted to a three-compartment pharmacokinetic model. Pharmacokinetic parameters were estimated by weighted non-linear least squares regression analysis using the WinNonlin computer program.
Results: Following single dosing, ravuconazole demonstrated linear plasma pharmacokinetics across the investigated dosage range. Cmax, AUC0, Vss, CL and terminal half-life (means ± SEM) ranged from 2.03 to 58.82 mg/L, 5.80 to 234.21 mg · h/L, 5.16 to 6.43 L/kg, 0.25 to 0.18 L/h/kg and 20.55 to 26.34 h, respectively. Plasma data after multiple dosing revealed non-linear disposition at the 20 and 40 mg/kg dosage levels as evidenced by a dose-dependent decrease in CL (from 0.1040.147 to 0.030 and 0.022 L/h/kg; P = 0.1053) and an increase in the dose-normalized AUC0
(from 2.403.01 up to 11.90 and 14.56 mg · h/L; P = 0.0382). Tissue concentrations 30 min after the last dose were highest in the liver (12.91562.68 µg/g), adipose tissue (10.57938.55 µg/g), lung (5.46219.12 µg/g), kidney (3.95252.44 µg/g) and brain tissue (2.37144.85 µg/g).
Conclusions: The pharmacokinetics of ravuconazole fitted best to a three-compartment pharmacokinetic model. The compound revealed non-linear pharmacokinetics at higher dosages, indicating saturable clearance and/or protein binding. Ravuconazole displayed a long elimination half-life and achieved substantial plasma and tissue concentrations including in the brain.
Keywords: mycoses , chemotherapy , drug development
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Introduction |
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The availability of an intravenous (iv) formulation is critical for treatment of fungal infections in severely ill immunocompromised patients. Ravuconazole di-lysine phosphoester (BMS-379224) confers solubility in aqueous solution and appears to be well-tolerated.1921 In contrast to the cyclodextrins used as the vehicle for the parenteral formulations of itraconazole and voriconazole,22 the lysine and phosphate residues are readily cleared and will not accumulate in the state of renal insufficiency. Little is known, however, about the disposition of ravuconazole following administration of this novel iv prodrug. The purpose of this study was therefore to characterize the compartmental plasma pharmacokinetics and tissue distribution of ravuconazole after administration of ravuconazole di-lysine phosphoester over a large dosage range in healthy laboratory animals.
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Materials and methods |
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Study drug
Ravuconazole di-lysine phosphoester (BMS-379224), the iv prodrug of ravuconazole (BMS-207147; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA),19 was dissolved in sterile 5% dextrose (D5W) to produce a 150 mg/mL stock solution that was maintained at +4°C. Prior to use, the drug was freshly diluted with sterile D5W as appropriate. Ravuconazole was administered at ambient temperature in a total volume of 5 mL as a slow iv bolus over 5 min through the indwelling central silastic venous catheter.
Animals
Healthy female New Zealand White rabbits (Hazleton, Denver, PA, USA) weighing 2.83.2 kg were used in all experiments. All animals were individually housed and maintained with water and standard rabbit feed ad libitum according to National Institutes of Health Guidelines for Laboratory Animal Care and in fulfilment of the guidelines of the National Research Council.23 Vascular access was established in each rabbit 72 h prior to experimentation by the surgical placement of a subcutaneous silastic central venous catheter as described previously.24
Single-dose plasma pharmacokinetics
Six groups of three animals each were studied. Animals received ravuconazole at 1.25, 2.5, 5, 10, 20 or 40 mg/kg of body weight as a steady iv bolus over 5 min. Plasma samples (2.0 mL of blood) were drawn immediately before administration, immediately following administration (Cmax), and then at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 16, 24, 30, 48, 54 and 72 h after the start of the iv bolus.
Multiple-dose plasma pharmacokinetics
After completion of the single-dose washout (72 h, day 4), the identical six groups of three animals each continued to receive ravuconazole at either 1.25, 2.5, 5, 10, 20 or 40 mg/kg of body weight once daily as a steady iv bolus over 5 min for another 7 days. On day 6, plasma samples (2.0 mL of blood) were drawn immediately before administration, immediately after administration (Cmax), and then at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 16 and 24 h after the start of the iv bolus.
Tissue distribution studies
For the assessment of tissue concentrations of ravuconazole achieved near peak concentrations in plasma after multiple dosing, animals received one more dose of the assigned regimen on day 7. All animals were euthanized 30 min after dosing by iv pentobarbital and the following tissues were obtained at autopsy for analysis of drug concentrations: brain tissue, cerebrospinal fluid (CSF), choroid, vitreous humour, aqueous humour, lung, liver, spleen, kidney, bone marrow, perirenal adipose tissue and psoas muscle.
Assessment of tolerance
All animals were evaluated clinically each day. Biochemical parameters of hepatic and renal toxicities were monitored in plasma samples obtained on the last day of the experiment. Values were compared with reference values established in healthy rabbits naive to prior drug exposure.
Processing of samples and analytical assay
Processing of blood and tissues
Blood samples were collected in heparinized syringes, and plasma was separated by centrifugation. All plasma, body fluid and tissue samples were stored at 80°C until assay.
Ravuconazole was extracted from heparinized plasma and other body fluids after protein precipitation with acetonitrile (1:2 v/v; 1:2 w/w for bone marrow) and centrifugation at 2000g for 10 min prior to injection. Tissue specimens were thoroughly rinsed with phosphate-buffered saline and blotted to dryness with Micro Wipes® (Scott Paper Company, Philadelphia, PA, USA). Specimens were then weighed and homogenized for two times 30 s each with ice-cold methanol (1:4 w/w) using a tissue homogenizer (Tissumizer; Tekmar, Cincinnati, OH, USA) with a 10 N head and placement of the sample in an ice bucket. The homogenates were incubated for 30 min at 4°C and centrifuged at 2000g for 10 min for injection. Standards and quality control samples were similarly prepared by adding known amounts of parent ravuconazole prepared in ethanol to either normal rabbit plasma (for serum, choroid and bone marrow; Gibco Laboratories, Grand Islands, NY, USA), commercially available CSF standards (Instrumentation Laboratories, Lexington, MA, USA), Hanks' balanced salt solution (for vitreous and aqueous humour; Mediatech, Herndon, VA, USA) or normal rabbit tissue homogenates. Blank samples of all matrices also were extracted to ensure the absence of interfering peaks.
Analytical assay
Concentrations of ravuconazole were determined using reversed phase HPLC. The mobile phase consisted of acetonitrile/deionized water (58:42 v/v), delivered at 1.2 mL/min. Samples were maintained in the autosampler at room temperature in glass vials. The injection volume was 125 µL. Ravuconazole eluted at 10 min, using a C-18 YMC ODS-AQ analytical column (150 x 4.6 mm ID, 5 µm particle size; YMC Inc., Wilmington, NC, USA) maintained at room temperature and ultraviolet detection at 284 nm.
Quantification was based on the peak height and the non-weighted concentration response of the external calibration standard BMS-207147 (Bristol-Myers Squibb Pharmaceutical Research Institute). Ten- to 13-point standard curves (range of concentrations, 0.052.5 and 0.0580 mg/L for plasma; 0.052.5 mg/L for other body fluids; and 0.05 to up to 80 mg/L for tissues) were linear with r2 values >0.980. Samples containing concentrations exceeding the upper limit of the high-range standard curves (0.0580 mg/L) were assayed after dilution with mobile phase and determination of over-curve concentration-response linearity. The lower limit of quantification (LLQ) was 0.05 mg/L in plasma and body fluids and 0.25 µg/g in tissues. Accuracies in plasma were within ±0.8 to 10.8, and intra- and inter-day variability ranged from 0.35 to 8.9% (tissues and non-plasma body fluids: within ±12% and <10%, respectively).
Pharmacokinetic data analysis
Pharmacokinetic modelling
Pharmacokinetic parameters for ravuconazole were determined using compartmental analysis. Experimental plasma concentration-versus-time profiles were fitted to a three-compartment open model with iv bolus input and linear first-order elimination from the central compartment using iterative weighted non-linear least squares regression with the WinNonlin computer program (Scientific Consultants, Lexington, KY, USA). Model selection was guided by visual inspection of the observed plasma profiles and Akaike's information criterion.25 The model fit the data well with r2 values for the individual fits ranging from 0.992 to 1.000 (mean 0.999). The regression lines through the plot of observed versus estimated concentrations did not differ from the line of identity, and no bias was observed. Cmax values were determined as model-estimated concentrations at 6 min after the start of the iv bolus, and Cmin values as model-estimated concentrations at 24 h post dosing, respectively. AUC0 values were calculated from estimated 24 h plasma concentration profiles using the trapezoidal rule and extrapolation to infinity by standard techniques.26 Dose-linearity after single and after multiple dosing was determined by comparison of the dose-normalized AUC0
across dosage levels by ANOVA and linear regression analysis. Accumulation was assessed for each dosage level by comparing the mean AUC between doses after multiple dosing as an approximation of AUC between doses at steady state with the mean AUC0
after single dosing. Distribution and clearance terms were normalized to body weight to allow for comparison across species.
Statistical analysis
All values are presented as means of three animals each ±SEM. Differences between the means of pharmacokinetic parameters across dosage levels were evaluated by KruskalWallis non-parametric ANOVA. A two-tailed P value of <0.05 was considered to be statistically significant.
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Results |
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The estimated plasma concentration-versus-time profiles of ravuconazole following single-dose administration of the di-lysine phosphoester prodrug are shown in Figure 1, and corresponding mean compartmental pharmacokinetic parameters are listed in Table 1.
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Multiple-dose studies
The estimated plasma concentration-versus-time profiles of ravuconazole following once daily administration of the di-lysine phosphoester prodrug for six continuous days are shown in Figure 2, and the corresponding mean compartmental pharmacokinetic parameters are listed in Table 2.
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Mean tissue concentrations of ravuconazole 30 min following the last of seven consecutive doses were overall highest in the liver (12.91 ± 1.50 to 562.68 ± 33.03 µg/g), followed by adipose tissue (10.57 ± 0.17 to 938.55 ± 33.28 µg/g), marrow (7.34 ± 0.93 to 319.41 ± 23.14 µg/g), kidney (3.95 ± 0.58 to 252.44 ± 41.59 µg/g), lung (5.46 ± 0.27 to 219.12 ± 4.75 µg/g), brain (2.37 ± 0.06 to 144.85 ± 22.61 µg/g), spleen (2.13 ± 0.09 to 130.88 ± 11.12 µg/g), choroid (0.59 ± 0.04 to 76.69 ± 7.38 mg/L) and muscle tissue (0.86 ± 0.02 to 51.26 ± 3.32 µg/g) (Table 3). Concentrations of ravuconazole in CSF, vitreous and aqueous were comparatively lower and exceeded the LLQ of 0.05 mg/L only at dosages exceeding 2.5, 2.5 and 5 mg/kg, respectively. Concentrations in the liver, adipose tissue, marrow, kidney, lung, brain and spleen exceeded concurrent plasma concentrations at the selected sampling time of 30 min post-dosing; whereas concentrations in all other tissues and body fluids were less than or equal to concurrent plasma concentrations.
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Compared with values obtained in drug-naive animals, there was a trend toward increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values (P = 0.1020 and 0.1183, respectively) and decreased potassium (P = 0.0522) and alkaline phosphatase (P = 0.0106) values at the 20 and 40 mg/kg dosage levels after treatment for 7 days (Table 4). Abnormal elevations in the mean blood urea nitrogen, serum creatinine, and bilirubin were not observed in samples determined after 8 days of treatment. Throughout the pharmacokinetic study, no apparent infusion-related toxicities or other clinical or behavioural abnormalities were observed and no abnormal weight changes were noted.
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Discussion |
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Published data on the pharmacokinetics of ravuconazole are limited. After oral administration of 10 mg/kg of ravuconazole to female rats, the mean elimination half-life was 16.9 h; throughout the 72 h wash out, drug concentrations in the lung were four- to 20-fold higher than concurrent plasma concentrations.27 In normal human volunteers, following 14 daily dosages ranging from 50 to 400 mg given as gelatin capsules, ravuconazole exhibited approximately linear pharmacokinetics with mean Cmax values ranging from 1.22 to 6.02 mg/L, mean AUC0 ranging from 24.68 to 119.12 mg · h/L, and the mean half-life ranging from 103 to 240 h. In comparison with the first dose, there was an 8.5- to 10.8-fold accumulation of ravuconazole on day 14.28 Following iv administration, across species, the di-lysine phosphoester prodrug is readily converted to ravuconazole.1921 In rats, dogs and monkeys, there were no principal differences in disposition compared with oral ravuconazole. The mean elimination half-life was in the order of 12, 14 and 7.4 h, respectively, and antifungal efficacy of the prodrug was similar to oral ravuconazole in a murine model of disseminated candidiasis.19,20 In a single-dose pharmacokinetic study in healthy male human volunteers, ravuconazole di-lysine phosphoester was administered as 1 h infusion at escalating dosages ranging from 25 to 600 mg. Ravuconazole exhibited linear pharmacokinetics; mean Cmax values ranged from 0.56 to 12.95 mg/L, mean AUC0
values from 28.60 to 787.6 mg · h/L, and the mean half-life was between 76 and 202 h.21 Overall, with its prolonged elimination half-life and significant accumulation in plasma and tissues, the pharmacokinetics of ravuconazole in the rabbit do not appear to be fundamentally different from those observed in other species. Based on the AUC0
, following single dose administration and the lack of relevant pharmacokinetic differences between non-infected and infected rabbits,14 dosages of 5, 10, 20 and 40 mg/kg of ravuconazole di-lysine phosphoester in the rabbit would approximately correspond to human dosages of 25, 50, 100 and 200 mg of the iv prodrug21 and to 50, 100, 200 and 400 mg of the capsule form, respectively.28
Cognizant of the limitations of drug concentrations in tissue homogenates29,30 and the prevalence of different equilibria during the dosing interval, assessment of tissue concentrations of ravuconazole after multiple once daily dosing for 7 days revealed substantial drug concentrations in lung, liver, spleen, marrow, adipose tissue and skeletal muscle near the completion of the initial distributive phase in plasma. As is characteristic for a lipophilic compound31 with high (>95% in mice and humans) binding to plasma proteins,14 drug concentrations were comparatively low in non-inflamed CSF, aqueous and vitreous fluid, but considerably higher in brain tissue and choroid, suggesting the potential therapeutic usefulness of ravuconazole also in these secluded compartments.
Ravuconazole achieved plasma and tissue concentrations that were several fold in excess of MIC90s of large collections of clinical Candida and Aspergillus isolates.6,7 In plasma, concentrations above these values (1 mg/L for Aspergillus spp. and 0.25 mg/L for Candida spp.) were maintained in a dose-dependent manner for up to 24 h. Similar to fluconazole,32,33 the ratio of free drug AUC024/MIC was the critical pharmacokinetic/pharmacodynamic parameter associated with treatment efficacy in a murine kidney-target model of invasive candidiasis.11 Whether this parameter may also be predictive of the efficacy of ravuconazole against invasive pulmonary aspergillosis remains to be determined. In vitro pharmacodynamic studies of itraconazole and voriconazole have demonstrated time- and concentration-dependent antifungal dynamics of antifungal triazoles against Aspergillus fumigatus.34 In persistently neutropenic rabbits with experimental invasive pulmonary aspergillosis, an AUC024/MIC ratio of 60 and plasma levels exceeding the median MIC of the test isolates for the entire dosing interval were equally associated with effective treatment.14 Nevertheless, formal pharmacodynamic studies comparing single versus split dosing regimens will be needed for a rigorous assessment of the most predictive pharmacokinetic/pharmacodynamic parameter in invasive pulmonary aspergillosis.
In the absence of severe illness, immunosuppression or any concurrent medication, ravuconazole was well tolerated. Laboratory abnormalities consisted of a trend toward mild dose-dependent increases in hepatic transaminases (ALT and AST) and a dose-dependent decrease in serum potassium. These trends appeared to be limited to the highest multiple dosage levels of 20 and 40 mg/kg. Increases in hepatic transaminases and decreases in serum potassium are known class effects of antifungal azoles.22,35 However, preliminary safety data in human subjects indicate no evidence of dose-dependent changes in hepatic transaminases or serum potassium21,28 and a similarly low level of hepatic and electrolyte disturbances when compared with fluconazole.17 The sporadic non-dose-dependent changes in serum alkaline phosphatase are of uncertain significance. These effects are usually not a component of triazole-induced hepatic changes. Effects on bone metabolism through interference with mammalian sterol and vitamin D metabolism may alter serum alkaline phosphatase activity.36,37 However, such changes are usually dosage dependent.
In conclusion, following administration of its iv di-lysine phosphoester prodrug, the pharmacokinetics of ravuconazole in healthy rabbits were best described by a three-compartment pharmacokinetic model. The compound displayed non-linear disposition in plasma at escalating dosages, indicating saturable elimination from the bloodstream and/or saturable protein binding. Ravuconazole achieved and maintained potentially therapeutic total plasma concentrations exceeding MICs of susceptible opportunistic fungi and produced high concentrations in tissues that are common sites of invasive fungal infections. The compound was well tolerated without evidence of clinical or major laboratory toxicity. Interspecies comparison of plasma pharmacokinetics and the dose-effect analysis in persistently neutropenic rabbits with experimental invasive pulmonary aspergillosis may assist in the dosage selection of iv ravuconazole in clinical trials.
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Acknowledgements |
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This work was presented in part at the Forty-second Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, USA, 2002.
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