A randomized comparative study to determine the effect of omeprazole on the peak serum concentration of itraconazole oral solution

Melissa D. Johnson1,*, Carol D. Hamilton1, Richard H. Drew1, Linda L. Sanders2, Gennethel J. Pennick3 and John R. Perfect1,4

1 Division of Infectious Diseases and International Health, Duke University Medical Center, Box 3306 DUMC, Durham, NC 27710; 2 Department of Medicine, Duke University Medical Center, Box 3827 DUMC, Durham, NC 27710; 3 Fungus Testing Laboratory, Department of Pathology, University of Texas Health Science Center, San Antonio, TX 78284; 4 Department of Microbiology, Duke University Medical Center, Box 3353 DUMC, Durham, NC 27710, USA

Received 21 June 2002; returned 4 November 2002; revised 12 November 2002; accepted 19 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
To determine the effect of omeprazole on peak serum concentrations (Cmax) of itraconazole oral solution (IOS), we carried out a randomized, open-label, prospective, crossover study. Fifteen healthy, non-pregnant adults received a single dose of IOS 400 mg on two occasions, at least 7 days apart, with omeprazole 40 mg nightly for 7 days before either IOS dose 1 or 2. Cmax, time to Cmax (Tmax) and AUC0–8 were determined for itraconazole and its active metabolite, hydroxyitraconazole, for each dose and compared. Omeprazole did not significantly affect the Cmax, Tmax or AUC0–8 of itraconazole or hydroxyitraconazole when administered as IOS.

Keywords: itraconazole, pharmacokinetics, omeprazole


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Itraconazole (Sporanox; Ortho Biotech, Bridgewater, NJ, USA) has enabled effective outpatient treatment for many fungal infections with reduced toxicity.1 Itraconazole has a potent, broad spectrum of activity, and has become the drug of choice for non-life-threatening histoplasmosis and blastomycosis, dematiaceous fungal infections and sporotrichosis.2 Studies have also supported its use for long-term suppressive therapy of systemic fungal infections, following an ‘induction’ phase with amphotericin B, for infections such as disseminated histoplasmosis, coccidioidomycosis, aspergillosis and cryptococcal meningitis.25 A new oral formulation of itraconazole in solution (IOS) demonstrates improved bioavailability and reduced pH dependency for adequate absorption when compared with capsules.1 However, no prospective studies have evaluated the pharmacokinetics of IOS in patients with either pathologically or pharmacologically induced gastric hypoacidity.

The proton-pump inhibitor omeprazole (Prilosec; Astra Merck, Wayne, PA, USA) reduces gastric basal acid output by up to 94% and peak acid production by as much as 86% after a single 40 mg dose.6 After 7 days of once-daily dosing, a 40 mg dose of omeprazole reduces peak acid production by 85% (range 76–96%) when measured 24 h after the last dose.6 Absorption of itraconazole capsules is reduced significantly by concomitant administration with omeprazole, and concurrent therapy is not recommended.7 It is not known what effect (if any) concurrent administration of a proton pump inhibitor may have on the bioavailability of IOS.

The primary objective of this open-label, single-dose, crossover study was to determine the effect of concurrent omeprazole administration on the time of (Tmax) and peak itraconazole serum concentration (Cmax) achieved after a single dose of IOS 400 mg in healthy volunteers. We also observed the resulting AUC0–8 among study subjects.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population

The protocol was approved by the Duke University Medical Center Investigational Review Board. Consenting healthy men or women (who were neither pregnant nor nursing an infant) of 18–55 years of age within 20% of their ideal body weight were included. Those unable to take oral medications or receiving concomitant medications known to alter itraconazole concentrations within 1 week of randomization (including phenytoin, phenobarbital, carbamazepine, isoniazid, rifampicin and rifabutin) or contraindicated with either study medication (astemizole, cisapride, clarithromycin, ciclosporin, diazepam, digoxin, felodipine, lovastatin, oral midazolam, quinidine, oral triazolam, simvastatin, tacrolimus, terfenadine, vincristine or warfarin) were excluded. Subjects with any underlying disease or anatomical disorder that would prevent them from absorbing, known liver dysfunction (defined as transaminases or alkaline phosphatase >3 times the upper limit of normal) or known hypersensitivity to azoles or omeprazole were also excluded.

Procedures

Physical examination and serum pregnancy test (for women of childbearing potential) were carried out at baseline. Subjects were also instructed to abstain from over-the-counter medications and alcohol for the duration of the study. Subjects fasted from midnight the night before IOS dosing until 4 h after IOS administration (including abstaining from drinking any beverages for 2 h after taking IOS).

Drug administration

The crossover design of the study took into account any possible ‘period effect’ by randomizing subjects in blocks of two to one of two treatment groups. Group I received the test study treatment first, followed by the reference study treatment. Group II received the reference study treatment first, followed by the test study treatment. The reference study period was 8 days, with no drug treatment on days 1–7 and IOS administered on day 8. The test study period was 8 days, with omeprazole administered on days 1–7 and IOS administered on day 8. There was always at least 7 days between IOS doses. IOS was administered as a single 400 mg dose (40 mL) followed by 240 mL of tap water between 8:00 and 9:00 a.m. Omeprazole was administered as two 20 mg capsules (40 mg) to be taken each evening at bedtime. Subjects recorded the date and time of each omeprazole dose in a diary, as well as any concomitant medications taken. Compliance was determined by a pill count and questionnaire at each study visit.

Pharmacokinetic determinations

Blood samples (4.5 mL) were obtained before each IOS dose, and then at 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 h after IOS administration. Samples were collected in sterile 9.5 mL serum-separator tubes (Becton Dickinson Vacutainer Systems, Rutherford, NJ, USA) from an indwelling venous catheter (‘heparin lock’), centrifuged within 1 h of sampling, pipetted into labelled containers and stored at –70°C. Itraconazole and hydroxyitraconazole were analysed by reverse-phase high performance liquid chromatography (HPLC) using a modified method described by Woestenborghs et al.8 The HPLC system utilized included a variable UV detector (263 nm), 3.9 x 50 mm C18 column, binary pump (flow rate 1.0 mL/min), Beckman System Gold Software (version 5.1 for DOS) and Gold Nouveau Software (version 1.7 for Windows). The lowest limit of quantification was 0.01 mg/L. The interday coefficients of variation (CVs) for itraconazole controls (0.05, 0.25 and 2.5 mg/L) were 12.31%, 6.56% and 6.23%, respectively. The interday CVs for hydroxyitraconazole controls (0.05, 0.25 and 2.5 mg/L) were 12.87%, 9.96% and 8.96%, respectively.

Cmax and Tmax were determined for itraconazole and hydroxyitraconazole by visual inspection of the serum concentration versus time curves. AUC0–8 for itraconazole and hydroxyitraconazole was calculated using the trapezoidal rule for each study subject using WinNonlin (version 2.1, Pharsight Corporation, Mountain View, CA, USA).

Statistical analysis

Based on prior studies, we assumed that a single 400 mg dose of IOS would yield an average Cmax of 2.4 mg/L with a standard deviation of 0.9. We also assumed that the within-person correlation between single oral doses of itraconazole solution is 0.7. Under these assumptions, we estimated that a sample size of 14 would enable 80% power to detect a 20% difference in mean peak serum concentrations using a significance level of 0.05.

Subjects were considered evaluable only if they completed both IOS doses and had at least 6 h of pharmacokinetic sampling after each itraconazole dose. SAS (Cary, NC, USA) was used for statistical analyses. A paired t-test was used to test differences in the pharmacokinetic parameters (Cmax, Tmax, AUC0–8) between the two treatments. In addition, the data were analysed for period and sequence effects as described by Pocock.9 Differences were considered statistically significant at P < 0.05. A 20% difference in mean maximum serum concentrations of itraconazole achieved after the two dosing regimens was considered significant.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twenty subjects were enrolled in the study and 15 (seven from Group I, eight from Group II) completed the entire study successfully. Eleven of these subjects were male and four were female. Their mean age was 26.33 years (range 23–41). Seven subjects were Caucasian, four were Asian, two were African-American and two were of Indian or Middle Eastern descent. Reasons for study discontinuation included family emergency (1), inability to have an intravenous line placed by study nurses (1) and adverse drug effects in three of 20 patients initially enrolled including vomiting (1) and rash (2) shortly after IOS administration. None of these events was severe or required hospitalization, but the investigators felt that these subjects should be withdrawn from further study participation.

All subjects completed at least 6 h of pharmacokinetic sampling after each IOS, and all but one completed 8 h. There were no statistically significant differences observed between treatments for Cmax, Tmax or AUC0–8 (Table 1). No period or carryover effects were observed for any of the pharmacokinetic parameters. Substantial inter-patient variability in mean serum itraconazole and hydroxyitraconazole concentration versus time curves was noted (see Figure 1).


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Table 1.  Pharmacokinetics of itraconazole and hydroxyitraconazole between treatments
 


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Figure 1. Mean serum itraconazole and hydroxyitraconazole concentration–time curves. Dashed lines, itraconazole serum concentrations; solid lines, hydroxyitraconazole serum concentrations; circles, reference treatment (IOS alone); squares, test treatment (IOS + omeprazole).

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Itraconazole (a weak base with a pKa of 3.7) is nearly insoluble in dilute acidic solutions and water.10 Its dependence on gastric acidity for absorption presents a significant problem for patients who lack gastric acidity due to pathological conditions (i.e. achlorhydria related to AIDS), pharmacotherapy that induces gastric hypoacidity (didanosine, proton pump inhibitors, H2-antagonists, antacids, etc.), patients with malabsorption secondary to radiochemotherapy and patients who cannot receive nourishment into the gastrointestinal tract.10

Unpredictable absorption of itraconazole capsules has been a limiting factor in optimal therapeutic use of this formulation.10 In contrast, bioavailability of IOS formulation has been shown to be 149 ± 68% of capsules.1

Since few studies have investigated the relationships between its pharmacokinetic and pharmacodynamic properties, an area under the inhibitory concentration curve (AUIC) target has not been established for itraconazole therapy, nor has a minimum AUIC been demonstrated in animal models to be associated with clinical outcomes. The need for serum itraconazole concentration monitoring to document adequate drug absorption is reflected in the recent guidelines for the treatment of aspergillosis published by the Infectious Diseases Society of America (IDSA).4 In our clinical practice these levels were frequently determined 2–4 h after oral dosing. Results from more recent clinical investigations would suggest that maintenance of a trough concentration >0.25–0.5 mg/L is correlated with therapeutic success, and has thus become the new standard.11

The present study confirms clinical observations by several other investigators regarding substantial inter-patient variability and absorption of IOS in populations with some degree of gastric hypoacidity. Cmax and AUC0–8 varied by as much as three-fold after IOS dosing (Figure 1). In addition, serum concentrations of itraconazole declined to <0.3 mg/L in as little as 8 h after dosing in some patients.

Our study was not intended to be a bioequivalence study, rather an observation of most clinically relevant pharmacokinetic parameters under clinically relevant conditions. The IOS dose used in this study is consistent with our current clinical practice for treating invasive fungal infections and consistent with IDSA guidelines for the treatment of invasive aspergillosis.4

Since omeprazole is known to inhibit CYP450 3A4, it is possible that such an interaction could elevate serum concentrations of itraconazole when the two agents are co-administered.6 However, a previous study with itraconazole capsules reported no such interaction. In fact, the mean AUC0–24 and Cmax of itraconazole were reduced by 64% and 66%, respectively, after 15 days of omeprazole therapy.7 Although omeprazole is metabolized by cytochrome P450 2C19 (which may be differentially expressed by individuals depending upon genetic morphology), results from other studies indicate that differences in metabolism of omeprazole that are apparent on day 1 of dosing diminish by day 7.12 Thus, it is likely that the pharmacogenetics of 2C19 played a minimal or no role in our study, and that all subjects had more than sufficient suppression of gastric acid production after 7 days of omeprazole dosing.

Our data demonstrate that IOS may be well-absorbed even in the presence of a potent gastric-acid inhibitor. Despite this pharmacokinetic advantage, the considerable inter-subject variability observed in this study and other trials suggests that serum concentration monitoring may be important for documenting adequate absorption of itraconazole after oral dosing independent of the oral formulation.


    Acknowledgements
 
The General Clinical Research Center is supported by grant MO1-RR-30, National Center for Research Resources, Clinical Research Centers Program, National Institutes of Health. This study was supported by the Duke University Mycology Research Unit (PO AI44975). Support for HPLC assays was provided by Janssen Pharmaceutica.

Presented in part at the Thirty-eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 1998.


    Footnotes
 
* Corresponding author. Tel: +1-919-684-2374; Fax: +1-919-681-7494; E-mail: johns200{at}mc.duke.edu Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Willems, L., van der Geest, R. & de Beule, K. (2001). Itraconazole oral solution and intravenous formulations: a review of pharmacokinetics and pharmacodynamics. Journal of Clinical Pharmacy and Therapeutics 26, 159–69.[CrossRef][ISI][Medline]

2 . Chapman, S. W., Bradsher, R. W., Jr, Campbell, G. D., Jr, Pappas, P. G. & Kauffman, C. A. (2000). Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clinical Infectious Diseases 30, 679–83.[CrossRef][ISI][Medline]

3 . van der Horst, C. M., Saag, M. S., Cloud, G. A., Hamill, R. J., Graybill, J. R., Sobel, J. D. et al. (1997). Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. New England Journal of Medicine 337, 15–21.[Abstract/Free Full Text]

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7 . Jaruratanasirikul, S. & Sriwiriyajan, S. (1998). Effect of omeprazole on the pharmacokinetics of itraconazole. European Journal of Clinical Pharmacology 54, 159–61.[CrossRef][ISI][Medline]

8 . Woestenborghs, R., Lorreyne, W. & Heykants, J. (1987). Determination of itraconazole in plasma and animal tissues by high-performance liquid chromatography. Journal of Chromatography 413, 332–7.[Medline]

9 . Pocock, S. J. (1984). Clinical Trials. John Wiley & Sons, Ltd, Hoboken, NJ, USA.

10 . Haria, M., Bryson, H. M. & Goa, K. L. (1996). Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 51, 585–620.[ISI][Medline]

11 . Harousseau, J. L., Dekker, A. W., Stamatoullas-Bastard, A., Fassas, A., Linkesch, W., Gouveia, J. et al. (2000). Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrobial Agents and Chemotherapy 44, 1887–93.[Abstract/Free Full Text]

12 . Zhou, Q., Yamamoto, I., Fukuda, T., Ohno, M., Sumida, A. & Azuma, J. (1999). CYP2C19 genotypes and omeprazole metabolism after single and repeated dosing when combined with clarithromycin. European Journal of Clinical Pharmacology 55, 43–7.[CrossRef][ISI][Medline]