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DRUG INTERACTIONS |
From the Office of Blood Review & Research (OBRR) (Dr Mahmood) and Office of Vaccine Review & Research (OVRR) (Dr Green), Center for Biologic Evaluation and Research, Food & Drug Administration (FDA), Rockville, Maryland (Dr Mahmood).
Address for correspondence: Iftekhar Mahmood, PhD, Office of Blood Review & Research (OBRR), Center for Biologic Evaluation and Research, Food & Drug Administration, 1451 Rockville Pike, Rockville, MD 20850; e-mail: Iftekhar.mahmood{at}fda.hhs.gov.
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ABSTRACT |
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Key Words: Drug interaction • therapeutic proteins • monoclonal antibodies
Drug interaction can alter the pharmacokinetics and/or pharmacodynamics of a drug. In pharmacokinetic drug interactions, the concentrations of 1 or more drugs are altered by another drug. This change in concentration in a given drug may be due to changes in absorption, distribution, metabolism, or elimination. The pharmacodynamic interaction can lead to additive, synergistic, or antagonistic effects of a drug2 and may be due to various mechanisms, including receptor interaction and changes in effector mechanisms.
Therapeutic proteins are macromolecules (>1000 Daltons) that are becoming widely popular for the management and cure of many diseases. Therapeutic proteins are diverse as well as complex. Therapeutic proteins are naturally occurring substances in the body and, due to their size and physicochemical properties such as protein folding, formulation, and lack of long-term stability, can pose unique challenges for pharmacokinetic studies. Administration of exogenous proteins can influence the stimulation or feedback mechanism of endogenous proteins, and thus, estimation of pharmacokinetic parameters may become difficult.3 Some important differences between therapeutic proteins and small-molecule drugs are shown in Table I.3 From Table I, it is apparent that the elimination mechanism of macromolecules differs significantly from that of small molecules. The role of protein binding in the metabolism and elimination of macromolecules is limited, and the process of gastrointestinal absorption also does not play any role because macromolecules and antibodies are rarely administered by the oral route.
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Proteins and macromolecules are mainly cleared by renal filtration and non-P450 liver metabolism. Receptor-mediated clearance is another important mechanism of elimination for therapeutic proteins. Any drug or chemical substance that influences the aforementioned routes of elimination of protein drugs can substantially alter the pharmacokinetics (PK) and/or pharmacodynamics (PD) of these drugs.3
To properly understand the mechanism of interaction of therapeutic proteins or monoclonal antibodies with other drugs (small as well as macromolecules), it is important to know the pharmacokinetic characteristics (especially metabolism and elimination) of these macromolecules.
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Absorption |
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Although for therapeutic proteins and monoclonal antibodies, the interaction in the gastrointestinal tract is not an issue, it is possible that the pharmacokinetics of a small-molecule drug given orally may be altered (due to inhibition or induction of the cytochrome P450 system in the liver or gastrointestinal tract) when coadministered with a macromolecule.3
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Distribution |
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Although plasma protein binding of macromolecules is not considered important, studies do indicate that there are binding proteins for macromolecules.5 For therapeutic proteins, plasma binding proteins may serve as transporters and activators, especially for those drugs that pass membranes by active processes. Binding proteins for insulin-like growth factors (IGFs), growth hormone, cytokines, and t-PA have been reported. Some proteins have their own naturally occurring binding proteins.5 For example, 6 specific binding proteins were identified for IGF-1, with IGFBP-3 being the most important binding protein. The elimination half-life of bound IGF-1 was comparatively longer (3-4 hours) than unbound IGF-1 (10 minutes). For growth hormone (GH), at least 2 binding proteins have been identified: 1 with high binding affinity and the other at low affinity. Growth hormone binding protein (GHBP) binds about 40% to 50% of circulating GH at concentrations of about 5 ng/mL. At higher concentrations of GH, the binding proteins become saturated. The clearance of unbound GH is 10 times faster than the bound GH.5 There are many other drugs such as interferon, interleukins, and tumor necrosis factor for which specific binding proteins have been identified.5
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Metabolism |
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Biotransformation-based drug-drug interactions may occur due to the presence of the cytochrome P450 system.2 The main sites of drug metabolism and interactions are the liver and/or gastrointestinal tract. The cytochrome P450 (CYP450) system refers to a group of enzymes that is located in the endoplasmic reticulum. Knowledge of the CYP450 system is critical in understanding drug metabolism and drug interactions. High concentrations of these enzymes are located in the liver and small intestine. The concentrations of the cytochrome P450 system can be altered by inhibition and induction and can vary from person to person. Many drugs may increase or decrease the activity of various CYP isozymes, which may result in adverse drug interactions, because changes in CYP enzyme activity may affect the metabolism and clearance of various drugs.
Over the span of the past 20 years, considerable progress has been made in the characterization of human cytochrome P450s. Animals as well as human liver microsomes (in vitro preparations) contain different cytochrome P450 isozymes that are responsible for the biotransformation of xenobiotics and endogenous substances. With the understanding of the role of cytochrome P450 in the biotransformation of drugs, it is possible to characterize the metabolic pattern of a drug. Analysis of the literature indicates that several isozymes, such as CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2C19, are responsible for drug metabolism. There are, however, 3 major isozymes (CYP3A4, CYP2D6, CYP2C9) that are responsible for the metabolism of almost 90% of drugs.6 Due to broad and overlapping specifications, sometimes 2 or more isozymes may be involved in the metabolism of a particular drug.6
Transporter-based drug-drug interactions play an important role in the processes of drug absorption, distribution, and excretion.7 Due to these characteristics, transporters are involved in clinically significant transporter-mediated drug interactions. The ultimate result of such interactions is alteration in the efficacy or safety of a given drug (the substrate). Drug transporters can be divided into 2: (1) the influx transporters, which play an important role in facilitating the entry of drugs into cells, and (2) the efflux transporters, which limit the entry of drugs or enhance the removal of drugs from cells.7 Transporter-based drug interactions can be inhibitory, inductive, or both.8,9 An important aspect of transporter-based interaction is that the concentrations of drugs in the tissues caused by inhibition of transporters result in much higher levels than those in blood or plasma.10,11 Transporter-mediated drug interaction with macromolecules has not been established.
It is widely believed that therapeutic proteins are metabolized by the same catabolic pathways as endogenous proteins and can be broken down into amino acid fragments.12 Generally, the metabolic products of proteins are not considered a safety risk. Compared to the conventional drugs, characterizing the metabolites of therapeutic proteins is a much more difficult task. These difficulties arise due to the lack of suitable analytical method(s) and abundance of potential sites of metabolism (due to the complex structure of therapeutic proteins). Most proteins are catabolized by the enzyme "proteolysis," which is distributed throughout the body. Proteolytic activity in the tissues can lead to protein degradation after subcutaneous administration.12 Furthermore, the rate and extent of production of the metabolites will depend on the route of administration. Although therapeutic proteins may not be metabolized by the cytochrome P450 system, they can inhibit or stimulate the cytochrome P450 system in the body (discussed later).
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Elimination |
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Chemical and enzymatic processes can lead to the degradation of proteins and peptides. Due to the presence of peptidases in the gastrointestinal mucosa, oral administration of proteins and peptides is not an appropriate route of administration. Chemical degradation of proteins involves deamidation, hydrolysis, oxidation, racemization, and disulfide exchange,14 whereas physical degradation of proteins involves denaturation and aggregation. The enzyme proteases are responsible for proteolysis, accelerating hydrolysis, and other chemical degradation processes.14
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Renal Excretion |
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Hepatic Elimination |
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Receptor-mediated endocytosis can lead to saturable clearance or nonlinear pharmacokinetics for peptide and protein drugs.3 In RME, circulating proteins are taken up by specific hepatic receptor proteins.13 Examples of drug clearance by target-mediated RME include insulin, epidermal growth factor, filgrastim, pegfilgrastim, and efalizumab. Receptor-mediated uptake for some proteins is so extensive that the clearance of such macromolecules reaches the liver blood flow.4
Pinocytosis is a nonspecific, nonsaturable, noncarrier-mediated form of membrane transport.17 The transport mechanism involves vesicular uptake of bulk fluid into cells from the surrounding medium.17 The proteins are internalized according to their concentration within plasma.13 Polymer conjugates, some antigen-antibody complexes, some glycoproteins, and pancreatic proteins are examples of proteins cleared from plasma by pinocytosis.
Some proteins can also be cleared from the systemic circulation by biliary excretion. Insulin and epidermal growth factor are examples of therapeutic proteins that are excreted in the bile.18
Antibody clearance mechanisms are complex.19 Antibodies may be eliminated via excretion or catabolism. Because the size of immunoglobulins is large, minimal intact immunoglobulins are filtered by the kidneys. Low molecular weight antibody fragments are, however, filtered but are not excreted; rather, they are reabsorbed and metabolized by proximal tubular cells. Some immunoglobulins are also excreted in the bile (approximately 3%), but the vast majority of immunoglobulins are eliminated by catabolism.19 Receptor-mediated drug disposition has led to nonlinearity in the pharmacokinetics of several monoclonal antibodies (omalizumab, trastuzumab, efalizumab, cetuximab, panitumumab, and abciximab).19
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PHARMACOKINETIC DRUG INTERACTION STUDIES |
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 TOPABSTRACTAbsorptionDistributionMetabolismEliminationRenal ExcretionHepatic Elimination PHARMACOKINETIC DRUG INTERACTION... INTERACTION WITH MONOCLONAL...PHARMACODYNAMIC DRUG INTERACTION...CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Effect of Interferons on the Cytochrome P450 System
Interferons are natural proteins of 143 to 187 amino acids produced by the cells of the immune system in most vertebrates in response to challenges by foreign agents. Interferons belong to the large class of glycoproteins known as cytokines. Interferons are antiviral and help the immune response by inhibiting viral replication within other cells of the body. Metabolism and excretion of interferons take place mainly in the liver and kidneys. Mainly due to the concern that interferons can affect the cytochrome P450 system, a wide variety of interaction studies involving interferons have been conducted. The following are some examples of interferon's impact on the cytochrome P450 system and on drug interactions.
Interferon-Alpha
Okuno et al20 studied the effect of interferon-alpha on drug-metabolizing activity in the human liver. Twelve patients (9 men and 3 women, 17-39 years of age) with chronic hepatitis B received 6 x 106 IU of interferon-alpha intramuscularly for 4 weeks. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Interferon-alpha treatment reduced the O-demethylase and O-deethylase activities in the liver by 31% and 33%, respectively. The extent of reduction in the enzymatic activities varied widely. In 2 patients, no inhibition of either enzyme was observed, whereas O-demethylase and O-deethylase activities in the remaining 10 patients varied from 9% to 61% and 16% to 62%, respectively.
The mechanism by which interferon-alpha inhibits the cytochrome P450 system is not well understood. It has been postulated that increased degradation of cytochrome P450 apoprotein may be the reason for depressed enzymatic activity.21 It is also possible that interferon increases the synthesis of xanthine oxidase, which in turn produces superoxide that destroys cytochrome P450.22 Some investigators23-25 have suggested that high antiviral or antitumor activity of interferons through the biochemical pathways that mediate these effects may depress the cytochrome P450 system.
In another study, Pageaux et al26 investigated the effect of therapeutic doses of interferon-alpha on cytochromes P450 1A2 and 3A in patients with chronic hepatitis C. Eighteen patients with chronic hepatitis C received 3 million units of interferon-alpha 3 times a week. The activities of 1A2 and 3A were determined 1 month before and 1 month after the administration of interferon-alpha. Cytochrome P450 1A2 and 3A activities were determined based on in vivo caffeine and cortisol metabolism, respectively. There were no significant differences in the caffeine index (CYP1A2) and in the 6-beta-hydroxycortisol/free cortisol urinary ratio (CYP3A) before and after alpha-interferon administration. Based on the results of this study, the authors suggested that substrates of CYP1A2 and CYP3A can be administered with interferon-alpha in patients with chronic hepatitis C without significant risks of drug interactions.
Effect of Interferon-Ribavirin Biotherapy on Cytochrome P450
Because the current trend for the treatment of chronic active hepatitis C is a combination of interferon-alpha (IFN-
) and ribavirin, Becquemont et al27 studied the effect of IFN- and ribavirin combination therapy on the activities of CYP1A2, CYP2D6, CYP3A4, and N-acetyltransferase-2 (NAT2) activities after 1 month of treatment. There were 14 patients (6 women and 8 men, 29-67 years of age) with chronic hepatitis C in the study. The patients received 3 million units of IFN- 3 times a week; 5 patients received 600 mg ribavirin twice a day, and 9 patients (who were less than 75 kg of body weight) received 500 mg ribavirin twice a day. Before the initiation of the therapy, the patients also received 80 mg dextromethorphan and 140 mg caffeine. CYP3A4 and CYP2D6 activities were determined by measuring the 3-methoxymorphinan/dextromethorphan and the dextrorphan/dextromethorphan metabolic ratios, respectively, in the 24-hour urine collection after dextromethorphan dosing. CYP1A2 activity was assessed by measuring the paraxanthine/caffeine plasma metabolic ratio obtained 5 hours after caffeine intake. NAT2 activity was determined by measuring the ratio of 5-acetylamino-6-formylamino-3-methyluracil and methylxanthine in the 24-hour urine collection after caffeine intake. The results of this study are as follows.
CYP3A4 activity increased from 0.18 ± 0.06 just before treatment to 0.48 ± 0.53 after 1 month of IFN- and ribavirin therapy. This difference, however, was not statistically significant mainly due to high interindividual variability. The increase in CYP3A4 activity was not in a single direction. There were 7 patients in which CYP3A4 activity increased from 112% to 1677%, whereas in 6 patients, CYP3A4 activity decreased by 47% to 67% from pretreatment values.
CYP2D6 activity increased from 148 ± 139 to 421 ± 641, but due to high interindividual variability, the difference in pre- and posttreatment activity could not reach the statistical significance. CYP2D6 activity increased from 120% to 322% in 9 patients and decreased from 42% to 93% in 5 patients. One patient was identified as a poor CYP2D6 metabolizer whose phenotype remained unchanged after 1 month of antiviral treatment.
CYP1A2 and NAT2 activities remained unchanged from the pretreatment period to 1 month after treatment. Smoking status did not alter CYP1A2 activity before and after treatment.
In this study, the authors also compared the activities of CYP3A4, CYP2D6, CYP1A2, and NAT2 between the healthy subjects and patients with hepatitis C. The activities of CYP3A4 and CYP2D6 were substantially lower in patients with hepatitis C, whereas activities of CYP1A2 and NAT2 were not different in patients with hepatitis C as compared to healthy subjects.
Interferon-Alpha-2b
Patients with high-risk melanoma generally receive high-dose interferon-alpha-2b. Islam et al28 studied the effect of high-dose interferon-alpha-2b on the activities of CYP enzymes. Seventeen patients with high-risk melanoma received interferon-alpha-2b (Intron A) intravenously at a dose of 20 million units (MU)/m2/day for 5 days/week for 4 weeks (induction phase) followed by subcutaneous administration of interferon-alpha-2b at a dose of 10 MU/m2/day for 3 days/week for 48 weeks (maintenance phase). In vivo CYP enzyme activities were measured by administrating the "Pittsburgh mixture." The 5-drug mixture was given orally simultaneously. Blood samples were obtained at 0, 4, and 8 hours, and urine was collected from 0 to 8 hours to measure the concentration of probe drugs and/or their metabolites. The enzymatic activities were measured over time (baseline [day -6] and days 1, 26, and 52). The results of the study indicated that high-dose interferon-alpha-2b has different degrees of effect on CYP enzymes. There was a 60% inhibition in CYP1A2 activity, whereas no effect on CYP2E1 activity was noted. Significant inhibition of 1A2 and 2D6 was noted immediately after the first interferon-alpha-2b dose, whereas significant inhibition of CYP2C19 was found on day 26. CYP inhibition led to side effects (fever and neurological toxicity) of interferon-alpha-2b in patients.
In patients with chronic hepatitis C treated with interferon-alpha-2b in combination with ribavirin, interferon-alpha-2b treatment did not affect ribavirin distribution or clearance.1
Effect of Interferon-Alpha-2b on Methadone Pharmacokinetics
Methadone is a racemic mixture and is primarily metabolized by N-demethylation—namely by CYP3A4, secondarily by CYP2D6, and, to a lesser extent, by CYP1A2 and CYP2B6.29 Gupta et al29 evaluated the effects of multiple doses of peginterferon-alpha-2b on the steady-state pharmacokinetics of methadone in patients with hepatitis C. Twenty adults with hepatitis C virus infection (36-57 years of age, 13 men and 7 women) received peginterferon-alpha-2b (1.5 µg/kg/wk) subcutaneously for 4 weeks and maintained their normal methadone regimen (approximately 40 mg/day). There was an approximately 15% increase in the exposure of R, S, and total methadone after 4 weekly doses of peginterferon-alpha-2b as compared to the exposure observed before peginterferon-alpha-2b administration. The authors concluded that this increase in methadone exposure may not be of any clinical significance.
Recombinant Human Interferon-Alpha A
Williams and Farrell30 studied the effect of recombinant human interferon-alpha A on the pharmacokinetics of antipyrine. Following a single intramuscular dose of interferon-alpha A in 9 patients, antipyrine clearance was found to be decreased. The decrease was variable, ranging from 5% to 47%.
In another study, Williams et al31 studied the effect of interferon-alpha A (single intramuscular dose) on theophylline clearance in 5 patients with stable chronic active hepatitis B and 4 healthy subjects. Like antipyrine, theophylline clearance was reduced and varied from 31% to 81% in 8 of 9 patients. In 1 patient, no change in theophylline clearance was observed.
Peginterferon-Alpha-2a
Peginterferon-alpha-2a is a covalent conjugate of recombinant alpha-2a interferon (molecular weight = 20 kD). Treatment with peginterferon-alpha-2a once weekly for 4 weeks in healthy subjects resulted in inhibition of P450 1A2 and a 25% increase in theophylline AUC. Based on the study, it was suggested that theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and peginterferon-alpha-2a (package insert). There was, however, no effect of peginterferon-alpha-2a on the pharmacokinetics of those drugs that are metabolized by CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
Sulkowski et al32 evaluated the effect of peginterferon-alpha-2a on the pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy for at least 3 months. The subjects (n = 24) received 180 µg subcutaneous peginterferon-alpha-2a once weekly for 4 weeks and continued their methadone regimen. The results of the study indicated that treatment with peginterferon-alpha-2a once weekly for 4 weeks was associated with methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is, however, unknown.
Effect of Peginterferon-Alpha-2b on Methadone Pharmacokinetics
Berk et al33 studied the effect of peginterferon-alpha-2b (1.5 mg/kg given subcutaneously, 2 doses given 1 week apart) on the steady-state pharmacokinetics of methadone (40-200 mg/day given orally) in 9 patients with hepatitis C virus and HIV. Overall, a 24% and 17% increase in mean methadone Cmax and AUC0-24 was observed after 2 weeks of peginterferon-alpha-2b administration. The authors suggested that no dosage adjustment of methadone is necessary when given with peginterferon-alpha-2b in patients with hepatitis C virus and HIV. (The pharmacodynamic part of this study is described under the Pharmacodynamic section.)
Interferon-Beta (IFN-β)
Okuno et al34 studied the effect of interferon-beta on the drug-metabolizing activity in the human liver. Seven patients with chronic hepatitis C were given interferon-beta at doses of 3 x 106 to 9 x 106 IU/day for 8 weeks. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Theophylline pharmacokinetics as an indicator of mixed-function oxidase activity were also evaluated before and after IFN-β treatment.
Interferon-beta treatment reduced the O-demethylase and O-deethylase activities in the liver by 53% and 58%, respectively. The extent of reduction in the enzymatic activities varied widely. In 1 patient, no inhibition of either enzyme was observed, whereas O-demethylase and O-deethylase activities in the remaining 6 patients varied from 24% to 81% and 23% to 75%, respectively. The magnitude of enzymatic inhibition was not dose dependent. The total body clearance of theophylline decreased from 0.76 to 0.56 mL/min/kg, and its elimination half-life increased from 8.4 to 11.7 hours. The extent of reduction in the O-demethylase and O-deethylase activities correlated well with the decreased clearance and increased half-life of theophylline.
In another study, Carelli et al35 investigated the effect of IFN-β on cytochrome P450 in mice. IFN-β (2 x 105 units/mouse) was given to mice as an intraperitoneal injection. Total cytochrome P450 and the activity of nicotinamide adenine dinucleotide phosphate (NADPH) cytochrome C reductase were reduced by 20% and 12%, respectively, 24 hours after IFN-β administration. The activity of 7-ethoxycoumarin O-deethylase was reduced by 29%. In phenobarbital-treated mice, IFN-β reduced the induction of total cytochrome P450 by 22%, whereas in beta-naphthoflavone-treated mice, IFN-β lowered the induction of total cytochrome P450 by 18%.
Hellman et al36 studied the effects of IFN-β on the CYP2C19 and CYP2D6 activities in patients with multiple sclerosis. CYP2C19 and CYP2D6 activities were determined using the probe drugs mephenytoin and debrisoquine, respectively, prior to and 1 month after initiating the treatment with IFN-β. There were 10 Caucasian patients (8 women and 2 men between 27 and 50 years of age) with multiple sclerosis. Patients received either IFNβ-1a (Avonex) 30 mg weekly intramuscularly, or as Rebif 22 or 44 mg thrice weekly subcutaneously, or IFNβ-1β (Betaferon) 250 mg every other day subcutaneously. The urinary S/R mephenytoin ratio (for determination of CYP2C19 activity) and debrisoquine metabolic ratios (for determination of CYP2D6 activity) were used to characterize the activity of the 2 CYPs. The results of the study indicated that 1-month IFN-β treatment did not alter CYP2C19 or CYP2D6 activities. Based on the results of this study, the authors suggested that CYP2C19 or CYP2D6 substrates can be administered without dose adjustment to patients with multiple sclerosis treated with IFN-β.
Clinical Consequences of the Effects of Interferons on the Cytochrome P450 System
The aforementioned studies provide some evidence that interferons may inhibit or induce hepatic drug metabolism in humans, and there may be some potential of toxic drug-drug interactions. However, the studies also indicate that inhibition or induction may not be of any clinical significance mainly due to the high variability and being bidirectional (inhibition in some subjects and induction in some). Because a limited number of interaction studies have been conducted and the studies have been of short duration, it is very difficult to make an outright conclusion about the clinical consequences of these studies.
Effect of Cytokines on the Cytochrome P450 System
Abdel-Razzak et al37 examined the role of 5 cytokines (interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma) on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. The results of the study indicated that among these cytokines, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were the most potent inhibitors of P450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were inhibited by at least 40%. Interferon-gamma suppressed CYP1A2 and CYP2E1 mRNA levels but had no effect on CYP3A and epoxide hydrolase mRNAs. On the other hand, interleukin-4 increased the CYP2E1 activity up to 5-fold, suggesting that different regulatory mechanisms may be involved. This change in drug-metabolizing capacity may be due to a down-regulation of P450 gene transcription and RNA modulation.
In a study, Elkahwaji et al38 administered different doses of human recombinant interleukin-2 (from 0 to 12 x 106 units/m2) to patients with hepatic metastases from colon or rectum carcinomas. Hepatic CYPs and monooxygenase activities were not significantly different in 5 patients receiving daily doses of 3 or 6 x 106 units/m2 compared to 7 patients who did not receive interleukin-2. On the other hand, in 6 patients receiving daily doses of 9 or 12 x 106 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37%, 45%, 60%, and 39%, respectively, of those in controls. Total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. The results of the study suggest that high doses of interleukin-2 may decrease total CYP and monooxygenase activities in man.
Interleukin-10-Prednisone
Interleukin-10 (IL-10) is a cytokine that is under investigation for various immune-related disorders. Corticosteroids are regularly used as an immunosuppressive agent, but their side effects have reduced their therapeutic benefit. Combination therapy of IL-10 and corticosteroids may be beneficial, and the combined use of these 2 drugs may result in mutual dose reduction. Chakraborty et al39 studied pharmacokinetic interactions of a single oral dose of prednisone and subcutaneous recombinant human IL-10 (8 µg/kg) in 12 healthy male volunteers. Single doses of IL-10 (8 µg/kg), IL-10 with prednisone (15 mg orally), placebo with prednisone, or placebo were administered on 4 separate occasions with at least 3-week washout periods. The results of the study indicated that prednisone had no effect on the pharmacokinetics of IL-10 or vice versa. Both prednisolone and prednisolone/IL-10 caused marked suppression of endogenous cortisol concentrations; however, IL-10 alone significantly increased the 24-hour AUC of endogenous cortisol by 20%.
Interaction With P-gp Substrates
Reguiga et al40 studied the in vivo effect of interferon-alpha on P-glycoprotein (P-gp) activity in rats. Digoxin, a P-gp substrate, was chosen to evaluate the effect of IFN- on the bioavailability of digoxin. Human recombinant IFN- was given to rats (5-7 rats per group) daily for 8 days at different doses (IntronA, 1 x 106, 2 x 106, or 4 x 106 IU/kg, subcutaneously), whereas pegylated IFN- was given as 29 µg/kg subcutaneously 3 times a week. Rats were then given digoxin (32 µg/kg) intravenously or orally. The pharmacokinetics of intravenous (IV) administered digoxin was not modified by IFN-, but a dose-dependent increase in the bioavailability of orally administered digoxin was noted. Pegylated IFN- did not modify digoxin bioavailability. The authors concluded that IFN- induced a significant dose-dependent inhibitory effect on intestinal P-gp activity that resulted in increased bioavailability of digoxin.
In an another study, Reguiga et al41 investigated the effect of recombinant human interferon-alpha (rhIFN-) and pegylated IFN- on the pharmacokinetics of docetaxel (Taxotere), a P-gp substrate, in the rat. Sprague-Dawley rats were subcutaneously pretreated either with rhIFN- for 8 days (Intron A, 4 MIU/kg once daily) or with pegylated IFN- (ViraferonPeg, 60 mg/kg, on days 1, 4, and 7). Rats received a single dose of 14C docetaxel (20 mg/kg) either orally or as an intravenous bolus injection. Blood samples were collected until 240 minutes. Tissue samples such as intestine, liver, kidneys, lung, heart, and brain were also collected at the end of 240 minutes for radioactivity quantitation. Nonpegylated and pegylated IFN- increased docetaxel bioavailability almost by 3-fold as compared to control. The absorption of docetaxel was also delayed by the interferons. Docetaxel levels decreased in the intestine and increased in the brain of the rat in both pretreated groups. Intravenous pharmacokinetics of docetaxel were not altered by interferons, and there was a limited effect on tissue distribution of radioactive docetaxel. Overall, both forms of interferon modified the P-gp-dependent pharmacokinetics of docetaxel and substantially increased the bioavailability of docetaxel.
The results of the aforementioned 2 studies could have important clinical relevance because IFN- is widely used in cancer and antiviral therapy and could be associated with P-gp substrates such as anticancer drugs (vincristine and doxorubicine) or antiviral drugs (indinavir and efavirenz). An increase in the bioavailability of P-gp substrates given with IFN- may lead to an increase in the efficacy or toxicity.
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INTERACTION WITH MONOCLONAL ANTIBODIES |
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Etanercept
Etanercept is a dimeric fusion protein and is indicated for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Drug interaction studies of etanercept have been conducted with several drugs. The summary of these drug-drug interaction studies is as follows.
Etanercept-Paclitaxel
Administration of paclitaxel in combination with etanercept resulted in a 2-fold decrease in etanercept clearance in a nonhuman primate study and in a 1.5-fold increase in etanercept serum levels in clinical studies (package insert).
Etanercept-Digoxin
Etanercept did not alter the pharmacokinetics of digoxin. On the other hand, digoxin reduced the Cmax and AUC of etanercept by 4.2% and 12.5%, respectively. The clinical significance of this change is most likely irrelevant. There were no clinically relevant changes in the electrocardiogram. The combined administration of etanercept and digoxin also did not increase the adverse events as compared to monotherapy.42
Etanercept-Warfarin
Etanercept did not affect the PK and PD of warfarin. Warfarin also did not alter the pharmacokinetics of etanercept.43
Etanercept-Methotrexate
The concurrent administration of methotrexate in patients with rheumatoid arthritis did not alter the pharmacokinetics of etanercept.44
Trastuzumab-Paclitaxel
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody for the treatment of cancer. Furtlehner et al45 studied the effect of trastuzumab on the pharmacokinetics of paclitaxel in 10 patients. Paclitaxel is metabolized in the liver by the CYP2C8 isozyme to the main metabolite 6-H paclitaxel and by CYP3A4 to the minor metabolites 3-OH paclitaxel and 3,6 DiOH-paclitaxel. The results of the study indicated that the Cmax and AUC values of paclitaxel were about 25% and 9% lower, respectively, when given with trastuzumab. Trastuzumab also caused a lower Cmax (22%) of the main metabolite 6-OH paclitaxel, but the AUC was not different between the 2 dosing schedules. The Cmax and AUC of minor metabolites of paclitaxel were not different in either dosing regimen. Overall, trastuzumab did not alter the PK of paclitaxel.
Cetuximab-Irinotecan
The current trend in the treatment of colorectal cancer is the simultaneous administration of 2 or 3 anticancer drugs. Irinotecan has been approved as a potent drug against metastatic colorectal cancer and is used in combination with 5-fluorouracil and leucovorin. Monoclonal antibodies are also becoming popular as anticancer agents. For example, cetuximab (Erbitux) is a recombinant chimeric monoclonal antibody against the epidermal growth factor receptor with an approximate molecular weight of 152 kDa.
Ettlinger et al46 investigated the impact of cetuximab on the pharmacokinetics of irinotecan. Patients with advanced colorectal cancer received irinotecan (350 mg/m2) every third week and cetuximab as a loading dose (400 mg/m2) on day 2, followed by a weekly maintenance dose (250 mg/m2). The results of the study indicated that cetuximab has no clinically relevant effect on the pharmacokinetics of irinotecan or its metabolites. The effect of irinotecan on the pharmacokinetics of cetuximab was not studied.
Panitumumab-Irinotecan
Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor with high affinity and has shown some therapeutic benefit in previously treated patients with epidermal growth factor-positive metastatic colorectal cancer. Although a formal drug interaction study has not been conducted, in a preliminary pharmacokinetic study,47 19 patients received weekly infusions of panitumumab 2.5 mg/kg with fluorouracil/leucovorin for metastatic colorectal cancer. Mean pharmacokinetic parameters for irinotecan and its metabolite, SN-38, were not different after the first and third doses of irinotecan, suggesting the lack of a pharmacokinetic interaction between panitumumab and irinotecan.
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PHARMACODYNAMIC DRUG INTERACTION STUDIES |
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TOPABSTRACTAbsorptionDistributionMetabolismEliminationRenal ExcretionHepatic EliminationPHARMACOKINETIC DRUG INTERACTION...INTERACTION WITH MONOCLONAL...PHARMACODYNAMIC DRUG INTERACTION...CONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Peginterferon-Alpha-2b and Methadone
To determine the effect of peginterferon-alpha-2b on opiate withdrawal symptoms, Berk et al33 tested their patients with HIV and chronic hepatitis C virus infection with the Subjective Opiate Withdrawal Scale (SOWS) and the Objective Opiate Withdrawal Scale (OOWS) at baseline and 7, 14, and 21 days after the administration of the first dose. Weekly clinical evaluation for signs and symptoms of methadone withdrawal of peginterferon-alpha-2b were conducted. The results of the study indicated that changes from baseline in SOWS and OOWS scores were not statistically significant. Therefore, the authors recommended that methadone dosage adjustment, when given with peginterferon-alpha-2b, is not necessary in patients with HIV and chronic hepatitis C virus infection.
Prednisolone and Interleukin-10
A pharmacodynamic interaction study between prednisolone and interleukin-10 was conducted by Chakraborty and Jusko.48 The study was conducted in 8 healthy subjects (4 men and 4 women, 25-40 years of age) with a commonly used synthetic corticosteroid and IL-10, using an in vitro phytohemagglutinin (PHA)-stimulated whole-blood lymphocyte proliferation technique. To determine the nature and intensity of the interaction between these 2 compounds, the authors used isobolograms along with parametric competitive and noncompetitive interaction models. The isobolographic model indicated that the effect of prednisolone and IL-10 is additive in suppressing lymphocyte proliferation. The competitive interaction model revealed the interaction to be slightly synergistic, whereas the noncompetitive interaction model indicated a small degree of antagonism.
Xemilofiban and Abciximab
Parenteral platelet glycoprotein (GP) IIb/IIIa receptor antagonists prevent thrombotic occlusions in patients with acute coronary syndromes and reduce ischemic complications of coronary angioplasty. In a clinical trial, Kereiakes et al49 evaluated the pharmacodynamic effects of xemilofiban, an oral nonpeptide GP IIb/IIIa antagonist, with or without abciximab (a human-mouse chimeric monoclonal antibody and a GPIIb/IIIa antagonist used in percutaneous coronary interventions to avoid platelet activation, thrombosis, and inflammation). Of the 74 patients enrolled in a placebo-controlled, dose-ranging study of xemilofiban, 17 patients received intravenous abciximab as a bolus (0.25 mg/kg) and 12-hour (0.6 mg/h) intravenous infusion. Oral xemilofiban was administered 8 to 18 hours after abciximab infusion was discontinued in doses of 5, 10, 15, or 20 mg on a twice-daily schedule and was continued for 2 weeks. Patients who were randomized to placebo received ticlopidine 250 mg orally twice daily. Ex vivo platelet aggregation was assessed at 2, 4, 6, 8, and 12 hours after the first dose of study drug and again at 7 days of continuous oral therapy. Both the magnitude and the duration of response to xemilofiban were enhanced by prior abciximab treatment, but this effect was no longer evident at 1 week. Despite the fact that the sample size was small and the patients were not randomly assigned to receive abciximab, it appears that the combination therapy of xemilofiban and abciximab may provide inhibition of platelet aggregation for an additional period of time and may be beneficial in deriving doses of orally administered compounds.
Heparin and Abciximab/Reviparin and Abciximab
In a randomized and placebo-controlled, parallel-group design, Klinkhardt et al50 studied the pharmacodynamic effect of unfractionated heparin or a low molecular weight heparin, reviparin, on abciximab or tirofiban. The study was conducted in 36 male volunteers between ages 18 and 40 years. All subjects were treated with 300 mg aspirin on day 1 and 100 mg on days 2 and 3. The subjects were randomly divided into 2 study groups, each consisting of 3 treatment groups (n = 6 in each group):
Group 1:Abciximab + aspirin
Abciximab + aspirin + unfractionated heparin
Abciximab + aspirin + reviparin
Group II: Tirofiban + aspirin
Tirofiban + aspirin + unfractionated heparin
Tirofiban + aspirin + reviparin
The pharmacodynamic effects measured were bleeding time, fibrinogen binding at the GPIIb/IIIa receptor, expression of the platelet secretion marker CD62, and adenosine disphosphate (ADP; 20 µM) and collagen (5 µg/mL) induced platelet aggregation. The results of the study showed that unfractionated heparin attenuated platelet aggregation and fibrinogen binding induced by abciximab or tirofiban, but reviparin did not exert any effect on their pharmacodynamic characteristics. According to the authors, the study suggests an advantage of reviparin over unfractionated heparin when given with abciximab or tirofiban.
Heparin + Aspirin and YM337
Graff et al51 investigated the pharmacodynamic effect of unfractionated heparin and aspirin on YM337, a Fab fragment humanized monoclonal antibody of the platelet GPIIb/IIIa receptor. Eighteen healthy male volunteers between 18 and 40 years were assigned to 3 treatment groups of 6 subjects each:
Aspirin + heparin + placeboYM337 + placebo + placebo
Aspirin + heparin + YM337
Each volunteer also received 325 mg aspirin or matching placebo for 3 days. The pharmacodynamic effects measured were bleeding time, expression of the platelet secretion marker CD62, and ADP (20 µM), and collagen (5 µg/mL) induced platelet aggregation. The results of the study indicated that unfractionated heparin and YM337 have strong synergistic effects on bleeding time, whereas coadministration of aspirin has strong inhibitory effects of YM337 on collagen-induced platelet aggregation.
Cetuximab Alone Versus Cetuximab and Irinotecan Combination Therapy
Cunningham et al52 studied the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in patients with metastatic colorectal cancer that was refractory to treatment with irinotecan. There were 111 patients on cetuximab monotherapy and 218 patients on cetuximab and irinotecan combination therapy. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. The results of the study indicated that the rate of response in the combination therapy group was significantly higher than that in the monotherapy group (22.9% vs 10.8%). The median time to progression (4.1 vs 1.5 months) and the median survival time (8.6 vs 6.9 months) were significantly greater in the combination therapy group than the monotherapy group. Toxic effects were more frequent in the combination therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. Overall, the study indicated a beneficial effect of cetuximab and irinotecan combination therapy compared to cetuximab-alone therapy in patients with metastatic colorectal cancer.
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CONCLUSIONS |
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The importance of a drug interaction study in both directions is illustrated by the irinotecan-cetuximab pharmacodynamic or clinical study discussed above, where it was noted that the combination therapy of irinotecan and cetuximab was more beneficial to patients with colorectal cancer than cetuximab monotherapy. The irinotecan-cetuximab PK interaction study indicated that cetuximab has no clinically meaningful impact on the PK of irinotecan, but the impact of irinotecan on the PK of cetuximab is not known. In light of a beneficial response with irinotecan and cetuximab combination therapy, it is desirable to know the effect of irinotecan on the PK of cetuximab. The beneficial response to irinotecan and cetuximab combination therapy in the patients may be due to decreased clearance of cetuximab (this is an assumption that may or may not be true). This will not be known without conducting a study that evaluates the impact of irinotecan on the PK of cetuximab. If, indeed, irinotecan has an impact on the PK of cetuximab, then the difference in PD response between combination therapy and monotherapy makes perfect sense (from a PK/PD perspective).
Considering that interferons (as examples of macromolecules) do inhibit or induce drug-metabolizing enzymes (although a long-term clinical effect of such inhibition or induction is not known), it is important to evaluate the effect of other classes of macromolecules (cytokines, interleukins, monoclonal antibodies) on drug-metabolizing enzymes.
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ACKNOWLEDGEMENTS |
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Financial disclosure: None declared.
The views expressed in this article are those of the authors and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.
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