HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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 (21) Citing Articles via Google Scholar Google Scholar Articles by Courtney, R. Articles by Swan, S. Search for Related Content PubMed PubMed Citation Articles by Courtney, R. Articles by Swan, S. Social Bookmarking                   What's this?

Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease

From Schering-Plough Research Institute, Kenilworth, New Jersey (Dr Courtney, Dr Sansone, Dr Statkevich, Ms Martinho, Dr Laughlin); New Orleans Center for Clinical Research, New Orleans, Louisiana (Dr Smith); Orlando Clinical Research Center, Orlando, Florida (Dr Marbury); and Hennepin County Medical Center and DaVita Clinical Research, Minneapolis, Minnesota (Dr Swan).

Address for reprints: Angela Sansone, PharmD, Schering-Plough Research Institute, K-15-4-4465, 2015 Galloping Hill Road, Kenilworth, NJ 07033.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL_CR = 50-80 mL/min), moderate (CL_CR = 20-49 mL/min), and severe chronic renal disease (CL_CR <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C_max, CL/F, and t_1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Key Words: Posaconazole • fungal infections • drug safety • pharmacokinetics • drug tolerability

Immunocompromised patients susceptible to fungal infections, such as recipients of solid organ transplants,^8-10 neutropenic oncology patients,^11,12 and HIV/AIDS patients,¹³ may require prophylactic or therapeutic antifungal treatment. Many of these patients may also have underlying chronic renal disease that could potentially influence the pharmacokinetics of the administered antifungal agent. Treatment options available to these patients are limited because the most widely used antifungal drug, amphotericin B, is nephrotoxic.¹⁴ Thus, there is a need for an antifungal agent with activity against a wide range of fungal pathogens and pharmacokinetics that is not significantly influenced by underlying chronic renal disease.

This study was conducted to compare the pharmacokinetics, safety, and tolerability of a single oral dose of posaconazole in healthy volunteers and in subjects who had varying degrees of chronic renal disease. Unlike other azole antifungal drugs,^15,16 posaconazole has no major circulating metabolites, and renal excretion is not the primary route of elimination. In a recent study that evaluated the absorption, metabolism, and excretion of posaconazole in healthy subjects, most (77%) of the administered posaconazole dose was eliminated as parent compound in the feces, with renal excretion (as multiple glucuronidated metabolites) accounting for 14% of the eliminated dose.¹⁷ In light of these findings, it was not expected that chronic renal disease would significantly affect the pharmacokinetics of posaconazole.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Study Populations
Men and women, aged 18 to 75 years inclusive, with normal renal function or varying degrees of chronic renal disease and weighing between 50 and 115 kg, were eligible for study participation. All subjects had to be free of any clinically significant disease or condition that would interfere with the study evaluations or procedures. Subjects were excluded from study participation if they required concurrent medications known to interact with azoles or had clinically significant local or systemic infection within 4 weeks before treatment administration. No medications (investigational, prescription, or over-the-counter medications, except acetaminophen within 72 hours) were to be taken by the healthy subjects; however, subjects with chronic renal disease were maintained on their established medications. Alcohol consumption was prohibited within 72 hours before posaconazole administration.

In accordance with the Declaration of Helsinki, written informed consent was obtained from all subjects before any study-related activities.

Study Design and Treatment Regimens
Twenty-four subjects (6 per group) were enrolled in this open-label, parallel-group, single-dose study conducted to evaluate the pharmacokinetics of posaconazole in patients with varying degrees of chronic renal disease. Creatinine clearance (CL_CR) values, as determined by a 24-hour urine collection at screening, were used to stratify subjects into 1 of 4 groups: group 1 (normal renal function; CL_CR >80 mL/min per 1.73 m² body surface area [BSA]), group 2 (mild renal disease; CL_cr 50-80 mL/min per 1.73 m² BSA), group 3 (moderate renal disease; CL_CR 20-49 mL/min per 1.73 m² BSA), and group 4 (severe renal disease and receiving outpatient hemodialysis treatment; CL_CR <20 mL/min per 1.73 m² BSA). Where possible, subjects were age, weight, and race matched between groups.

Following an overnight fast on the morning of day 1, subjects were administered a single 400-mg dose of posaconazole oral suspension (40 mg/mL) with a standardized high-fat breakfast. Hemodialysis-dependent subjects underwent 2 phases of dosing (interdialysis dosing and dialysis dosing) with a single 400-mg dose of posaconazole administered in each phase. Specifically, these subjects received the first dose between a dialysis session and the second dose on a dialysis day (6 hours before hemodialysis) after an approximately 3-week washout period.

Sample Collection for Pharmacokinetic Analysis
Venous blood samples (6 mL) were collected into heparinized tubes before dose (0 hours) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48, 72, 96, and 120 hours after dose from the subjects in groups 1 to 3. Venous blood samples from subjects in group 4 were collected at the above-mentioned times on the interdialysis day only (period 1). If a subject underwent dialysis before collection of the 96- and 120-hour blood samples, these samples were not collected.

During the hemodialysis phase, in which subjects were dosed 6 hours before hemodialysis (period 2), postdialyzer blood samples were collected immediately before the second 400-mg dose (before dose, 0 hours) and at 1, 2, 3, 4, 5, and 6 hours after dose. Thereafter, predialyzer (arterial) and postdialyzer (venous) blood samples were collected at the start of the hemodialysissession; at 6.5, 7, 8, and 9 hours after dose; and at the end of hemodialysis. Additional postdialyzer blood samples were collected after completion of hemodialysis at 10, 12, 24, 48, 72, 96, and 120 hours after dose.

Venous plasma samples collected at the time of the maximum plasma concentration (t_max) and at 24 hours after dose were also used to determine plasma protein binding of posaconazole. In addition, for subjects in group 4, protein binding was determined after both the first and second doses of posaconazole (before and during hemodialysis).

Total urine output was collected in 6- or 12-hour blocks from all subjects, where possible, up to 72 hours after dosing (group 4; first dose only).

Posaconazole Concentration Determinations
Posaconazole concentrations in plasma and urine were determined using liquid chromatography with tandem mass spectrometric detection (LC/MS/MS), as previously described.¹⁷ The plasma and urine assays had lower limits of quantification (LLOQs) of 1.00 ng/mL and 35.0 ng/mL, respectively. These assays had linear ranges of 1.0 to 4000 ng/mL and 35.0 to 1400 ng/mL, respectively. Plasma LC/MS/MS interassay precision (percent coefficient of variation [CV]) and interassay accuracy (percent bias) values were in the ranges of 7.1 to 15.7 and –7.6 to –0.50, respectively. Urine LC/MS/MS interassay precision and interassay accuracy values were in the ranges of 5.7 to 7.6 and 1.4 to 7.0, respectively.

Plasma ultrafiltrate was collected using an ultrafiltration technique (Centrifree micropartition device; Millipore, Billerica, Mass), and the concentrations of posaconazole in the ultrafiltrate were determined using an LC/MS/MS method with an LLOQ of 0.250 ng/mL and a linear range of 0.250 to 250 ng/mL. Interassay precision and interassay accuracy values for the ultrafiltrate LC/MS/MS assay were in the ranges of 3.7 to 14.5 and –4.4 to 3.1, respectively.

Pharmacokinetic Analysis
Primary pharmacokinetic parameters were determined using model-independent methods.¹⁸ Maximum plasma concentrations (C_max), t_max, and the time of the final quantifiable sample (tf) were the observed values. Terminal phase rate constant (k) was calculated as the negative of the slope of the log-linear terminal portion of the plasma concentration-time curve using linear regression. Terminal phase half-life (t_1/2) was calculated as ln(2)/k. Area under the plasma concentration-time curve (AUC) from time 0 to the time of the final quantifiablesample(AUC_tf) and to 72 hours after dose (AUC_0-72h) was calculated using the trapezoidal method. AUC_tf was extrapolated to infinity using the following equation:

where Cest_tf is the estimated concentration at tf. Total body clearance (CL/F) was calculated as the ratio of dose to AUC. Apparent volume of distribution (Vd/F) was expressed as the ratio of CL/F to k. Renal clearance values could not accurately be determined because the urine concentrations of posaconazole were below the LLOQ in most samples.

Statistical Analyses
Linear regression analysis was used to determine the relationship between CL_CR and the AUC, C_max, t_1/2, and CL/F values of posaconazole. Log-transformed data were used for the AUC and C_max values and the original scale for the t_1/2 and CL/F values. A linear model was used to fit the data, and the intercept, slope, and r² (total variation explained by the model) were determined. Residual plots were used to review the deviation from the linear model. The overall significance of the obtained model was tested using an F test, which was equivalent to testing the slope against zero.

Safety Evaluations
Safety evaluations, physical examinations, vital signs, electrocardiograms (ECGs), and clinical laboratory tests were conducted at screening, before dosing, at frequent intervals after drug administration, and at the conclusion of the study. The study investigators assessed adverse effects for severity and determined the relationship of the adverse effect to the study drug.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Subject Demographics
Twenty-four subjects (17 men and 7 women) enrolled in and completed the study (Table I). Most (71%) subjects were men, and the mean age was 52 years. An attempt was made to match demographic variables such as age, gender, and ethnicity in each of the 4 groups; however, these characteristics were not evenly distributed (Table I). Because posaconazole pharmacokinetics is not significantly influenced by age, gender, or ethnicity,^19,20 it is unlikely that differences in these demographic factors among the 4 groups confounded the interpretation of the study results.

Pharmacokinetic Findings
Chronic renal disease had no clinically significant effect on the pharmacokinetics of posaconazole. Mean posaconazole plasma concentration-time profiles were similar among subjects with normal renal function and those with varying degrees of chronic renal disease (Figure 1).

View larger version (14K): [in this window] [in a new window]   Figure 1. Mean posaconazole plasma concentration-time profiles following administration of a single oral dose of 400 mg posaconazole to subjects with normal renal function and varying degrees of chronic renal disease.

Healthy subjects and subjects with mild to moderate chronic renal disease (groups 1-3). There was no correlation between the pharmacokinetics of posaconazole and mild to moderate chronic renal disease (groups 13; Table II); the slopes of the linear regressions of CL_CR compared with posaconazole AUC, C_max, CL/F, and t_1/2 values were not significantly different from zero (P > .130). Posaconazole was orally bioavailable in all 3 groups after administration of a single 400-mg dose of posaconazole oral suspension. However, the t_max values increased slightly with the severity of renal disease, with a median t_max value of 5.5 hours in healthy subjects (range, 5-8 hours) and 8.0 hours in subjects with moderate renal disease (range, 5-12 hours) (Table II). In all 3 groups, posaconazole was slowly eliminated (t_1/2 range, 24.1-29.6 hours) and was widely distributed to the tissues (apparent Vd/F range, 834-1073 L). Most urine concentrations of posaconazole were below the LLOQ of the assay; therefore, renal clearance of posaconazole was negligible compared to total body clearance (24.4-26.2 mL/min) and represented a minor elimination pathway (Table II). Plasma posaconazole concentrations in groups 1 through 3 exhibited low to moderate intersubject variability, with the CV for the mean AUC values ranging from 27% to 42%.

Hemodialysis-dependent subjects (group 4).During the hemodialysis phase, predialyzed and postdialyzed posaconazole plasma AUC_tf values differed by only 3%, indicating that posaconazole was not removed by hemodialysis (Table III). However, mean posaconazole C_max and AUC_tf values during the interdialysis days (period 1) were slightly higher than those during the hemodialysis phase (period 2). This small difference might have been caused by the disparity in tf values between periods (68 hours and 76 hours, respectively) because the mean posaconazole postdialyzer AUC values between period 1 (14 751 ng·h/mL) and period 2 (14 656 ng·h/mL) were comparable. The exposure of posaconazole (AUC, C_max, and CL/F) in group 4 was highly variable (>81% CV; eg, AUC_tf values ranged from 2004-49 438 ng·h/mL) compared with the exposure in healthy volunteers and in subjects with mild or moderate chronic renal disease. The reason for the high variability in pharmacokinetic parameters among subjects with severe renal disease is unknown but could be related to the larger number of concomitant medications in these subjects. Thus, taking this variability in plasma concentrations between subjects into account, there was no clinically significant difference in posaconazole exposure between the interdialysis and the hemodialysis periods.

Linear regression of the CL_CR values between subjects with severe chronic renal disease and the other renal function groups could not be performed because subjects in group 4 had anuria or were unable to attain stable serum CL_CR values or because their hemodialysis sessions were intermittent.

The protein binding of posaconazole was not affected by varying degrees of chronic renal disease. In subjects with normal renal function and in those with mild or moderate chronic renal disease, mean protein-binding values for posaconazole were 98.5%, 98.6%, and 98.5%, respectively. In patients with severe chronic renal disease, mean protein-binding values for posaconazole before and after hemodialysis were 98.4% and 98.2%, respectively.

Safety and Tolerability
Subjects with normal renal function did not report any adverse effects. Thirteen of the 18 remaining subjects—3 with mild renal disease, 5 with moderate renal disease, and 5 with severe renal disease—reported at least 1 treatment-emergent adverse effect. Only 2 adverse effects (somnolence and diarrhea), which were reported by 2 subjects with moderate renal disease, were considered treatment-related. No clinically significant ECG findings were observed in any of the subjects. Five subjects with chronic renal disease had mild to moderate elevations in their liver function test (LFT) results. Four of the 5 subjects had LFT abnormalities at baseline; therefore, the elevated LFTs observed in these subjects were considered unlikely to be related to posaconazole treatment. A fifth subject, who was in group 4, had grade 2 elevations in aspartate aminotransferase (AST) levels and grade 1 elevations in alanine aminotransferase (ALT) levels 5 days after the second posaconazole dose (hemodialysis phase). Twelve days after the last dose of posaconazole, follow-up laboratory tests indicated that AST levels had returned to normal but that ALT levels remained elevated. Because LFT results were normal at baseline in this subject, a relationship to posaconazole administration could not be excluded, even though the elevations occurred 5 days after administration of a single dose of posaconazole. No clinically significant changes in outcomes of other clinical laboratory tests (hematology, chemistry, urinalysis) were noted other than those associated with chronic renal disease (ie, elevated blood urea nitrogen and creatinine).

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Fungal infection is an increasingly prevalent complication of immunosuppression. As a consequence of previous amphotericin B administration, immunosuppressive drug regimens, or underlying disease, immunocompromised patients may have significant renal disease that could limit the choice of appropriate agents for the treatment of their invasive fungal infections. Thus, there is a need for efficacious, safe, and well-tolerated broad-spectrum antifungal agents that do not require dose modifications in patients with chronic renal disease.

Exposure to posaconazole after administration of a single 400-mg dose in all renal function groups was similar to that observed in a previous study of healthy volunteers.²¹ In addition, posaconazole had a large apparent volume of distribution and was slowly eliminated, suggesting extensive and prolonged exposure of the drug in the tissues. After the administration of increasing single and multiple doses to healthy subjects, posaconazole exhibited dose-proportional pharmacokinetics up to 800 mg/d.²¹ Based on this observation, a single-dose study design was chosen to evaluate the effect of chronic renal disease on posaconazole pharmacokinetics because the multiple-dose results may be extrapolated from the single-dose data.

The pharmacokinetics of posaconazole was not significantly altered in subjects with mild (CL_CR = 80-50 mL/min) or moderate (CL_CR = 20-49 mL/min) chronic renal disease compared with healthy volunteers. There was no correlation between individual subject CL_CR values and the exposure and elimination of posaconazole. Thus, dosage adjustments for patients with varying degrees of chronic renal disease are not required. This result was anticipated based on a previous clinical study in which ¹⁴C-labeled posaconazole was administered to healthy volunteers with normal renal function.¹⁷ Results from the radiolabeled study indicated that renal excretion is a minor route of elimination for posaconazole. In addition, metabolite profiling indicated that posaconazole was primarily eliminated as parent compound in the feces with minor amounts of glucuronidated metabolites excreted in the urine (<14% of the administered dose).¹⁷

Wide variability existed in some pharmacokinetic parameters of posaconazole among the hemodialysis-dependent subjects (group 4) for reasons that could not be entirely explained. Mean AUC_tf values might have been underestimated compared with those of subjects with normal renal function (group 1). One hemodialysis-dependent subject had plasma concentrations only up to 48 hours, and the remaining 5 subjects had plasma concentrations up to 72 hours after dose (the last time point sampled). In contrast, all 6 subjects in group 1 had plasma concentrations up to 120 hours. Subjects in group 4 were also taking a number of concomitant medications. Coadministering drugs that modify uridine 5'-diphosphate-glucuronosyltransferase activity may affect posaconazole pharmacokinetics to a limited extent and, therefore, might have contributed to the variability in pharmacokinetic parameters observed in this group. Because posaconazole is not significantly eliminated through the kidneys, no effect of severe renal disease on the pharmacokinetics of posaconazole is expected in the clinic, and no dose adjustment is recommended.

Results of this study also demonstrated that posaconazole was not removed by hemodialysis. This is evidenced by the fact that posaconazole concentrations before and after dialysis were essentially identical, and the mean CL/F values before and during hemodialysis were similar (84.9 L/h and 98.3 L/h, respectively). This result was expected because posaconazole is highly protein bound in the plasma (98%), has a large apparent volume of distribution, and is unlikely to be removed by hemodialysis. Thus, results from this study suggest that hemodialysis cannot be used to remove posaconazole from the systemic circulation if an overdose occurs.

Some currently marketed antifungal agents require dosage adjustments in patients with chronic renal disease. Approximately 80% of a fluconazole dose is eliminated as parent drug in the urine.²² Consequently, reduced renal function markedly affects fluconazole pharmacokinetics, necessitating a dose reduction of 50% in patients with CL_CR values 50 mL/min.²² In contrast to posaconazole concentrations, plasma fluconazole concentrations are decreased by approximately 50% after a 3-hour hemodialysis session, necessitating the administration of a full dose of fluconazole on completion of the dialysis session.²² Chronic renal disease does not affect the pharmacokinetics of orally administered voriconazole. However, the intravenous formulation of voriconazole should not be administered to patients with moderate renal disease (CL_CR 20-49 mL/min)^15,23,24 because of the significant accumulation of the vehicle sulfobutylether-cyclodextrin,²³ which has been associated with histopathologic changes in animal kidneys and bladders.^23,25

In this evaluation of posaconazole in subjects with varying degrees of chronic renal disease, a single 400-mg oral dose was safe and well tolerated. The incidence of adverse effects was low. Most adverse effects were considered unrelated to posaconazole treatment and were consistent with the underlying renal disease. Although 5 subjects with chronic renal disease had mild to moderate elevations in their LFT results, 4 had abnormal LFTs at baseline, which suggests that posaconazole was not responsible. The fifth patient had normal LFTs at baseline; however, 5 days after the second dose (hemodialysis dose), both AST and ALT were elevated. Follow-up tests nearly 2 weeks after the last dose of posaconazole showed that AST had normalized, but ALT remained elevated. Because the subject had normal LFTs at baseline, it is not possible to exclude the contribution of posaconazole to these elevations.

In conclusion, the results of this single-dose study demonstrate that chronic renal disease had no clinically relevant effect on the pharmacokinetics of posaconazole. Posaconazole was generally well tolerated. One subject had elevated LFTs that may have been related to posaconazole administration, but further study in larger populations is warranted to establish the true safety and tolerability profile of posaconazole. Chronic renal disease, the severity of the disease, or hemodialysis did not affect the protein binding of posaconazole. Therefore, dose adjustments for patients with varying degrees of chronic renal disease are not required. Posaconazole is expected to provide a favorable alternative to other available antifungal agents that require dose modifications for chronic renal disease.

	FOOTNOTES

 
DOI: 10.1177/0091270004271402

Submitted for publication April 16, 2004; Revised version accepted September 23, 2004.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 

1. Manavathu EK, Cutright JL, Loebenberg D, Chandrasekar PH. A comparative study of the in vitro susceptibilities of clinical and laboratory-selected resistant isolates of Aspergillus spp. to amphotericin B, itraconazole, voriconazole and posaconazole (SCH 56592). J Antimicrob Chemother. 2000;46: 229-234.[Abstract/Free Full Text]

2. Pfaller MA, Messer SA, Hollis RJ, Jones RN. In vitro activities of posaconazole (Sch 56592) compared with those of itraconazole and fluconazole against 3,685 clinical isolates of Candida spp. and Cryptococcus neoformans. Antimicrob Agents Chemother. 2001;45: 2862-2864.[Abstract/Free Full Text]

3. Pfaller MA, Messer SA, Hollis RJ, Jones RN. Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus spp. and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother. 2002;46: 1032-1037.[Abstract/Free Full Text]

4. Sun QN, Fothergill AW, McCarthy DI, Rinaldi MG, Graybill JR. In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother. 2002;46: 1581-1582.[Abstract/Free Full Text]

5. Hachem RY, Raad II, Afif CM, et al. An open, non-comparative multicenter study to evaluate efficacy and safety of posaconazole (SCH 56592) in the treatment of invasive fungal infections (IFI) refractory (R) to or intolerant (I) to standard therapy (ST) [abstract]. Paper presented at: 40th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2000; Toronto, Ontario, Canada.

6. Ullmann AJ, Cornely OA, Burchardt A, et al. Safety and efficacy of posaconazole (POS) in a pharmacokinetic study in patients with febrile neutropenia (FN) or refractory invasive fungal infections (rIFI). Poster presented at: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 14-17, 2003; Chicago.

7. Walsh T, Patterson T, Langston A, et al. Posaconazole for treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional therapy: an externally controlled blinded trial [abstract]. Blood. 2003;102: 195-196.

8. Paya CV. Prevention of fungal and hepatitis virus infections in liver transplantation. Clin Infect Dis. 2001;33(suppl 1): S47-S52.

9. Altiparmak MR, Apaydin S, Trablus S, et al. Systemic fungal infections after renal transplantation. Scand J Infect Dis. 2002;34: 284-288.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis. 1993;16: 677-688.[Web of Science][Medline] [Order article via Infotrieve]

11. Wingard JR, Leather HL. Empiric antifungal therapy for the neutropenic patient. Oncology (Huntingt). 2001;15: 351-363.

12. Wingard JR. Infections due to resistant Candida species in patients with cancer who are receiving chemotherapy. Clin Infect Dis. 1994;9(suppl 1): S49-S53.

13. Marty F, Mylonakis E. Antifungal use in HIV infection. Expert Opin Pharmacother. 2002;3: 91-102.[CrossRef][Medline] [Order article via Infotrieve]

14. Deray G. Amphotericin B nephrotoxicity. J Antimicrob Chemother. 2002;49(suppl 1): 37-41.[Abstract]

15. VFEND IV (voriconazole) prescribing information. New York: Pfizer; 2003.

16. Sporanox (intraconazole) prescribing information. Beerse, Belgium: Janssen Pharmaceutica NV; 2002.

17. Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother. 2004;48: 3543-3551.[Abstract/Free Full Text]

18. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982.

19. Courtney R, Sansone A, Kantesaria B, Soni PN, Laughlin M. Effect of ethnicity on the pharmacokinetics of posaconazole in healthy volunteers. Paper presented at: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 14-17, 2003; Chicago.

20. Courtney R, Sansone A, Statkevich P, Martinho M, Zhang M, Laughlin M. Effect of age and gender on the pharmacokinetics of posaconazole in healthy volunteers. Poster presented at: 43rd Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 14-17, 2003; Chicago.

21. Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother. 2003;47: 2788-2795.[Abstract/Free Full Text]

22. Diflucan (fluconazole) prescribing information. New York: Pfizer; 2001.

23. Hoffman HL, Rathbun RC. Review of the safety and efficacy of voriconazole. Expert Opin Investig Drugs. 2002;11: 409-429.[CrossRef][Medline] [Order article via Infotrieve]

24. Ullmann AJ. Review of the safety, tolerability, and drug interactions of the new antifungal agents caspofungin and voriconazole. Curr Med Res Opin. 2003;19: 263-271.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

25. Food and Drug Administration. Background document for the antiviral drug products advisory committee meeting, voriconazole tablets and injection, Pfizer Global Research and Development, NDAs 21-266 and 21-267. Rockville, Md: Food and Drug Administration; 2001: 1-56.
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. I. Morris Posaconazole: A new oral antifungal agent with an expanded spectrum of activity Am. J. Health Syst. Pharm., February 1, 2009; 66(3): 225 - 236. [Abstract] [Full Text] [PDF]

				J. E. Conte Jr., J. A. Golden, G. Krishna, M. McIver, E. Little, and E. Zurlinden Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects Antimicrob. Agents Chemother., February 1, 2009; 53(2): 703 - 707. [Abstract] [Full Text] [PDF]

				R. Y. Hachem, A. A. Langston, J. R. Graybill, J. R. Perfect, L. D. Pedicone, H. Patino, and I. I. Raad Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment J. Antimicrob. Chemother., December 1, 2008; 62(6): 1386 - 1391. [Abstract] [Full Text] [PDF]

				E. J Rachwalski, J. T Wieczorkiewicz, and M. H Scheetz Posaconazole: An Oral Triazole with an Extended Spectrum of Activity Ann. Pharmacother., October 1, 2008; 42(10): 1429 - 1438. [Abstract] [Full Text] [PDF]

				A. Sansone-Parsons, G. Krishna, J. Simon, P. Soni, B. Kantesaria, J. Herron, and R. Stoltz Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers Antimicrob. Agents Chemother., February 1, 2007; 51(2): 495 - 502. [Abstract] [Full Text] [PDF]

				J. Meletiadis, S. Chanock, and T. J. Walsh Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy Clin. Microbiol. Rev., October 1, 2006; 19(4): 763 - 787. [Abstract] [Full Text] [PDF]

				A. Sansone-Parsons, G. Krishna, A. Calzetta, D. Wexler, B. Kantesaria, M. A. Rosenberg, and M. A. Saltzman Effect of a Nutritional Supplement on Posaconazole Pharmacokinetics following Oral Administration to Healthy Volunteers. Antimicrob. Agents Chemother., May 1, 2006; 50(5): 1881 - 1883. [Abstract] [Full Text] [PDF]

				A. J. Ullmann, O. A. Cornely, A. Burchardt, R. Hachem, D. P. Kontoyiannis, K. Topelt, R. Courtney, D. Wexler, G. Krishna, M. Martinho, et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob. Agents Chemother., February 1, 2006; 50(2): 658 - 666. [Abstract] [Full Text] [PDF]

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 (21) Citing Articles via Google Scholar Google Scholar Articles by Courtney, R. Articles by Swan, S. Search for Related Content PubMed PubMed Citation Articles by Courtney, R. Articles by Swan, S. Social Bookmarking                   What's this?