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Journal of Antimicrobial Chemotherapy (2005) 56, Suppl. S1, i17–i22 doi:10.1093/jac/dki220 Making sense of itraconazole pharmacokinetics Archibald Grant Prentice1* and Axel Glasmacher2 1 Department of Haematology, Royal Free Hospital, Pond Street, London NW3 2QG, UK; 2 Department of Internal Medicine I, University of Bonn, Bonn, Germany The triazole, itraconazole, has a wide spectrum of antifungal activity in vitro. Confirming this activity in vivo has been a long and difficult task because of problems with formulation, delivery and uncertainty about effective bioavailability. The physicochemical properties of the drug make it insoluble in water but strongly protein bound. The absorption and blood levels of the original capsular formulation were predictable with non-linear, saturation kinetics in normal volunteers. Tissue penetration was high and sustained. In neutropenic patients with haematological malignancies, levels were very variable and the doses required to achieve effective antifungal levels were higher than predicted from normal subjects’ results. The solubility of the drug and predictability of blood levels were improved by the formulation of an oral solution with cyclodextrin. Wash-out times were prolonged in patients with this new formulation implying that tissue penetration was maintained. A high volume of distribution suggests that loading may be necessary. An intravenous cyclodextrin solution is also now available allowing rapid loading and avoidance of the wellknown gut side effects of the oral solution. Clinical studies have suggested minimum bioavailable dosage and minimum trough blood levels for effective prophylaxis against systemic fungal infection. Interactions are also now well documented and manageable. The drug can be measured reliably, quickly and comparatively cheaply by HPLC in serum and plasma. The frequency of such testing in clinical practice depends on the need to ensure adequate levels and to avoid unwanted toxicity. Keywords: drug levels, systemic fungal infections Introduction The azole group of synthetic aromatic compounds (imidazoles and triazoles) are all structurally similar with a five-membered azole ring and a complex side chain. They have a broad range of mostly fungistatic activity which varies significantly between the members of the group and two in vitro studies have shown that itraconazole may be fungicidal against certain species in certain concentration ranges.1,2 The introduction of these orally administered and systemically active antifungal agents was a major development in therapeutics but, despite repeatedly encouraging results from the clinical investigation of itraconazole over more than 20 years, its use in antifungal prophylaxis has increased relatively slowly. Early anecdotal evidence suggested the efficacy of capsule formulations, even with relatively poor bioavailability, provided that adequate serum drug levels could be achieved. Then improved bioavailability of newer oral and intravenous (iv) solutions offered potentially greater protection for more patients. Why has the clinical development of this drug taken so long whilst it has been shown simultaneously to be so safe and so effective in so many patients? While there have been expensive and protracted difficulties in improving bioavailability, there are still problems of compliance with the oral solution and the drug has idiosyncratic and more universal (but manageable) side effects. There is also widespread scepticism amongst many haematologists and microbiologists about the need for any anti-infective prophylaxis in our patients. However, these problems alone do not explain the relative commercial inertia of this drug when compared with the more successful efforts in market penetration of rival products with inferior evidence of efficacy. The clinical activity of itraconazole is determined not only by its wide in vitro antifungal spectrum of activity but also by its handling in vivo. Physicochemical characteristics The absorption, metabolism and elimination of any drug are dependent on the physical and chemical properties of its structure. The concentration of a drug in any part of the body is determined by these processes and the time course of drug concentrations in different parts of the body for any given dose determines the pharmacokinetic (PK) profile. This profile will affect the clinical efficacy of the drug. Itraconazole, like all triazoles, has three nitrogen atoms in its azole ring which might improve tissue penetration, prolong ............................................................................................................................................................................................................................................................................................................................................................................................................................. *Corresponding author. Tel: +44-20-7472-6100; Fax: +44-20-7830-2092; E-mail: [email protected] ............................................................................................................................................................................................................................................................................................................................................................................................................................. i17 The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] Prentice and Glasmacher Table 1. Basic pharmacokinetic data for itraconazole7,8,10 Volume of distribution (VD SS) Protein binding Apparent terminal elimination half-life in steady state (tg 1/2 SS) Elimination route Dose reduction in renal failure Dose reduction in liver failure CNS penetration in healthy animals Relation lung tissue to serum concentration 11 L/kg 99% 34 – 9 h liver metabolism no (oral form) drug monitoring low 3 : 1 half-life and increase specificity for fungal enzymes.3 The nitrogen atoms interact with the haem iron of the fungal cytochrome P450 3A (CYP3A), inhibiting the function of lanosine 14a-demethylase which converts lanosterol to ergosterol, the main sterol in the fungal cell membrane.4 This inhibits replication and promotes cell death, or, in the case of yeast cells of Candida albicans, transformation into hypothetically invasive hyphae.5 Itraconazole has little effect on mammalian cytochrome P450 enzymes even at high concentrations6 or on the sterol and steroid pathways of the human pituitary–adrenal–testicular axis.7 Itraconazole is a very weak base (pKa = 3.7), is ionized at a low pH such as in gastric secretion, and is highly lipophilic being practically insoluble in water and in dilute acid solutions. Concentrations greater than 10 mg/mL can be achieved in organic solvents such as dimethyl sulphoxide or acidified polyethylene glycols (PEGs) and aqueous solutions at a concentration of 5 mg/mL require the addition of 5% dimethyl-b-cyclodextrin (cyclodextrin). Thus the physicochemical properties of this drug could both proffer beneficial broad-spectrum antifungal activity, strong protein binding (99.8%), tissue saturation and prolonged half-life and limit oral delivery of adequate bioavailability. Pharmacokinetic studies in animals and humans, and clinical trials illustrate this conflict and reveal how it may have been resolved. Table 1 gives a summary of the basic pharmacokinetic properties of itraconazole. Animal studies Studies in animals have shown that itraconazole has a much higher volume of distribution and longer elimination half-life than other imidazoles, with stable tissue concentrations of itraconazole which were higher than plasma concentrations on repeated dosing. The ratio of tissue to plasma levels varied from 3 : 1 for lung to 10 : 1 for liver and over 25 : 1 for fat. These findings confirmed itraconazole’s potential for penetration of tissues and therefore continuous and superior bioavailability at sites of tissue infection.8 Very little drug is found in aqueous body solutions such as the tears, saliva and CSF but any bodily fluid rich in organic matter, such as sputum, bronchial exudates and even pus, will contain high concentrations. These studies also suggested that oral absorption (and therefore bioavailability) of itraconazole improved with food and was dependent on dose. As the dose of itraconazole was increased from 50 to 200 mg, increases in the area under the curve (AUC) and maximum concentration (Cmax) were non-linear, implying saturation of the first pass sites for metabolism by hydroxylation in the gut mucosa and liver. At doses of 5 to 10 mg/kg, itraconazole may be superior to amphotericin B against superficial and systemic infections with Aspergillus spp., Candida albicans and a range of other moulds9–11 and the cyclodextrin solution was effective intravenously in the treatment of experimental systemic Aspergillus and Candida infections in immunocompromised animals.10 Perhaps the most significant result of a pharmacokinetic or pharmacodynamic animal study was that reported by Berenguer et al.12 This showed a strong inverse relationship between plasma concentrations of itraconazole and the pulmonary burden of Aspergillus fumigatus following therapy for experimental infection (r = 0.87, P < 0.001). This provided further evidence of the potential for tissue bioavailability of this drug and implied that a minimal concentration might be needed for effective therapy or prophylaxis. Studies in normal volunteers As in animal studies, absorption of itraconazole from oral capsules has been shown to be improved after food in studies of normal human volunteers.13 Non-linear, saturation kinetics were confirmed in these studies; the Cmax after a dose of 200 mg per day was 147% higher than the Cmax after a dose of 100 mg per day at day 1, but 160% higher at day 15, and the AUC was three or four times greater for each dosage measured between days 1 and 15. Extensive tissue binding has been shown in women undergoing hysterectomy14 after a single 200 mg dose of the drug and in skin scrapings and hair from normal subjects after 28 days of 100 mg daily.8 Very little drug has been shown to be excreted unchanged by the kidney. In addition to dose dependency and a mean absolute bioavailability of 55%, studies with capsules in normal subjects have shown marked inter-subject variation in plasma concentrations.8,13 Absorption from capsules has been shown to be reduced by a mean of 20% by concomitant use of the H2-antagonists cimetidine and ranitidine.15 The potential combination of the capsules’ intrinsically low bioavailability, poor diet and the use of such antacids in clinical practice led the development of pharmacokinetic studies of the cyclodextrin oral solution. In normal subjects, this increased bioavailability by 30–37% after single dosing and by 23–31% at steady state with multiple dosing.16 It has been estimated that the bioavailability of itraconazole from the oral solution taken in fasting conditions may be up to 60% higher than from capsules taken after food. Studies in normal volunteers have also shown that the first pass metabolite of the drug, hydroxy-itraconazole, accumulates at approximately twice the rate of the parent drug. This form of the drug has a similar spectrum of antifungal activity in vitro, thus increasing overall absolute bioavailability of oral drug further to at least 80%.17 Pharmacokinetics in haematological patients In haematological malignancy, the primary aim of pharmacokinetic studies has been to determine whether sufficient levels of drug could be obtained reliably to provide effective prophylaxis against systemic fungal infection. When these studies began, there was evidence that plasma levels above 250 ng/mL could protect against invasive pulmonary aspergillosis.18 The question of whether the drug is effective therapy for such infections has been pursued with less interest. To what extent do studies in animals and normal i18 Neutropenic antifungal prophylaxis depends on pharmacokinetics of itraconazole 631 – 358 ng/mL to 1292 – 357 ng/mL and from 8770 – 5050 ng·h/mL to 25 154 – 6460 ng·h/mL, respectively. Children appeared to be the only group of patients in whom the Cmin at 14 days did not usually exceed 500 ng/mL. The co-existence of even severe mucositis and the concomitant use of H2 antagonists did not appear to reduce these levels significantly in the adult chemotherapy or transplant patients. In the children at day 14 however, levels of hydroxy-itraconazole were much higher than those of the parent drug with Cmin at 437 – 246 ng/mL and AUC at 13 450 – 7190 ng·h/mL.25 In adult studies where hydroxy-itraconazole was measured, there was confirmation of the greater rate of accumulation of this first pass metabolite as was first seen in normal volunteers.17 The studies in adults given chemotherapy for acute myeloblastic leukaemia24 and autologous stem cell transplantation26 showed that a single daily dose of 5 mg/kg is as effective in achieving adequate steady-state plasma levels as half this dose given twice daily. The high volume of distribution of itraconazole suggests that loading doses are necessary to reach clinically active trough concentrations quickly and reliably. According to standard pharmacokinetic equations, 11 mg/kg of itraconazole must be available to reach a trough concentration of 1000 ng/mL. Using a combination of capsules (800 mg/day from day 1 to 7) and oral solution (400 mg per day starting on day 1 until the end of therapy)28 or by combining the same oral solution dose with intravenous solution (400 mg per day on day 1 and 2) (A. Glasmacher and C. Hahn, unpublished observations), the majority of patients can be shown to reach trough concentrations of itraconazole above 1000 ng/mL at the end of the first week (Figure 1). Such serum concentrations are relevant to the published breakpoint of 1000 ng/mL (marking resistance) to test the in vitro susceptibility of itraconazole in Candida spp.29 This breakpoint does not include the equally active first pass metabolite, hydroxyitraconazole, which accumulates at approximately twice the rate of the parent drug. Most patients will achieve higher concentrations of itraconazole provided they receive adequate doses. In the patient cohort in Bonn, 97.6% of neutropenic patients with haematological malignancies who received oral itraconazole solution and a loading dose of capsules had combined itraconazole and hydroxyitraconazole trough concentrations over 1000 ng/mL, 92% had over 1500 ng/mL, 83.5% had over 2000 ng/mL and 49.5% had over 3000 ng/mL (A. Glasmacher and C. Hahn, unpublished observations). 4000 Itraconazole (ng/mL, HPLC) subjects predict the results of pharmacokinetic studies and clinical trials in patients? The first randomized controlled trial of itraconazole capsules as prophylaxis, in patients being treated for haematological malignancy, was abandoned in the UK in 1985 because so many patients had undetectable drug in the plasma. In retrospect, this result could have been predicted and was followed by several pharmacokinetic studies of the capsule in such patients. A double-blind cross-over study of PEG and pelleted forms of the itraconazole capsule (200 mg daily) in patients receiving remission induction therapy for acute myeloblastic leukaemia showed that a significant number of patients had levels below 250 ng/mL and that there was wide inter- and intra-patient variation in levels with both preparations.19 This study also showed that the day 14 median Cmax was approximately half that obtained with half the dose used in normal volunteers,8 even with good compliance, and compliance was in fact variable. In another study, even with daily doses of 400 and 600 mg of the capsule, plasma levels of greater than 250 ng/mL were not reliably obtained by day 10 in patients receiving chemotherapy for acute leukaemia or in those receiving an autologous bone marrow transplant.20 Despite these discouraging results, one key retrospective comparative study of the use of the capsule form of the drug during chemotherapy for acute leukaemia (76 patients and 148 courses) versus no systemic prophylaxis (47 patients and 112 courses) did suggest both that higher plasma levels can be obtained with higher doses and that these significantly reduce the risk of systemic fungal infections.21 The end point was death from proven systemic fungal infection, which was reduced in the itraconazole patients from 8.8% to 0.9% (P = 0.005). In those patients given 400 mg daily, the median trough plasma concentration was 520 ng/mL (range 230–793 ng/mL) and in those given 600 mg daily 760 ng/mL (370– 1200 ng/mL). Another retrospective analysis of incidence rates of breakthrough proven or probable systemic fungal infection in the treatment of haematological malignancy receiving itraconazole prophylaxis showed that trough (Cmin) plasma itraconazole concentrations of less than 500 ng/mL carried a significantly increased risk (P = 0.039) of invasive yeast but mainly pulmonary aspergillosis infections.22 Many of the patients in this last study had received the capsule form of the drug. In vitro, most Candida and Aspergillus spp. are inhibited by itraconazole concentrations greater than 1000 ng/mL.23 The co-existence of equally effective hydroxy-itraconazole, at concentrations approximately twice that of the parent drug,16 should ensure such overall antifungal activity in vivo. These human studies also confirm the animal model correlating plasma itraconazole levels with the pulmonary burden of aspergillosis.12 Dissatisfaction with the reliability of bioavailability of the capsule form of the drug in neutropenic patients with haematological malignancy led to pharmacokinetic studies in these patients of the cyclodextrin solution which had provided much greater Cmax and AUC values in normal volunteers. There have now been pharmacokinetic studies of the cyclodextrin solution in patients receiving intensive chemotherapy for acute myeloblastic leukaemia,24 children treated for a variety of haematological malignancies,25 patients receiving stem cell autografts for haematological malignacies26 and those receiving allogeneic stem cell transplants for leukaemia.27 By day 14 or 15 after daily doses of 5 mg/kg, means (– standard deviation) of Cmin range from 223 – 145 ng/mL in the children to 845 – 221 ng/mL in the adults treated for acute myeloblastic leukaemia. The Cmax and AUC values range from 3000 2000 1000 0 Day 3 Day 7 Day 11 Day 20 Figure 1. Itraconazole trough concentration after combining 400 mg/day itraconazole oral solution (starting on day 1) with itraconazole iv solution (400 mg/day on day 1 and 2). The line marks 500 ng/mL (A. Glasmacher and C. Hahn, unpublished observations). i19 Prentice and Glasmacher When either formulation is used alone, all studies suggest that the oral solution is more bioavailable than the capsule form. Loading as described above will reduce inter-patient variation and increase the probability of high levels. Variation in PK profiles is due not only to variable bioavailability but also to interindividual variation of the cytochrome P450 genotypes which express phenotypically variable rates of metabolism of all azoles. In addition, a significant proportion of patients will not tolerate the taste of the oral itraconazole solution30 and variable ingestion is a powerful determinant of variation of bioavailability of any oral preparation. In clinical practice, it is not clear how often blood levels should be measured but in patients at high risk of systemic fungal infections, where absorption or compliance are uncertain or where unnecessarily high levels are possible, weekly measurement of trough levels is recommended. The application of the HPLC method would require a small investment compared with the overall cost of care and to the likely benefit of reducing risk. The intravenous preparation of the cyclodextrin solution circumvents all the problems of bioavailability and poor compliance although it cannot influence cytochrome P450-determined rates of metabolism. In two pharmacokinetic studies of switching from oral to iv use, the iv preparation has been used to either load patients quickly at induction of neutropenia before switching to oral solution31 or to substitute for the oral solution should compliance fail.32 The latter study illustrated that levels of drug continued to rise with a daily dose of 200 mg iv and that the rate of rise of hydroxyitraconazole slows on switching to the iv preparation, presumably because the rate of exposure to hepatic hydroxylation is reduced. These results indicate that less than 200 mg daily iv may provide adequate bioavailability and support further the need for measurement of plasma levels. Interactions Although itraconazole exhibits greater specificity for fungal than for human and other mammalian CYP450, its binding to nonfungal types has been extensively investigated in vitro and in vivo. Itraconazole’s inhibition of rat microsomal enzyme activity was weak, it did not induce hepatic drug-metabolizing enzymes, and even at high doses, it did not interact in vitro with coumarins or methohexital.33,34 It did not change the pharmacokinetics of antipyrine, a marker of microsomal oxidation, when given to normal volunteers.35 There is, nevertheless, a long list of drugs known to interact with itraconazole and these interactions can be divided into those which affect itraconazole levels and those affecting levels or activity of others.36 Metabolism of itraconazole is induced by rifampicin, carbamazepine, phenytoin, phenobarbitone and isoniazid. Absorption of itraconazole is potentially reduced by any drug which reduces gastric acid. These preceding interactions further justify measurement of plasma levels of itraconazole with subsequent dose adjustment. The second group of interactions is perhaps more important. The metabolism of cyclosporin, tacrolimus and digoxin is reduced and their concentrations should be monitored to adjust doses as necessary. Midazolam, triazolam, cisapride, terfenadine and astemizole should be avoided because of potentially dangerous increases in their levels being induced by itraconazole. Calcium channel blockers should also be avoided if possible or at least there should be careful monitoring of the ECG because of prolongation of the QT interval with concomitant use of itraconazole. Coumarin derivatives may also be potentiated, so close monitoring of coagulation tests is needed. Itraconazole should be avoided in combination with vincristine and probably other vinca alkaloids because of the risk of severe neurotoxicity. There are no descriptions yet of the clinical interactions between itraconazole and the taxanes and busulphan but there is a theoretical possibility of these and concomitant administration is best avoided. The most serious interaction is probably least known since it has only recently been reported. In a randomized controlled trial of itraconazole versus fluconazole in bone marrow transplant patients, an excess of clinically significant renal and hepatic toxicity was observed in the itraconazole arm with a lower probability of survival.37,38 The hepatic toxicity was worst in the patients conditioned with cyclophosphamide and preliminary analysis of cyclophosphamide pharmacokinetic data suggests that these toxicities are related to an interaction leading to an excess of cyclophosphamide metabolites. When the trial protocol was amended, from starting itraconazole with conditioning to starting at day 0 on stem cell infusion, the difference in these toxicities in the two arms was no longer apparent. It should be noted however that these patients were given the highest recorded dose of itraconazole for prophylaxis at 7.5 mg/kg per day, that most patients were given iv drug and it is not clear how many patients needed dose reductions if their plasma levels were deemed too high. A similar comparative study in transplant patients, given itraconazole and fluconazole only after conditioning therapy, found no excess toxicity with itraconazole.39 Pharmacokinetic studies have shown that potentially protective plasma concentrations of itraconazole can be delivered by all the cyclodextrin preparations of the drug available. The itraconazole trough concentration should be above 500 ng/mL. Bioavailability is only absolutely reliable if the drug is given iv but the solution achieves greater levels than the capsule. It is possible to switch between the iv and the oral solutions depending on compliance, but, considering the high volume of distribution of the drug, oral or iv loading doses are needed to reach protective levels quickly. Owing to the inter-patient variation of bioavailability and metabolism (which is seen in all azoles), there is no way of predicting levels in individual patients so these should be routinely measured to ensure adequate bioavailability. The iv dosing schedule which will not result in a continuing rise in serum levels is not yet known and it is not clear from clinical studies if there is a maximum tolerable level. The contribution of hydroxy-itraconazole to effective bioavailability has been underestimated in many pharmacokinetic and in vitro susceptibility studies. In patients at high risk of systemic fungal infection, weekly trough level measurements may be necessary to ensure potentially protective trough levels. There are serious interactions but with careful management, these can be either avoided or monitored to reduce their clinical impact. Understanding the pharmacokinetic properties of itraconazole has informed attempts to demonstrate its clinical efficacy in reducing the risk of systemic fungal infection in the therapy of haematological malignancy. Transparency declarations A. G. P. has received reimbursement for attending advisory boards and symposia from Janssen-Cilag, Johnson and Johnson, OrthoBiotech, Pfizer, Gilead, Merck and Schering-Plough, for speaking i20 Neutropenic antifungal prophylaxis depends on pharmacokinetics of itraconazole from Janssen-Cilag, Gilead, Merck and Pfizer and as a consultancy fee from Ortho-Biotech/Janssen-Cilag but to his knowledge does not own directly any shares in any pharmaceutical company. A. G. has received the following: Gilead (speaker’s honoraria), Janssen-Cilag/Ortho-Biotech (consultant, research support, speaker’s honoraria), Merck Sharp & Dohme (consultant, research support, speaker’s honoraria), Pfizer (research support, speaker’s honoraria), Schering-Plough (consultant). References 1. Manavathu EK, Cutright JL, Chandrasekar PH. Organismdependent fungicidal activities of azoles. Antimicrob Agents Chemother 1998; 42: 3018–21. 2. Johnson EM, Szekely A, Warnock DW. In-vitro activity of voriconazole, itraconazole and amphotericin B against filamentous fungi. J Antimicrob Chemother 1998; 442: 741–5. 3. Zuckerman JM, Tunkel AR. Itraconazole: a new triazole antifungal agent. Infect Control Hosp Epidemiol 1994; 15: 397–410. 4. Vanden Bossche H, Marichal P, Gorrens J et al. Mode of action studies. Basis of the search for new antifungal drugs. Ann NY Acad Sci 1988; 544: 191–207. 5. Haria M, Bryson HM, Goa KL. Itraconazole. 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