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Clinical Cancer Research Vol. 8, 2480-2487, August 2002
© 2002 American Association for Cancer Research

Clinical Trials

Differential Effect of IFN{alpha}-2b on the Cytochrome P450 Enzyme System: A Potential Basis of IFN Toxicity and Its Modulation by Other Drugs1

Mohammed Islam, Reginald F. Frye, Thomas J. Richards, Ibraham Sbeitan, Sandra S. Donnelly, Paul Glue, Sanjiv S. Agarwala and John M. Kirkwood2

Melanoma Center, University of Pittsburgh Cancer Institute [M. I., T. J. R., I. S., S. S. D., S. S. A., J. M. K.], Department of Medicine, School of Medicine [J. M. K.], and Department of Pharmaceutical Sciences, School of Pharmacy and Center for Clinical Pharmacology [R. F. F.], University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and Schering Plough Research Institute, Kennilworth, New Jersey 07033 [P. G.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Patients and Methods
 Results
 Discussion
 REFERENCES
 
Purpose: High-dose IFN{alpha}-2b therapy (HDI) is the standard of adjuvant therapy for patients with high-risk melanoma, but toxicities of this regimen have limited its application. IFNs affect cytochrome P450 (CYP) enzymes, which metabolize many endogenous (e.g., steroids, fatty acids) and exogenous (e.g., drugs) substrates. No systematic studies have been performed to evaluate the effect of HDI on CYP enzymes. A significant inhibitory effect of HDI on CYP enzymes would increase the potential for adverse drug reactions and altered homeostasis through effects on hormone metabolism.

Methods: To evaluate the potential effect of HDI on CYP enzymes, 17 patients with high-risk melanoma were treated with HDI, and CYP enzyme activity was measured by administration of selectively metabolized probe drugs over time (days -6, +1, +26, and +52 of HDI). Probe drugs and/or metabolites were quantified and used to derive indexes of enzyme activity.

Results: The results indicate that HDI differentially impairs CYP-mediated metabolism, having no effect on some enzymes (CYP2E1) and substantial effects on others (CYP1A2; median 60% decrease). A significant association was found between the magnitude of CYP inhibition and the occurrence of side effects including fever and neurological toxicity, which may form a novel basis of the underlying pathophysiology of some IFN{alpha}-2b-induced toxicity.

Conclusion: These data suggest that strategies to minimize the impairment of CYP enzymes could alter the toxicity profile of HDI and augment its therapeutic utility, and that recognition of these potential interactions is important in the therapeutic application of IFNs.


   Introduction
Top
 ABSTRACT
 Introduction
Patients and Methods
 Results
 Discussion
 REFERENCES
 
IFNs are cellular proteins of 143–187 amino acids produced by stimulated immune and nonimmune cells that exhibit antiviral, differentiating, antiproliferative, and immunomodulatory functions. IFN{alpha}-2b exhibits variable therapeutic responses when used in combination with various chemotherapies and cytokines in metastatic melanoma (1, 2, 3) . However, no therapy has yet demonstrated unequivocal effects on survival in patients with metastatic disease. In the adjuvant setting, survival and relapse-free interval were significantly prolonged in the pivotal E1684 trial of the Eastern Cooperative Oncology Group, and in the most recent intergroup trial E1694 (4 , 5) . Despite the significant therapeutic gain associated with adjuvant HDI3 therapy, toxicity and adverse effects have impeded adoption of this therapy by physicians and patients. Approximately 78% of patients receiving IFN therapy in E1684 experienced grade 3 toxicity, and 24% discontinued therapy because of this toxicity (6 , 7) . The management or prevention of toxicities associated with HDI therapy is one of the greatest challenges in broadening and improving the efficacy of this regimen.

The CYP enzymes are a superfamily of heme-containing enzymes distributed widely throughout the body that are involved in the synthesis and metabolism of endogenous substrates including steroid hormones, fatty acids, and lipids, as well as the metabolism of exogenous substrates such as drugs and environmental chemicals. IFNs have been shown to decrease the expression and activity of CYP enzymes in animal models (8, 9, 10, 11) . Human data are less extensive and primarily limited to patients with hepatitis being treated with comparatively low-dose IFNs (12, 13, 14, 15) , but the available data indicate a detrimental effect on drug metabolism. However, the selectivity and magnitude of the effect on individual drug metabolizing enzymes is largely unknown. In addition, there are no data on the effect of HDI used to treat patients with melanoma on drug-metabolizing enzymes. A deleterious effect on the CYP enzyme system would have important consequences because of the increased potential for drug-induced adverse effects related to concomitant drug treatment (i.e., drug-cytokine interactions) and also the potential for altering homeostasis through effects on endogenous substrates such as hormones. Thus, this study was conducted to examine the effects of acute and chronic high-dose IFN{alpha}-2b monotherapy on several important drug-metabolizing CYP enzymes in vivo using known enzyme-selective probe drugs (16, 17, 18) .


   Patients and Methods
Top
 ABSTRACT
 Introduction
 Patients and Methods
Results
 Discussion
 REFERENCES
 
Study Design.
Seventeen patients with high-risk, resected melanoma who were scheduled to undertake adjuvant therapy with high-dose IFN{alpha}-2b participated in this study after providing written informed consent. Eligibility criteria included biopsy-proven high-risk melanoma, normal renal (serum creatinine <2.0 mg/dl) and liver function (total bilirubin <1.5 mg/dl), and no history of allergy to sulfa drugs. All of the subjects were instructed to abstain from alcohol, caffeine, barbecued meat, and grapefruit or grapefruit juice consumption for at least 2 days before each visit (19) . Patients with other underlying medical diseases taking drugs known to affect the CYP enzyme system that could not be safely interrupted were excluded from the study.

All of the patients received i.v. IFN-{alpha}2b (INTRON A; Schering Plough, Kenilworth, NJ) at a dose of 20 million units (MU)/m2/day for 5 days/week x 4 weeks (induction phase) followed by s.c. IFN-{alpha}2b at a dose of 10 MU/m2/day for 3 days/week x 48 weeks (maintenance phase).

CYP Cocktail Studies.
CYP enzyme activities were studied on day -6 (baseline), day 1 (first dose of i.v. IFN{alpha}-2b), day 26 (last dose of i.v. IFN{alpha}-2b), and day 52 (end of 1 month of s.c. IFN{alpha}-2b) as shown in Table 1Citation . CYP enzyme activities were estimated in vivo using the "Pittsburgh mixture" approach, which involves the simultaneous oral administration of five drugs for which the metabolism has been well characterized. Each patient received the mixture of five drugs during each visit as shown in Table 2Citation . We have shown previously that there is no interaction between the mixture drugs at the doses given (20) . Blood samples (20 ml) were obtained at 0, 4, and 8 h, and urine was collected from 0 to 8 h to measure the concentration of probe drugs and/or their metabolites. Plasma harvested by centrifugation, and urine aliquots were stored frozen at -20°C until analyzed. The probe drugs and their metabolites were analyzed by high-performance liquid chromatography for the determination of caffeine and paraxanthine, (21) , 4-hydroxymephenytoin, (20) , debrisoquine, and 4-hydroxydebrisoquine (18) , chlorzoxazone and 6-hydroxychlorzoxazone (17) , dapsone and N-hydroxydapsone in urine, and dapsone and monoacetyldapsone in plasma (22) . Probe drug analyses were conducted such that all of the samples for a given patient were analyzed within the same run so as to minimize within-subject variation because of analytical procedures. The interday coefficients of variation for each of these assays were <15%. In addition, all of the assay procedures were cross-validated to ensure that no analytical interference would occur with simultaneous administration of these drugs. Phenotypic trait measures (Table 2)Citation that serve as indexes of enzyme activity were calculated from the quantified drugs and metabolites as described previously (20) .


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  		Table 1 Schema of study designed to evaluate the differential effect of HDI therapy on the CYP enzyme system

 

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  		Table 2 Five probe drugs regimen or "Pittsburgh mixture" and their doses, corresponding CYP, and activity measure

 
IFN Pharmacokinetics Study.
The pharmacokinetics of IFN were determined in each subject on study days 1, 26, and 52. Blood samples were obtained before IFN administration and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h after i.v. administration, or 4, 8, 10, 12, 16, and 24 h after s.c./i.v. administration. After clotting, the samples were centrifuged, and the resulting serum was stored at -20°C until analyzed. IFN{alpha}-2b concentrations were measured as described previously (23) using an electrochemiluminescence immunoassay with a limit of quantitation of 4 IU/ml.

Pharmacokinetic Data Analysis.
Pharmacokinetic parameter estimates were calculated by noncompartmental analysis using WinNonlin version 3.1 (Pharsight Corp., Mountain View, CA). The Cmax and Tmax were determined by visual inspection of the data. The AUC was estimated by the linear trapezoidal rule with extrapolation to infinity.

Statistical Analysis.
Changes in individual CYP enzyme activity profiles were examined using multivariate permutation methods. To control for multiple comparisons, an omnibus test was performed at level {alpha} = 0.05 to test the global null hypothesis that none of the enzyme activity estimates varied at any subsequent time point from its baseline activity level. CYP enzyme activity estimates were randomly permuted under the null hypothesis in a multivariate Wilcoxon signed-rank test. After rejection of the null hypothesis, Ps for null hypotheses of no change in activity for individual enzymes were examined. On rejection of an individual null hypothesis, Ps were computed for comparing enzyme activity at subsequent time points to activity at baseline. Changes from baseline at time points found to differ significantly were related to incidence of adverse events. Adverse events with onset dates between day 7 and day 26 of i.v. IFN administration were attributed to the i.v. phase of treatment; adverse events occurring between day 7 of the s.c. phase and the off-study date were attributed to the s.c. phase of treatment. The following adverse events were included if deemed to be possibly treatment-related: (a) all of the grade 2 or higher adverse events in the gastrointestinal, cardiovascular, hematological, and neurological systems; (b) all of the instances of fatigue (a neurological event) of grade 1 or higher; (c) all of the instances of neutropenia (a hematologic event) of grade 1 or higher; and (d) all of the flu-like symptoms of grade 1 or higher. Logistic regression analysis was used to relate incidence of adverse events to magnitude of CYP enzyme inhibition. IFN Cmax and AUC data were related to CYP enzyme inhibition using regression and correlation and to incidence of adverse events using logistic regression.


   Results
Top
 ABSTRACT
 Introduction
 Patients and Methods
 Results
Discussion
 REFERENCES
 
CYP Enzyme Activity.
Study drugs were well tolerated by all of the subjects participating in this study. The summary results of phenotypic measures for each probe drug determined after simultaneous administration of the five drug mixture at baseline (day -6), day 1 (first dose of i.v. IFN{alpha}-2b), day 26 (last dose of i.v. IFN{alpha}-2b, and day 52 (end of one month of s.c. IFN{alpha}-2b) are shown in Table 3Citation . The omnibus P for testing all of the enzyme profiles was P = 0.002, and Ps for individual isozymes are listed in the second column of Table 3Citation (rows are ordered by statistical significance of individual isozyme profiles). As the individual time point comparisons in Table 3Citation indicate, activity of two CYP enzymes, 1A2 and 2D6, were found to be significantly inhibited immediately after the first IFN dose, whereas significant inhibition of CYP2C19 and dihydrodial was first detected at day 26. Significant inhibition was not found for either N-acetyltransferase or CYP2E1. Figs. 1Citation and 2Citation depict isozyme activity levels of each patient during the i.v. phase. The median percentage of changes of the trait measures observed during high-dose i.v. and s.c. IFN{alpha}-2b treatment phases are shown in Fig. 3Citation .


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  		Table 3 Inhibition of P450 isozyme activity, by time

 


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  		Fig. 1. Individual and summary boxplot data of caffeine (CYP1A2), debrisoquine (CYP2D6), and dapsone hydroxylation during IFN{alpha}-2b treatment.

 


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  		Fig. 2. Individual and summary box plot data of chlorzoxazone (CYP2E1) and mephenytoin (CYP2C19) activity during IFN{alpha}-2b treatment.

 


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  		Fig. 3. Summary of median percentage of decrease from baseline of individual CYP enzyme activities during HDI treatment.

 
IFN Pharmacokinetics.
Data from 15 patients were available for pharmacokinetic analysis after i.v. IFN administration and from 12 patients after s.c. administration. The Cmax values [median (range)] were 1575 IU/ml 200–3(1,200–3,230 IU/ml) and 2630 IU/ml 090–4(1,090–4,020 IU/ml) on study days 1 and 26, respectively, and were 149 IU/ml (4–16 IU/ml) after s.c. administration on day 52. The AUC [median (range)] values were 2,469 IU x h/ml 463–6(1,463–6,537), 7,247 IU x h/ml 122–17(2,122–17,262), and 2,254 IU x h/ml 098–3(1,098–3,025) on days 1, 26, and 52, respectively. The Tmax after SC administration was observed at 8 h (range, 4–16). IFN{alpha}-2b exposure as measured by AUC was positively correlated with the percentage of inhibition of CYP1A2 at day 26, the last day of i.v. IFN{alpha}-2b administration (r = 0.68; P = 0.01). No other enzyme inhibition data were found to correlate with either AUC or Cmax. Neither AUC nor Cmax was found to be associated with any type of adverse event during i.v. or s.c. phase of IFN{alpha}-2b administration.

Adverse Events and CYP Enzyme Activity.
Adverse events during i.v. and s.c. phases of HDI were observed, and the association with CYP activities was assessed. The number of patients who experienced each type of adverse event during the i.v. and s.c. phases is listed in Table 4Citation . The number of patients who experienced at least one adverse event in a particular organ is separately recorded during i.v. and s.c. phases (n = 17). A single patient could have adverse events of more than one subtype. Binary indicators for each type of adverse event were analyzed separately in relation to each CYP enzyme that was found to exhibit a significant level of inhibition (CYP1A2, 2D6/IV, and 2C19/SC). The Ps for the association of particular isozymes and each subtype of toxicity, derived from logistic regression models with binary response variables indicating adverse events of each type, are presented in Table 4Citation . Identical conclusions were also reached using absolute change from baseline as the covariate. For neurological toxicities, the estimated relative risk for each 1% increase in inhibition of CYP1A2 is 1.1. The estimated relative risk for flu-like symptoms in relation to CYP2D6 inhibition is 1.1 for each 1% increase in CYP2D6 inhibition. The estimated relative risk for fever in relation to CYP2D6 inhibition is 1.2 for each 1% increase in CYP2D6 inhibition.


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  		Table 4 Adverse events by body system and relation to P450 isozyme inhibition

 

   Discussion
Top
 ABSTRACT
 Introduction
 Patients and Methods
 Results
 Discussion
REFERENCES
 
It has been known for many years that viral infection, influenza vaccination, Bacillus Calmette-Guérin inoculation, and fever are associated with impaired CYP-mediated metabolism of drugs such as theophylline, phenytoin, and aminopyrine (24, 25, 26) . Such impairment of drug metabolism has been attributed in part to release of endogenous IFNs (9, 10, 11 , 27) and partially corroborated in animal models. High-dose IFN{alpha}2b therapy was approved 6 years ago by the United States Food and Drug Administration and regulatory authorities worldwide as the first systemic adjuvant intervention capable of significant survival benefit, administered at maximal tolerable dosages i.v. for 4 weeks and s.c. for 48 weeks. This has posed new challenges for the patient on HDI therapy and the treating physician because of the toxicities of HDI. We report here the first comprehensive in vivo data showing that HDI impairs CYP-mediated metabolism in a differential fashion in high-risk resected melanoma patients. The observed effects on CYP ranged from no change (CYP2E1) to substantial impairment (CYP1A2), and we have also shown an association between the magnitude of inhibition and the occurrence of adverse effects including fever and neurological effects. These observations are an important platform for improved understanding of adverse effects that are associated with HDI in patients with melanoma and may allow for the avoidance of toxicity in patients with reduced levels of CYP function on HDI in the future.

Previous studies evaluating the effect of IFN treatment on drug metabolism have been conducted with the doses used to treat hepatitis (i.e., 3–6 million units three times per week) and in some cases after only a single dose. Even at these relatively lower doses, it was shown that IFN treatment adversely affects drug metabolism. For example, Williams et al. (13) evaluated theophylline clearance in 5 patients with chronic active hepatitis B and 4 normal healthy volunteers. Theophylline clearance was assessed 1–2 weeks before and 20 h after a single i.m. injection of IFN{alpha}. Inhibition of theophylline clearance ranged from 33 to 81% and was observed in 8 of the 9 subjects. Theophylline clearance was also decreased in 7 patients with hepatitis C who were treated with IFN-ß for 8 weeks (14) . The disposition of antipyrine, a probe of hepatic oxidative metabolism that is metabolized by multiple CYP enzymes, was evaluated in patients receiving IFN with the results generally showing a decrease in antipyrine clearance of ~20% (range 5 to 47; Refs. 28 , 29 ) Theophylline, and to a lesser extent antipyrine, are predominately metabolized by CYP1A2; data on other CYP enzymes are lacking. Our in vivo data clearly show that IFN{alpha}-2b therapy has a differential effect on CYP-mediated metabolism. Activities of CYP1A2, CYP2D6, and CYP2C19 were decreased, whereas CYP2E1 was not changed. The hydroxylation of dapsone was also significantly decreased but more difficult to interpret because multiple CYP enzymes including CYP2C8, CYP2C9, CYP2E1, and CYP3A4 contribute to the metabolism of dapsone (30 , 31) . The clinical implication of our findings is that the clearance of drugs predominately metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes would be decreased, which may result in increased drug exposure and, therefore, increased potential for adverse effects. Thus, the drug-cytokine interaction observed during IFN{alpha}-2b therapy might have significant clinical consequences. CYP1A2, CYP2D6, and CYP2C19 are involved in the metabolism of sedatives, narcotics, psychotherapeutics, antiepileptics, beta blockers, proton pump inhibitors, anesthetics, bronchodilators, and antibiotics (11, 12, 13, 14 , 32, 33, 34, 35) . Therefore, caution is indicated when such agents of which the metabolism is inhibited by IFN are being used during and after HDI therapy. Selected representatives of the classes of drugs metabolized by these CYP enzymes are shown in Table 5Citation .


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  		Table 5 Selected listing of clinically relevant drugs metabolized by CYP enzymes

 
The mechanism(s) by which IFN{alpha}-2b inhibits hepatic CYP is not definitively known (36 , 37) . It has been suggested that inhibition of CYP by IFN may require production of free radicals by xanthine oxidase (38) . More recently, Ghezzi et al. (39) provided additional evidence for this hypothesis by observing that free radical scavengers (N-acetylcystein and {alpha}-tocopherol) or xanthine oxidase inhibitors (allopurinol) can protect against IFN{alpha}-2b-mediated loss of CYP activity. Because IFN{alpha}-2b modulates production of cytokines, it is reasonable to presume cytokine-mediated inhibition of the CYP enzyme system. We are not able to differentiate between direct and indirect IFN{alpha}-2b effects in the current study; however, earlier studies failed to demonstrate a role for the cytokines tumor necrosis factor, IL-1, IL-6, and nitric oxide in IFN{alpha}-2b-mediated CYP enzyme inhibition (40 , 41) , and it may be therefore presumed that the effects observed in this study are more likely direct effects of IFN{alpha}-2b.

The significant association between the degree of CYP inhibition and IFN-induced adverse effects may form a new basis of the underlying pathophysiology of IFN{alpha}-2b-induced adverse effects. The associations of CYP2D6 inhibition with flu-like symptoms, and CYP1A2 with neuropsychiatric symptoms and fatigue are significant and demand additional study. The sample size for analyzing associations between enzyme inhibition and incidence of adverse events is small, but not inordinately so for an exploratory study, because inhibition of a single P450 isozyme was the only predictor variable used in each data analysis. Because only 2 patients experienced anemia during the i.v. phase, the possible association in Table 4Citation between anemia and CYP2D6 inhibition in the i.v. phase may be a statistical artifact. The 2 patients with anemia during the i.v. phase had two of the four highest values for CYP2D6 inhibition. But for hypothesis generation the number of adverse events may be sufficient for both the neurological system and flu-like symptoms. In addition, the link between CYP inhibition and fever is plausible because it has been shown that CYP inhibitors augment and CYP inducers attenuate lipopolysaccharide- and IL-1-induced fever in mice (42 , 43) . The mechanism by which this occurs is thought to involve alternative pathways of arachidonic acid metabolism. Cyclooxygenase enzymes metabolize arachidonic acid to proinflammatory eicosanoids (e.g., prostaglandins, thromboxanes, and so forth), whereas CYP enzymes produce anti-inflammatory epoxyeicosatrienoic acids and mono-hydroxyeicosatetraenoic acids. The observed association between CYP1A2 inhibition and neurological toxicities may be related to the altered metabolism of endogenous neurotransmitters and neurohormones. CYP enzymes have been implicated in both the formation (44) and metabolism (45 , 46) of dopamine, suggesting that modulation of CYP enzymes may alter neurotransmission. This is a reasonable hypothesis but warrants additional study.

Knowledge of the substrates, inhibitors, and inducers of CYP enzymes is critical to the avoidance of drug-drug interactions and unwitting exacerbation of toxicities associated with IFN{alpha}-2b therapy. A better understanding of the regulation of CYP enzymes and their interactions with cytokines such as IFN{alpha}-2b may permit avoidance of toxicity. More importantly, a better understanding of the role of the CYP enzyme system in terms of both exogenous and endogenous mediators of neurotransmission will ultimately permit more rational therapies to be developed.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by NIH/NCRR/GCRC Grant #5M01 RR00056. Back

2 To whom requests for reprints should be addressed, at Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center, 200 Lothrop Street, Montefiore Hospital N-755, Pittsburgh, PA 15216. Phone: (412) 648-6571; Fax: (412) 648-6599; E-mail: jmk{at}jimmy.harvard.edu Back

3 The abbreviations used are: HDI, high-dose IFN{alpha}-2b; AUC, area under the plasma concentration-time curve; Cmax, maximum observed serum concentration; CYP, cytochrome P450; IL, interleukin; Tmax, time to achieve maximum serum concentration. Back

Received 11/16/01; revised 3/23/02; accepted 4/ 2/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Patients and Methods
 Results
 Discussion
 REFERENCES
 

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