Itraconazole Pharmacokinetics in Patients with Renal Dysfunction

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 1988, p. 1595-1597

Vol. 32, No. 10

0066-4804/88/101595-03$02.00/0 Copyright © 1988, American Society for Microbiology

Itraconazole Pharmacokinetics in Patients with Renal Dysfunction J. BOELAERT,l* M. SCHURGERS,1 E. MATTHYS,' R. DANEELS,' A. VAN PEER,2 K. DE BEULE,2 R. WOESTENBORGHS,2 AND J. HEYKANTS2

Renal Unit, Algemeen Ziekenhuis St.-Jan, Brugge 8000,1 and Janssen Pharmaceutica, Beerse 2340,2 Belgium Received 17 May 1988/Accepted 22 July 1988

The single-dose pharmacokinetics of 200 mg of oral itraconazole were studied in seven uremic patients, seven patients treated by hemodialysis, and five patients treated by continuous ambulatory peritoneal dialysis. Plasma concentration-versus-time profiles showed wide intersubject variation. This study could not demonstrate any significant effect of renal dysfunction and hemodialysis or continuous ambulatory peritoneal dialysis treatment upon the pharmacokinetics of itraconazole, and firm conclusions concerning dosing in such patients should await confirmation of our data in a larger patient population.

after drug intake. The mean blood flow through the dialyzer (Gambro Lundia R; Gambro, Lund, Sweden) with a surface of 1 m2 was 176 ml/min (range, 145 to 200 ml/min), whereas the dialysate flow was maintained around 500 ml/min (measured values ranging between 487 and 621 ml/min). During hemodialysis, sampling was performed at hourly intervals from blood pre- and postdialyzer and from the effluent dialysate. For CAPD patients, a new peritoneal dialysis cycle was started immediately after itraconazole dosing. For all peritoneal effluent dialysates, the volume was recorded and a sample was frozen at -20°C. Unchanged itraconazole was assayed in plasma and in dialysate by high-performance liquid chromatography (7). The detection limit of the assay was 2 ng/ml. The plasma protein binding of itraconazole was determined in the blank blood samples of the nondialyzed uremic patients by an equilibrium dialysis method (4). Pharmacokinetic analysis was performed by standard methods (1). Differences in itraconazole peak concentration in plasma (Cmax), peak time, and area under the curve (AUC) among patient groups were statistically evaluated by the nonparametric Mann-Whitney U test and by the Wilcoxon test for paired observations on off-dialysis and on-dialysis days. Figure 1 shows the individual itraconazole plasma concentration-versus-time curves up to 24 h for the three groups of individuals studied. The rather high interindividual variability within each group might be compatible with variations in oral absorption and in elimination through hepatic metabolism (3). Table 1 compares values for time to Cmax, Cmax, and AUC from zero to 8 h (AUCO_8) in the three groups of patients. These parameters showed no significant differences between the uremic patients, the hemodialysis patients studied either on or off dialysis, and the CAPD patients. Because in some patients the concentrations of the drug in plasma beyond 8 h were lower than the detection limit of the assay, the AUC, 8 was used for comparison among the th1ee patient groups. The elimination half-life could be calculated only over 72 h in the uremic patients not yet on dialysis and averaged 25.1 + 9.2 h (mean + standard deviation). In these uremic patients, the mean AUC from zero hour to infinity (AUC>OO) was 3,454 + 3,132 ng h/ml. Plasma protein binding of itraconazole in the uremic patients was 99.80% ± 0.04%. When the pharmacokinetics of itraconazole obtained for the uremic patients (mean age, 66 years) were compared with those reported for young healthy volunteers after single 200-mg doses, itraconazole pharmacokinetic parameters were in the same range, with a Cmax of 272 + 81 ng/ml, a time to Cmax of 3.0 ± 0.7 h, an AUCQ,,O of 4,161 ± 1,949 ng. h/ml,

Itraconazole is a triazole antifungal drug. It has a wide antifungal spectrum that includes Aspergillus species. As opposed to ketoconazole, it has only little affinity to the mammalian hepatic cytochromal P-450 enzymes, which should minimize the risk for interaction with other drugs at this level (3, 5, 6). Pharmacokinetics of the drug in human volunteers are characterized by good absorption with oral administration, extensive tissue distribution, biotransformation into a large number of antifungally inactive metabolites, minimal renal excretion of the parent drug, and elimination half-life of about 1 day (3). The purpose of the present study was to examine the single-dose pharmacokinetics of itraconazole in uremic patients and to examine whether hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) influence these pharmacokinetics. A total of 19 subjects were studied, consisting of 7 uremic patients (4 males and 3 females) with a mean age of 66 years (range, 55 to 76 years) and a mean creatinine clearance of 13 ml/min 1.73 m2 (range, 6 to 25 ml/min 1.73 m2), 7 patients with chronic uremia treated by thrice-weekly hemodialysis (6 males and 1 female) with a mean age of 62 years (range, 28 to 78 years), and 5 patients with chronic uremia treated by CAPD (2 males and 3 females) with a mean age of 66 years (range, 62 to 73 years). For the dialysis patients, mean duration on hemodialysis was 3.7 years (range, 0.5 to 6 years) and mean duration on CAPD was 2.4 years (range, 0.5 to 7 years). Exclusions were for heart failure, laboratory signs of liver dysfunction, rifampin treatment, pregnancy, known allergy to azole derivatives, and, in the case of CAPD patients, a recent episode of CAPD peritonitis. The study protocol was approved by the hospital ethical committee, and the subjects gave informed consent. After an overnight fast, all subjects were administered a single 200-mg oral dose of itraconazole immediately after breakfast. The drug was given as four 50-mg polyethylene glycol capsules. Blood was taken at regular intervals up to 72 h after dosing, except from the hemodialysis patients for whom sampling had to be stopped after 24 h to avoid the possible pharmacokinetic interference of the next hemodialysis session. Plasma was frozen at -20°C until assay. Hemodialysis patients were studied twice: on an interdialytic day (off dialysis) and on the day of a 4.5-h hemodialysis (on dialysis). In the latter case, dialysis was started 4.5 h * Corresponding author. 1595

NOTES

1596

ANTIMICROB. AGENTS CHEMOTHER. 600

600

-

C

b 500

-

500

400

-

400

.-co

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C

1-

300

300

200

200

0 0

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0

6

0

12

18

24

12

Time (hours)

18

6

0

24

Time (hours)

Time (hours)

FIG. 1. Itraconazole concentrations in plasma after single oral doses of 200 patients on an off-dialysis day (b), and CAPD patients (c).

and an elimination half-life of 20.7 9.3 h. (2, 3). In these healthy volunteers, the plasma concentration-versus-time profiles also showed wide intersubject variations, so that the high interindividual variability observed in the present uremic population cannot be ascribed only to some of the consequences of renal insufficiency. Binding of itraconazole to plasma proteins, mainly albumin, is 99.8% in normal individuals (3), which is the same value as that obtained in the uremic patients. In the hemodialysis patients, values for Cmax and AUC were lower than in nondialyzed uremic patients, although the difference was not significant. These lower values cannot be ascribed to a dialysis-induced effect upon pharmacokinetics, since they were also observed on an interdialytic day. Figure 2 shows the mean itraconazole plasma concentrationversus-time curves obtained in the same hemodialysis patients, studied both off dialysis and on dialysis. The nearly parallel course of the curves during the hemodialysis period suggests little removal through the dialyzer. This is also indicated by the following data: the AUC>_95 values off dialysis (702 + 559 ng. h/ml) and on dialysis (573 + 409 ng * h/ml) were similar; comparison of the mean itraconazole concentrations in plasma obtained simultaneously pre- and postdialyzer showed 2 to 14% higher values postdialyzer, which can be explained by hemoconcentration during dialysis; and finally, in no instance could itraconazole be detected in the dialysate. This very poor to absent dialyzability of itraconazole is consistent with its high molecular weight of ±

mg to

uremic patients not

on

hemodialysis (a), hemodialysis

705 and with its very extensive plasma protein binding (99.80% 0.04%). The mean Cmax in the CAPD patients was one third of the mnean value in the nondialyzed uremic patients. This is probably related either to a decreased drug absorption or to an increased first-pass effect, the cause of which is unclear. Since itraconazole is not available for intravenous use, no study is possible with an intravenous formulation of the drug, which could have provided some help in understanding these data. It is possible that decreased food intake at breakfast by these patients led to decreased oral bioavaila±

300-

Off-dialysis *On-dialysis

D

*

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7E 0.

50

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0

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TABLE 1. Pharmacokinetic results after 200 mg of oral itraconazolea 5-

Tmax (h) Cmax (ng/mI) (ng.AUCOSh8 h/mi)

Patient group (n)

Uremic (7) Hemodialysis Off dialysis (7) On dialysis (7) CAPD (5) a

TmX

Time to

AUg (ngb¶ii)

haemodialysis

4.0 ± 1.2 213 ± 178 1,026 ± 819 3,454 ± 3,132 4.7 ± 1.4 140 ± 119 4.1 ± 0.9 113 ± 83 4.4 ± 2.2 77 ± 29

Cnax. Values are means ±

634 ± 507 507 ± 371 325 ± 107 standard deviation.

0

2

4

6

8

10

Time (hours) FIG. 2. Itraconazole concentrations in plasma after single oral doses of 200 mg given to hemodialysis patients studied on both off-dialysis and on-dialysis days (mean + standard error of the

mean).

VOL. 32, 1988

bility of the drug, since the oral bioavailability of itraconazole is known to be increased after food intake (3). Although several patients were taking calcium carbonate or aluminum hydroxide or both on the study day, the CAPD patient with the lowest Cmax and AUC value was not taking these drugs, making an absorption interaction less likely. Since unchanged itraconazole could not be detected in any effluent peritoneal dialysate, the lower mean Cmax and AUC value found in these patients cannot have been due to an enhanced elimination through peritoneal dialysis. This absence of peritoneal removal is in keeping with the very high protein binding of the drug. In conclusion, the single-dose pharmacokinetics of itraconazole given orally at 200 mg are not significantly affected by renal dysfunction. However, this conclusion should be considered preliminary, awaiting confirmation. Indeed, the patient groups studied were small, a wide interindividual variability was observed, and drawing conclusions for chronic dosing based upon single-dose pharmacokinetics may be hazardous. Indeed, multiple dosing could lead to saturation of some hepatic metabolic pathway or to retention of some metabolites which were not assayed in the present study. The drug is not or is only minimally eliminated by hemodialysis or peritoneal dialysis. Dosage for uremic patients, whether dialyzed or not, should not be lower than for patients with normal renal function. If further studies confirm the trend toward lower itraconazole concentrations in the plasma of CAPD patients, this would indicate the need for increasing dosage for this patient population. (Part of this work was presented previously [J. Boelaert, S. Sas, A. Van Peer, and P. De Doncker, Program Abstr.

NOTES

1597

26th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 801, 1986; J. Boelaert, R. Daneels, M. Schurgers, E. Matthys, V. Van De Velde, K. De Beule, and R. Woestenborghs, 27th ICAAC, abstr. no. 778, 1987].) LITERATURE CITED 1. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed. Marcel Dekker, Inc., New York. 2. Hardin, T. C., J. R. Graybill, R. Fetchick, R. Woestenborghs, M. G. Rinaldi, and J. G. Kuhn. 1988. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob. Agents Chemother. 32:1310-1313. 3. Heykants, J., M. Michiels, W. Meuldermans, J. Monbaliu, K. Lavrijsen, A. Van Peer, J. C. Levron, R. Woestenborghs, and G. Cauwenbergh. 1987. The pharmacokinetics of itraconazole in animals and man: an overview, p. 223-249. In R. A. Fromtling (ed.), Recent trends in the discovery, development and evaluation of antifungal agents. J. R. Prous Science Publishers, Barcelona, Spain. 4. Meuldermans, W., and J. Heykants. 1986. The plasma protein binding of itraconazole and its distribution in blood. Preclinical Research Report R 51211/33. Janssen Pharmaceutica, Beerse, Belgium. 5. Saag, M. S., and W. E. Dismukes. 1988. Azole antifungal agents: emphasis on new triazoles. Antimicrob. Agents Chemother. 32: 1-8. 6. Van Cauteren, H., J. Heykants, R. De Coster, and G. Cauwenbergh. 1987. Itraconazole: pharmacological studies in animals and humans. Rev. Infect. Dis. 9:S43-S46. 7. Woestenborghs, R., W. Lorreyne, and J. Heykants. 1987. Determination of itraconazole in plasma and animal tissues by highperformance liquid chromatography. J. Chromatogr. 413:332337.