Steady-state pharmacokinetics and metabolism of voriconazole in patients

Transcription

1 J Antimicrob Chemother 013; 68: doi: /jac/dkt9 Advance Access publication 13 June 013 Steady-state pharmacokinetics and metabolism of voriconazole in patients Marcus J. P. Geist 1, Gerlinde Egerer,Jürgen Burhenne 1, Klaus-Dieter Riedel 1, Johanna Weiss 1 and Gerd Mikus 1 * 1 Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, D-6910 Heidelberg, Germany; Department of Internal Medicine V: Haematology, Oncology and Rheumatology, Heidelberg University Hospital, Im Neuenheimer Feld 410, D-6910 Heidelberg, Germany *Corresponding author. Tel: ; Fax: ; gerd.mikus@med.uni-heidelberg.de Present address: Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, D-6910 Heidelberg, Germany. Received 6 November 01; returned 4 March 013; revised 8 April 013; accepted 16 May 013 Objectives: Voriconazole exhibits non-linear pharmacokinetics in adults and is said to be mainly metabolized by CYPC19 and CYP3A4 to voriconazole-n-oxide. The aim of this study was to obtain data on steady-state pharmacokinetics after dosing for at least 14 days in patients taking additional medication and in vivo data on metabolites other than voriconazole-n-oxide. Patients and methods: Thirty-one patients receiving voriconazole as regular therapeutic drug treatment during hospitalization participated in this prospective study. Pharmacokinetic profiles were obtained for the 1 h (dosing interval) after the first orally administered dose (400 mg) or (if possible and) after an orally administered maintenance dose (00 mg) following intake for at least 14 days (n¼14 after first dose; n¼3 after maintenance dose). Blood and urine samples were collected and the concentrations of voriconazole and three of its metabolites (the N-oxide, hydroxy-voriconazole and dihydroxy-voriconazole) were determined, as well as the CYPC19 genotype of the patients. All other drugs taken by the participating patients were evaluated. Results: A high variability of exposure (AUC) after the first dose was slightly reduced during steady-state dosing for voriconazole (8% to 71%) and the N-oxide (86% to 56%), remained high for hydroxy-voriconazole (79%) and even increased for dihydroxy-voriconazole (97% to 17%). In 16 of the steady-state patients, trough plasma concentrations were, mg/ml. N-oxide plasma concentrations during steady state stayed almost constant. Hydroxylations of voriconazole seem to be quantitatively more important in its metabolism than N-oxidation. Conclusions: High variability in voriconazole exposure, as well as low steady-state trough plasma concentrations, suggest that the suggested steady-state dosage of 00 mg twice a day has to be increased to prevent disease progression. Therapeutic drug monitoring is probably necessary to optimize the voriconazole dose for individual patients. Keywords: exposure variability, therapeutic drug monitoring, voriconazole-n-oxide, hydroxy-voriconazole, dihydroxy-voriconazole Introduction Compared with its derivative fluconazole, the triazole voriconazole with its expanded antimycotic activity provides an improved therapeutic option for the treatment of severe fungal infections. 1 Voriconazole is used in the treatment of candidiasis, invasive aspergillosis as well as other mould infections. Its use as initial treatment for immunocompromised patients with invasive aspergillosis gave higher survival rates compared with initial therapy with amphotericin B. Voriconazole is well absorbed with a high oral bioavailability of 96%, based on healthy volunteer data, permitting a change from intravenous to oral administration (00 mg intravenous dose twice a day and 300 mg oral dose twice a day) if clinically needed. 3 The recommended oral dosing scheme in adults weighing 40 kg is 400 mg twice on the first day and 00 mg twice on the following days. 4 Maximal plasma concentrations are observed 1 h after drug administration. The volume of distribution is estimated to be 4.6 L/kg and the plasma protein binding is 58%. A terminal elimination t1 of 8 h has been reported in CYPC19 extensive metabolizers and 15 h in CYPC19 poor metabolizers. 5 Owing to possible saturation of metabolism, voriconazole exhibits nonlinear pharmacokinetics with increased dosages relative to body weight. The pharmacokinetics are non-linear in the dosage range # The Author 013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please journals.permissions@oup.com 59

2 Pharmacokinetics and metabolism of voriconazole JAC that provides similar exposures as achieved in adults. 3 In patients, the overall estimate for bioavailability has been reported to be 86% 6 and there might also be some influence of the CYPC19 genotype. 7 Only % of a voriconazole dose is excreted unchanged in the urine. 8 The main metabolite is voriconazole-n-oxide, which has only minimal antifungal activity. 9 Recently, hydroxy-voriconazole and dihydroxy-voriconazole were identified as two additional quantitatively important metabolites in humans. 7 Voriconazole is mainly metabolized via the hepatic cytochrome P450 isoenzyme CYPC19 and to a lesser extent by CYP3A4 and CYPC9. 10,11 CYPC19 is polymorphically expressed, 1 with.% of the Caucasian population being poor metabolizers 13 having a genetically determined absence of active enzyme. It is known that voriconazole pharmacokinetics are substantially influenced by the CYPC19 genotype. 5,14,15 A reduction of voriconazole metabolic clearance (CL MET ) in CYPC19 poor metabolizers is expected; data published so far indicate 3-fold higher voriconazole AUC or C max values in CYPC19 poor metabolizers compared with homozygous 5,14 16 extensive metabolizers. The aim of this study was to present data on voriconazole steady-state pharmacokinetics after therapeutic oral intake of the drug according to its indications for at least 14 days by patients receiving additional medication in a clinical setting. Furthermore, we obtained in vivo pharmacokinetic profiles of two other substantial metabolites of voriconazole in humans in addition to the N-oxide. Patients and methods The study protocol (EudraCT: ) was approved by the ethics committee of Heidelberg University Hospital, Germany, and authorized by the competent authority (BfArM, Germany). It was conducted in accordancewith good clinical practiceand the Declaration of Helsinki. We obtained written informed consent from each patient prior to any study-related activity. Study population Overall, 31 patients receiving voriconazole as regular therapeutic drug treatment during hospitalization participated in this study. A subject was included when receiving the first dose of voriconazole or after intake for at least 14 days according to the indications stated in the investigators brochure. 4 Voriconazole was prescribed for the pre-emptive treatment of probable invasive fungal infection by the treating physicians. This was not modified in any way by the investigators. Next to multiple myeloma and other haematological diseases, the most common diagnosis in the participating patients was acute myeloid leukaemia. Patients had to be 18 years old to be admitted to the trial. Exclusion criteria included haemoglobin,7 g/dl at the last laboratory screening (not. days previously), inability to communicate well with the investigator due to language problems or poor mental development and contraindications or warnings according to the investigators brochure. 4 Study design This prospective clinical study was carried out at Heidelberg University Hospital. A 1 h (dosing interval) pharmacokinetic profile after dosing was obtained from each participating patient on a study day. Subjects had to go through one study day if they had received voriconazole for at least 14 days (00 mg oral dose twice a day). If possible, subjects investigated after the first dosing (400 mg oral loading dose) went through an additional study day at least 14 days later. The duration and dosage of any previous dosing of voriconazole was evaluated, as well as all other drugs taken by the participating patients (duration, dosage, type of administration), in order to identify possible drug drug interactions. Any adverse events that occurred were documented. Sample collection Blood samples (4.5 ml) for determining plasma voriconazole concentrations were collected in lithium heparin tubes immediately prior to dosing (0 h) and at 1,, 3, 4, 6, 8, 10 and 1 h post-dose if a patient had taken voriconazole forat least 14 days. In the case of first dosing, blood samples were collected immediately prior to dosing (0 h) and at 0.5, 1, 1.5,, 3, 4, 6, 8, 10 and 1 h post-dose. Blood samples were immediately centrifuged at 48C and separated plasma was stored at 08C until analysis. One additional blood sample (.7 ml) was taken in an EDTA-containing tube for genotyping. Urine was collected for a 1 h period after dosing and a 10 ml aliquot was kept frozen at 08C until analysis. CYPC19 genotyping Genomic DNA was isolated from white blood cells using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer s instructions. The presence of the inactive CYPC19* and CYPC19*3 alleles was determined using the LightCycler CYPC19 Mutation Detection Kit (Roche Applied Science, Mannheim, Germany) on a LightCycler (Roche Applied Science, Mannheim, Germany) according to the manufacturer s instructions. The CYPC19*17 allele, which correlates with high in vivo CYPC19 activity, was detected using PCR restriction fragment length polymorphism as recently published. 17 The presence of the wild-type allele CYPC19*1 was assumed in the absence of the *, *3 and *17 alleles. Determination of concentrations of voriconazole and its metabolites Plasma and urine concentrations of voriconazole and its metabolites were determined using a fully FDA-validated liquid chromatography tandem mass spectrometry assay described previously in detail. 18 The lower limits of detection in plasma and urine were 0.0 mg/ml for voriconazole and voriconazole-n-oxide and mg/ml for hydroxy- and dihydroxyvoriconazole. Data analysis Nonparametric pharmacokinetic parameters were calculated using Win- Nonlin 5.0 (Pharsight, Mountain View, CA, USA). The following voriconazole pharmacokinetic parameters were determined: maximum observed plasma concentration (C max ), minimum observed plasma concentration (C min ), area under the plasma concentration time curve from time zero to the last measurable concentration (AUC 0-1 ), area under the plasmaconcentration time curve extrapolated to infinity (AUC 0-1 ), calculated using the linear trapezoidal rule, and the terminal elimination t1. Renal clearance (CL R ) of voriconazole and its metabolites was determined as the amount excreted in urine (0 1 h) divided by the corresponding AUC 0-1 value; partial CL MET of the metabolites was determined as the amount of metabolite formed via a definite pathwayexcreted in urine (0 1 h) divided by the corresponding AUC 0-1 value of voriconazole. Statistics Data are presented as mean values and range (+SD). In order to compare the data after the first dose and during steady-state dosing, the plasma concentrations after the first 400 mg dose were halved and the concentrations during steady state (dose 00 mg) were used unchanged. Differences 593

3 Geist et al. in the pharmacokinetic parameters between intake after the first dose and steady state were assessed using the Mann Whitney test. A P value,0.05 was considered to be significant. Voriconazole trough plasma concentrations (0 and 1 h) were compared using the Wilcoxon matched-pairs signed-rank test to assess steady-state conditions. Results Fourteen patients participated in the study after intake of the first voriconazole dose and 3 after intake of a maintenance dose for at least 14 days. Six patients took part in both parts of the study. To be able to compare kinetic parameters after the first dose (400 mg) and steady-state dosing (00 mg) the tables show dosecorrected (00 mg) values for the first voriconazole dose. Inspection of the voriconazole concentration time profiles revealed that during steady-state dosing patient 1 had very low voriconazole concentrations. The accidental treatment of this patient with the contraindicated combination of voriconazole and rifampicin, a CYP450 inducer, led to a dramatic decrease in the voriconazole plasma concentration and a large increase in the concentrations of its metabolites. The treatment error was identified by the authors of this study and has been reported in detail before. 19 Patient 1 also showed very low voriconazole exposure after first dosing (only 4% of the mean AUC), while the metabolites were in the normal range. Both subjects have been excluded from the final pharmacokinetic analysis. The influence of the data of both patients on the voriconazole clearance is shown in Table 1. Comparison of voriconazole trough plasma concentrations immediately before (1.9 mg/ml) and 1 h after steady-state dosing (1.61 mg/ml) showed no significant differences; thus, the steady state was actually achieved in the corresponding patients. Also, no differences were observed for the three metabolites measured. Voriconazole pharmacokinetics Compared with the first dose, mean voriconazole plasma concentrations were higher during steady state (Figure 1a). There was a statistically significant increase in C max (dose corrected versus mg/ml; P¼0.000) but no difference for AUC (dose-corrected AUC versus AUC mg.h/ml; P¼0.98). The calculated apparent oral clearance did not change significantly during steady state (P¼0.1887). All the pharmacokinetic parameters that were obtained are shown in Table 1. Pharmacokinetics of voriconazole s major metabolites The 1 h pharmacokinetic profiles of voriconazole-n-oxide, hydroxy-voriconazole and dihydroxy-voriconazole after intake of the first dose and during steady state are shown in Figure 1(b d). Steady-state plasma concentrations of voriconazole-n-oxide remained almost constant, while concentrations of the other two metabolites decreased after having reached their maximum. Voriconazole-N-oxide was the major metabolite in plasma, with dose-corrected C max values after intake of the first dose of nmol/ml, which significantly increased during steady state to mg/ml (P¼0.0001). Hydroxy-voriconazole was the metabolite with the lowest maximum plasma concentration (dose corrected mg/ml and steady state mg/ml; P, ). The quantitative order for AUC was equal (Table ). Comparison of first and maintenance dose within patients Comparison between the AUCs for voriconazole and its metabolites after the first dose and during steady-state dosing was Table 1. Pharmacokinetic parameters of voriconazole after the first dose (dose corrected per 00 mg) and during steady-state treatment, and after the exclusion of patient 1 (first dose) and patient 1 (steady state) in the bottom half of the table First dose (n¼14) Steady-state (n¼3) mean +SD CV (%) mean +SD CV (%) C max (mg/ml) C min (mg/ml) AUC 0-1 (mg.h/ml) AUC 0-1 (mg.h/ml) l z (1/h) t1 (h) CL () First dose (n¼13) Steady-state (n¼) mean +SD CV (%) mean +SD CV (%) C max (mg/ml) C min (mg/ml) AUC 0-1 (mg.h/ml) AUC 0-1 (mg.h/ml) l z (1/h) t1 (h) CL ()

4 Pharmacokinetics and metabolism of voriconazole JAC (a) 6 Plasma voriconazole (µg/ml) 4 0 (c) 0.6 Plasma hydroxy-voriconazole (µg/ml) (b) (d) Plasma voriconazole-n-oxide (µg/ml) Time (h) Time (h) Plasma dihydroxy-voriconazole (µg/ml) Time (h) Time (h) Figure 1. Mean (+SD) plasma concentration time curves of voriconazole (a), voriconazole-n-oxide (b), hydroxy-voriconazole (c) and dihydroxy-voriconazole (d) after the first dose (circles; n¼13, dose corrected per 00 mg) and during steady-state treatment (squares; n¼). possible in six patients who participated in both parts of the study. One of these was excluded from the calculation of the mean values due to concomitant rifampicin treatment, as mentioned earlier. The dose-corrected AUC after the first dose of voriconazole was mg.h/ml and during steady-state dosing was mg.h/ml (n¼5), which was not different as assessed by the paired t-test. This was also observed for the three metabolites. Metabolism of voriconazole The amounts of metabolites measured in urine and their proportion of the voriconazole dose during steady-state dosing are shown in Table 3. Voriconazole-N-oxide represented the lowest proportion and dihydroxy-voriconazole the largest proportion of the voriconazole dose excreted inurine as metabolites. Hydroxy- anddihydroxyvoriconazole showed high CL R, while those of voriconazole itself and voriconazole-n-oxide were relatively low (Table 3). Partial CL MET of the N-oxidation from voriconazole to voriconazole-n-oxide was , whereas clearance via hydroxylation reactions to hydroxy- and dihydroxy-voriconazole was.10-fold higher ( ). Hydroxylation of hydroxy- to dihydroxy-voriconazole showed a partial CL MET of (Figure ). CYPC19 genotyping Sixteen patients were homozygous for the CYPC19 wild-type allele (*1/*1), six patients were heterozygous (*1/*), eight patients were heterozygous for the *17 allele and only one had the combination */*17. Therefore, none of the patients was classified as a CYPC19 poor metabolizer. Thus, a comparison of voriconazole pharmacokinetics and metabolism according to CYPC19 genotype was not possible. Concomitant medication Because of their haematological diseases, all participating patients were receiving complex and individually very different concomitant medications. Some took.15 drugs daily. Although many of the medications taken are not metabolized by the three CYP enzymes of interest, strong inhibitors of CYPC19, CYP3A4 or CYPC9 (clarithromycin, diltiazem or erythromycin) were also taken. Apart from the patient who was accidentally treated with rifampicin, the trough concentration ratios of voriconazole and its metabolites showed high variability during steady state, but no notable aberration from the study population. Thus, there were no obvious influences of CYP3A4, CYPC19 or CYPC9 inhibitors on the pharmacokinetics of voriconazole and its three metabolites. 595

5 Geist et al. Table. Pharmacokinetic parameters of voriconazole-n-oxide, hydroxy-voriconazole and dihydroxy-voriconazole after the first dose (n¼13; dose corrected per 00 mg) and during steady-state treatment (n¼) First dose Steady-state mean +SD CV (%) mean +SD CV (%) Voriconazole-N-oxide C max (mg/ml) AUC 0-1 (mg.h/ml) AUC 0-1 (mg.h/ml) l z (1/h) t1 (h) Hydroxy-voriconazole C max (mg/ml) AUC 0-1 (mg.h/ml) AUC 0-1 (mg.h/ml) l z (1/h) t1 (h) Dihydroxy-voriconazole C max (mg/ml) AUC 0-1 (mg.h/ml) AUC 0-1 (mg.h/ml) l z (1/h) t1 (h) Table 3. Urinary excretion and CL R of voriconazole and its metabolites during steady-state (n¼) Urinary excretion, mean+sd (CV%) mg % of dose CL R (), mean+sd (CV%) Voriconazole (100.8) (100.8) (75) Voriconazole and conjugates (69.5) (69.5) Voriconazole-N-oxide (66.5) (66.5) (67.4) Voriconazole-N-oxide and conjugates (89.9) (89.9) Hydroxy-voriconazole (77.9) (77.9) (65.4) Hydroxy-voriconazole and conjugates (54.1) (54.1) Dihydroxy-voriconazole (84.0) (84.0) (68.) Dihydroxy-voriconazole and conjugates (68.9) (68.9) Discussion This is the first work describing voriconazole pharmacokinetics and metabolism in patients after oral intake according to the indications of this drug that also includes voriconazole characteristics with respect to its elimination. Apart from published studies in healthy volunteers, Lazarus et al. 0 examined voriconazole pharmacokinetics in patients at risk of fungal infection; however, a proven fungal infection or antimycotic treatment was one of the exclusion criteria of the study. Brüggemann et al. 1 examined pharmacokinetics in stem cell transplant recipients after 14 days intake of intravenous voriconazole. Voriconazole steady-state pharmacokinetics The pharmacokinetic parameters of voriconazole after the first dose were within the expected range from previous studies. The mean increase in C max during steady state compared with the first dose suggests the accumulation of voriconazole after multiple dosing, but the AUC (dose-corrected AUC versus AUC mg.h/ml) showed only minor accumulation. AUCs from the five patients who participated in both parts of the study also did not show accumulation of voriconazole, despite the low number of subjects. A study in healthy volunteers using different oral doses showed voriconazole accumulation ratios of C max and AUC after multiple dosing (1.97 and 3.55 after 3 mg/kg voriconazole twice a day), even greater than predicted from single-dose data (1.19). 3 Using the recommended dosing scheme (400 mg twice a day on the first day, 00 mg twice a day thereafter) seems to secure constant exposure to voriconazole from the first dose. An enormous (.70%) intersubject variability in voriconazole exposure (AUC) was found, which has also been observed by others, 596

6 Pharmacokinetics and metabolism of voriconazole JAC Conjugates Conjugates CL R = ± ± 4.49 hydroxy-voriconazole 1.3 ± 1.59 voriconazole-n-oxide CL R = 1.60 ± ± ± ± 364. Voriconazole CL R = 1.39 ± ± 0.87 Conjugates CL R = 36.9 ± dihydroxy-voriconazole.5 ± Conjugates Figure. Metabolism of voriconazole in humans, with partial CL MET and CL R during steady-state voriconazole treatment (n¼). suggesting genetic polymorphism of CYPC19 as a possible reason. 4 However, in our study no patient was identified as a CYPC19 poor metabolizer, and even without poor metabolizers very high variability in voriconazole exposure was observed. In contrast to healthy volunteers, in whom CYPC19 polymorphism was reported to make a major contribution to the variability, 5 in patients the variability seems to result from various possible contributing factors, like changes in drug absorption, co-medication or disease. Therapeutic drug monitoring (TDM) can be an effective tool to optimize drug therapy with voriconazole, which was 6 9 also concluded from several recently published studies. Troke et al. 30 recommended considering the MIC in addition to voriconazole plasma concentrations, and offered an appropriate TDM target to achieve clinical efficacy with voriconazole treatment. The present study furthermore revealed plasma trough concentrations of voriconazole of, mg/ml ( mg/ml) during steady-state dosing in 16 of patients. Smith et al. 31 described a significant relationship between disease progression and drug concentration, with voriconazole concentrations of, mg/ml leading to disease progression or poor treatment outcome, while a positive response was observed in patients with concentrations. mg/ml. 3 The corresponding patients in our study would have had no adequate antimycotic effect at particular times. The currently suggested maintenance dose of 00 mg every 1 h is probably not adequate for the effective treatment or prophylaxis of severe fungal infections. Voriconazole metabolism Data on voriconazole metabolism were published for the first time by Roffey et al.; 9 however, they only described kinetic data of voriconazole-n-oxide in animals. Since then, only a few studies have generated metabolite data, mainly in volunteers 7,33 and some in patients. 17,34 Our study presents a detailed characterization of voriconazole s three major metabolites in patients. The highest exposure after the first dose (dose-corrected AUC mg.h/ml) as well as during steady state (AUC mg.h/ml) was found for voriconazole- 597

7 Geist et al. N-oxide, and this is thus the main circulating metabolite in humans (Table ). CL R of the metabolites showed that hydroxy- and dihydroxy-voriconazole are more extensively excreted via the kidneys than voriconazole and voriconazole-n-oxide (Table 3). The N-oxidation and hydroxylations of the fluorinated pyrimidine ring, as well as hydroxylation of the methyl group in position 4, have been described as the metabolic pathways of voriconazole in humans. 9 N-oxidation and hydroxylations of the fluorinated pyrimidine ring have been confirmed by others identifying hydroxyvoriconazole and dihydroxy-voriconazole as another two important metabolites of voriconazole in humans, 7 but no products of hydroxylation of the methyl group in position 4 were found. In our study, voriconazole-n-oxide only represented 1%, hydroxyvoriconazole 3% and dihydroxy-voriconazole 14% of the administered voriconazole dose in urine during steady state. Furthermore, partial CL MET of N-oxidation was very low ( ), unlike the clearance via hydroxylations to hydroxy-voriconazole and dihydroxy-voriconazole ( ). These results are in strong contrast to the findings of Roffey et al., 9 in which voriconazole-n-oxide represented about 1% of the voriconazole dose in urine. Thus, the results of our study do not confirm N-oxidation as the main metabolic pathway of voriconazole. The hydroxylations of the fluorinated pyrimidine ring to hydroxyvoriconazole and dihydroxy-voriconazole quantitatively play a more important role in the metabolism of voriconazole, confirming the data obtained previously in healthy volunteers. 7 Low plasma concentrations of hydroxy-voriconazole can be explained by further metabolism to dihydroxy-voriconazole. Partial CL MET of hydroxylation from hydroxy-voriconazole to dihydroxyvoriconazole was high ( ). Despite a low CL MET of N-oxidation, high plasma levels of voriconazole-n-oxide result from a very low CL R ( ) and minimal conjugation of voriconazole-n-oxide (Figure ). Interaction with concomitant medication Drug drug interactions are possible between voriconazole and all other substances that are metabolized by hepatic CYP3A4, CYPC19 or CYPC9 isoenzymes. Owing to the non-linear kinetics of voriconazole, difficulties in predicting possible drug drug interactions have been anticipated. 35 Our study shows complex and individually different concomitant medications in haematological patients. Compounds like clarithromycin, diltiazem and erythromycin, which are strong inhibitors of CYP3A4, and other drugs that are also metabolized by the three important isoenzymes, were taken by the patients in our study. Variability of trough plasma concentrations was high during steady-state dosing; however, there seemed to be no obvious influence of concomitant drugs on the pharmacokinetics and metabolism of voriconazole, with the exception of rifampicin, which we previously described in detail. 19 Voriconazole, a strong inhibitor of CYP3A4 itself, seemed not to be displaced by other substances at the binding site of the enzyme, which confirms the potent inhibition of CYP3A4 by voriconazole. Literature research provided information on drug drug interactions between voriconazole and erythromycin, but not for other CYP450 inhibitors that occurred among the medications concomitantly taken by the participating patients. In line with our results, Purkins et al. 16 concluded that erythromycin has an effect on steady-state voriconazole pharmacokinetics that is not of clinical interest. Only a few studies are available dealing with the effects of other drugs on voriconazole; studies of the influence of voriconazole on other drugs are more often reported. According to our study, it seems that in clinical routine many drugs are combined with voriconazole without reliable data. Conclusions The high variability of exposure of voriconazole, as well as low steady-state trough plasma concentrations, lead us to question the suggested steady-state dosage of 00 mg voriconazole twice a day and propose an increased dose to prevent disease progression, probably under TDM conditions to optimize the voriconazole dose for each patient. Concerning the metabolism of voriconazole, hydroxylations to hydroxy-voriconazole and dihydroxy-voriconazole seem to be quantitatively more important than N-oxidation to voriconazole-n-oxide. However, high N-oxide steady-state plasma concentrations can be explained by a very low CL R compared with hydroxy-voriconazole and dihydroxyvoriconazole. Acknowledgements Parts of the results were presented as a poster at the Fiftieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston, MA, USA, 010 (presentation number A1-046). We are grateful for the excellent technical assistance of Ms Magdalena Longo and Ms Jutta Kocher during the analytical procedures. Funding The Department of Clinical Pharmacology and Pharmacoepidemiology has received a grant from Pfizer, New York, USA to establish and make available an HPLC method for the determination of voriconazole in plasma that is validated according to FDA standards. Transparency declarations None to declare. References 1 Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 003; 36: Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 00; 347: Purkins L, Wood N, Ghahramani P et al. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 00; 46: FachInfo-Service. Fachinformation VFEND # Mikus G, Schowel V, Drzewinska M et al. Potent cytochrome P450 C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther 006; 80: Hope WW. Population pharmacokinetics of voriconazole in adults. Antimicrob Agents Chemother 01; 56: Scholz I, Oberwittler H, Riedel KD et al. Pharmacokinetics, metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYPC19 genotype. Br J Clin Pharmacol 009; 68:

8 Pharmacokinetics and metabolism of voriconazole JAC 8 Donnelly JP, De Pauw BE. Voriconazole: a new therapeutic agent with an extended spectrum of antifungal activity. Clin Microbiol Infect 004; 10 Suppl 1: Roffey SJ, Cole S, Comby P et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 003; 31: Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 003; 31: Geist MJ, Egerer G, Burhenne J et al. Safety of voriconazole in a patient with CYPC9*/CYPC9* genotype. Antimicrob Agents Chemother 006; 50: Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYPC subfamily. Br J Clin Pharmacol 001; 5: Shimizu T, Ochiai H, Asell F et al. Bioinformatics research on inter-racial difference in drug metabolism I. Analysis on frequencies of mutant alleles and poor metabolizers on CYPD6 and CYPC19. Drug Metab Pharmacokinet 003; 18: Ikeda Y, Umemura K, Kondo K et al. Pharmacokinetics of voriconazole and cytochrome P450 C19 genetic status. Clin Pharmacol Ther 004; 75: Rengelshausen J, Banfield M, Riedel KD et al. Opposite effects of short-term and long-term St John s wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 005; 78: Purkins L, Wood N, Ghahramani P et al. No clinically significant effect of erythromycin or azithromycin on the pharmacokinetics of voriconazole in healthy male volunteers. Br J Clin Pharmacol 003; 56 Suppl 1: Hassan A, Burhenne J, Riedel KD et al. Modulators of very low voriconazole concentrations in routine therapeutic drug monitoring. Ther Drug Monit 011; 33: Shah VP, Midha KK, Findlay JW et al. Bioanalytical method validation: a revisit with a decade of progress. Pharm Res 000; 17: Geist MJ, Egerer G, Burhenne J et al. Induction of voriconazole metabolism by rifampin in a patient with acute myeloid leukemia: importance of interdisciplinary communication to prevent treatment errors with complex medications. Antimicrob Agents Chemother 007; 51: Lazarus HM, Blumer JL, Yanovich S et al. Safety and pharmacokinetics of oral voriconazole in patients at risk of fungal infection: a dose escalation study. J Clin Pharmacol 00; 4: Brüggemann RJ, Blijlevens NM, Burger DM et al. Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 010; 65: Leveque D, Nivoix Y, Jehl F et al. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents 006; 7: Purkins L, Wood N, Greenhalgh K et al. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 003; 56 Suppl 1: Keirns J, Sawamoto T, Holum M et al. Steady-state pharmacokinetics of micafungin and voriconazole after separate and concomitant dosing in healthy adults. Antimicrob Agents Chemother 007; 51: Weiss J, Ten Hoevel MM, Burhenne J et al. CYPC19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 009; 49: Clifton IJ, Whitaker P, Metcalfe R et al. Pharmacokinetics of oral voriconazole in patients with cystic fibrosis. J Antimicrob Chemother 011; 66: Dolton MJ, Ray JE, Chen SC et al. Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 01; 56: Pascual A, Csajka C, Buclin T et al. Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis 01; 55: Mitsani D, Nguyen MH, Shields RK et al. Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity. Antimicrob Agents Chemother 01; 56: Troke PF, Hockey HP, Hope WW. Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother 011; 55: Smith J, Safdar N, Knasinski V et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 006; 50: Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 009; 53: Dowell JA, Schranz J, Baruch A et al. Safety and pharmacokinetics of coadministered voriconazole and anidulafungin. J Clin Pharmacol 005; 45: Hafner V, Czock D, Burhenne J et al. Pharmacokinetics of sulfobutylether-b-cyclodextrin and voriconazole in patients with end-stage renal failure during treatment with two hemodialysis systems and hemodiafiltration. Antimicrob Agents Chemother 010; 54: Gubbins PO, Amsden JR. Drug-drug interactions of antifungal agents and implications for patient care. Expert Opin Pharmacother 005; 6: