Open Journal Systems

REVIEW ARTICLES

Received: December 26^th 2014

Judged: February 17^th 2015

Review of pharmacokinetic monitoring of 5-Fluorouracil as a tool to increase efficacy and safety

Juan Antonio Matus-Santos,^a José Luis Aguilar-Ponce,^b Fernando Ulises Lara-Medina,^a Ángel Herrera-Gómez,^c Abelardo Meneces-García,^d Mireya López-Gamboa^e,f

^aServicio de Oncología Médica

^bSubdirección de Medicina Interna

^cDirección Médica

^dDirección General

^eCentro Institucional de Farmacovigilancia

^fDirección Operativa, Pro Pharma Research Organization

^a,b,c,d,eInstituto Nacional de Cancerología, Secretaría de Salud

Ciudad de México, México

Communication with: Mireya López-Gamboa

Teléfono: (55) 5628 0400, extensión 384

Email: mireya@propharmaresearch.com; dralopezg@gmail.com

Recent progress in medical knowledge has indicated that both clinical and biological markers will determine the response to different medical treatments: age, gender and genetics will determine the success of treatment. Genetic variability in this respect is fundamental and determines efficiency and safety of drugs, as well as susceptibility and illness’ development. Fortunately, personalized medicine now offers individually tailored treatment strategies for each patient’s needs. This is of outmost importance in oncology, since treatment is per se toxic and the commonly found low serum drug concentrations result in low treatment efficacy. Personalized medicine will allow a better approach to this, until now, a poorly managed disease. In this review we intent to raise awareness of personalized medicine and of clinical pharmacologic monitoring, with the aim to achieve adequate levels of efficacy and safety in the use of the cytotoxic drug 5-Fluorouracil (5-FU). Additionally, the importance of pharmacogenomics for the use of 5-FU is discussed. We designed this discussion towards medical practitioners challenged with treatment decisions every day, together with their patients.

Keywords: Fluorouracil; Pharmacokinetics; Clinical pharmacology; Pharmacogenomics; Area under curve

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5-FU in cancer treatment: metabolism and antineoplastic effect

5-fluorouracil (5-FU) (sold as adrucil, arumel, carac, carzonal, effluderm, efudex, efudix, efurix, FU, fluoroblastin, fluoroplex, fluracil, fluracilum, fluri, fluril, fluro uracil, fluorouracil, kecimeton) is a cytotoxic drug that was first introduced in 1957.¹ 5-FU today is a cornerstone in the treatment of gastrointestinal, pancreatic, breast, skin, and head and neck cancer, as it has broad antitumor activity, plus it can act synergistically with other cytotoxic drugs.

5-FU is administered as a prodrug, which can access the catabolic metabolism pathway (mainly at the liver, where it is inactivated and the drug is eliminated from the body) or the anabolic pathway, which competes with the previous route through the substrate, resulting in the formation of cytotoxic active compounds of interest. In most body tissues, 80 to 85% of 5-FU is catabolized into inactive metabolites by the enzyme dihydropyrimidine dehydrogenase (DPD), which is expressed in many tissues, which is considered the first limiting factor for the catabolism of 5-FU.² The remaining percentage (1 to 3%) is processed by more than ten anabolic enzymes that produce, among others, the two cytotoxic metabolites of interest, 5-fluorodeoxyuridine monophosphate (5-FdUMP) and 5-fluorouridine triphosphate (5-FUTP).² 5-FdUMP forms ternary compounds with the DNA-synthesizing enzyme thymidylate synthetase (TS), assisted by the folate cofactor. By inhibiting TS, 5-FdUMP prevents the formation of thymidylate, which is the precursor of the thymidine triphosphate nucleotide and is necessary for DNA synthesis and repair. This deficiency leads to a lack of thymine, DNA damage, and cell death.² The second important anabolic metabolite of 5-FU, 5-FUTP, is produced from the activity of three enzymes,² and joins to RNA instead of uridine triphosphate (UTP), which causes errors during RNA transcription, thereby interfering with the maturation of this acid and its function.²

The problem of a standard dosage for 5-FU

Because 5-FU is an antimetabolite whose activity depends on time, it is mainly administered by venous infusion.³ For dose calculation, as with other cytotoxic agents, the formula of drug per body surface area (BSA) is used: mg/m². For most of these drugs, these doses are the maximum tolerated established in early clinical studies. However, the dosage of 5-FU based on this methodology is associated with interpatient and intrapatient pharmacokinetic variability, causing up to 100 fold differences in plasma concentration levels, causing both toxicity and treatment failure.⁴ There are several sources of possible interindividual pharmacokinetic variability for cytotoxic drugs, such as pharmacogenomic differences in drug absorption, distribution, metabolism, and excretion,⁴ in addition to the effect of the patient’s functional condition, age, gender, weight, and circadian variation.⁵ 

Pharmacogenomics in treatment with 5-FU

Pharmacogenomics studies the different responses to the drug associated with genetic differences between individuals. Of the two million patients taking 5-FU annually, approximately 10 to 40% develop severe toxicities (neutropenia, nausea, vomiting, severe diarrhea, stomatitis, mucositis, hand and foot syndrome, and neuropathies), which in some cases threaten the life of the patient.⁶ Genetic heterogeneity of DPD is an important factor in pharmacokinetic variability, since this enzyme is responsible for the rapid destruction of the drug.² Inadequate function of DPD results in elevated treatment toxicity, which can cause death.² The variability of response to therapy of 5-FU is also influenced by the variability in the gene for the enzyme TS,² so pharmacogenomics studies of 5-FU have focused mainly on these two enzymes.

Polymorphism in the DPD enzyme gene

Usually, the relevant genetic variability for the action of a drug is due to a single variation in a nucleotide (called single nucleotide polymorphism or SNP) of a major gene for metabolism, transport, or excretion of the drug. However, insertions and deletions of DNA sequences also cause genetic variability. A first evidence of predisposition to develop greater toxicities under treatment with 5-FU was the case of a death from this medicine in the mid-eighties.⁶ Subsequently, efforts to elucidate the origin of this predisposition managed to identify the DPD gene, DPYD. This gene is located on chromosome 1p22 and has more than 50 described genetic variations (alleles), but only some of the alleles that produce a nonfunctional enzyme have been classified as risky. Current information indicates that individuals homozygous for the alleles identified as DPYD*2A, DPYD *3, DPYD *13, and rs67376798T>A are deficient in DPD activity. Individuals homozygous for some of these alleles (0.2% of patients) have an increased risk of toxicities when treated with 5-FU.³ Furthermore, individuals heterozygous for any combination of these alleles (between 3 and 5% of patients) have intermediate DPD activity and are not at high risk with treatment with 5-FU.³ Individuals who do not express these alleles have normal DPD activity levels and are not considered at high risk of developing toxicity with this treatment.³

The most common variation of the DPD gene, DPYD*2A, is due to an SNP. The frequency of this allele in the normal population is 1.8 to 3.5%, but in patients DPYD*2A is at higher frequencies and is associated with a higher prevalence of neutropenia, coupled with the fact that this allele can be expressed predominantly in leucocytes.³ A study of 419 Caucasian patients indicated a 4% frequency of DPYD mutations in patients in treatment with fluoropyrimidine, but did not report the presence or absence of toxicity. However, patients in treatment who developed grade 3 or 4 toxicities had a 12% frequency of mutations in this gene (p = 0.001),⁷ confirming the risk relationship with the presence of mutations.

There are also different expression frequencies of these mutations and alleles according to ethnic group. The influence of ethnicity and the association of some genes with others (linkage disequilibrium) was demonstrated in a study of Japanese and Caucasian patients and healthy volunteers, which found 55 variations and different frequencies of SNP in the DPYD gene with clinical relevance in both populations.⁸ The inactivating mutations of the DPYD gene are autosomal codominant. The most recently characterized variant, Y186C, was found in 26% of African American volunteers with low DPD activity, while this variation was not found in Caucasian volunteers.⁹ We also know that gender also influences the response to medicine, reporting 15% lower DPD activity in women (0.194 nmol/min/mg protein) than in male patients (0228 nmol/min/mg protein) (p = 0.03),⁵ although different activity has not been reported by age.  

Although mutations in the DPYD gene is only present in relatively few patients, these are at high risk of toxicities with the drug, especially in the case of those who are homozygous for certain alleles.⁷ Therefore the Food and Drug Administration (FDA) of the United States has requested changes in product safety information for 5-FU and prodrugs as Xeloda (capecitabine), and has specified that this drug is contraindicated in patients with DPD deficiency (Xeloda, prescribing information).

Gene polymorphism of TS enzyme

The aforementioned TS is considered a key enzyme to the effect of 5-FU, since its inactivation inhibits DNA synthesis and repair.¹⁰ Two major TS polymorphisms have been reported in the gene for this enzyme (TYSM).^11,12 The first involves a polymorphic repetition of a region of 28 base pairs (bp) in the region not translated into protein (TSER*2), but which is responsible for variations in response to fluoropyrimidine therapy; the second is a deletion of 6 bp.^11,12 Patients homozygous for the TSER*2 allele were considered high risk for 5-FU toxicity, whereas patients homozygous for the deletion of 6 bp expressed about three times less messenger RNA of this gene, and therefore also are considered at risk of toxicity. However, due to incomplete knowledge of the pharmacogenomics of 5-FU, there is no consensus in the scientific community about the significance of the genetic variation of this enzyme and toxicity in patients receiving 5-FU.

There are genetic variations in other genes involved in the metabolism of 5-FU. These include the glutathione S-transferase and its polymorphic gene GSTP1, and methylenetetrahydrofolate reductase (MTHFR),¹³ an enzyme involved in folate metabolism. The relevance of gene polymorphism of these two enzymes on the effect of 5-FU has not been established.¹³

Taken together, these studies suggest the need to underdose patients in the risk category due to mutations, ethnicity, or gender. Although there is no formal recommendation for testing enzyme deficiency and metabolic components of drugs such as 5-FU, there are genetic tests that can be done to determine the existence of individual SNPs and other genetic characteristics. Studies of polymorphisms through microarrays use molecular biology techniques and a sample from the patient to detect large numbers of SNPs relevant to certain populations or medical treatments.¹⁴ For example, in Mexico the Instituto de Ciencia y Medicina Genómica, in Torreon, Coahuila, has a public service that analyzes 49 SNP related to 5-FU metabolism (http://www.institutodeciencia.com). On the other hand, chromatographic techniques have been developed to detect differences in DPD activity that were caused by genetic polymorphisms.¹⁵ These techniques provide tools for both doctor and patient before starting treatment with 5-FU, given that the risk group that is determined a priori, from the detection of abnormalities or risk alleles in enzyme activity. This way one can change the dose or consider other therapeutic pathways for the disease.

Pharmacokinetics in treatment with 5-FU

Due to the low oral bioavailability of 5-FU (less than 75% of the dose reaches systemic circulation),¹⁶ the most common route of administration is intravenous (bolus or infusion), although recently oral formulations of prodrugs like capecitabine have been developed. 5-FU administered in bolus has a half-life of less than 30 minutes, with 90% eliminated by metabolism and less than 10% excreted in urine.¹⁶ The pharmacokinetics of 5-FU has been defined by determining its plasma concentration with variations when monitoring the patient immediately after administration. The need to characterize the pharmacokinetics of 5-FU individually is because this drug has:

• A wide systemic distribution.
• Biotransformation dependent on enzymes, each with genetic variations.
• Nonlinear pharmacokinetics.
• Difficulty maintaining concentrations in the treatment window.

Although it is not common to do pharmacokinetic testing in each patient medicated with 5-FU, the most widely used methods for drug measurement, due to their high sensitivity, are gas chromatography and liquid chromatography paired with mass spectrometry; however, both require sophisticated instruments and are expensive.^17,18 However, to determine the pharmacokinetics and monitor concentrations of 5-FU, the doctor also has the immunoassay, which uses specific monoclonal antibodies that react with metabolites or prodrugs of 5-FU, such as dehydro-5-FU (1.0%) or fluoropyrimidines and precursors of 5-FU capecitabine (0.05%) or tegafur (0.23%). In addition, the immunoassay only requires a small amount of plasma (<10 µL) and takes only a few minutes to do.¹⁹ Therefore, immunoassay is a tool that should be considered for studies of the pharmacokinetics of 5-FU (Table I).  

Variation in plasma concentrations of 5-FU with standard dosing

The therapeutic window of a drug is a range that is between the maximum tolerated blood concentration of any drug, and the minimum effective concentration of the drug. Due to its cytotoxic action, and like other drugs used in oncology, 5-FU has a narrow therapeutic window. Predicting concentrations of 5-FU for each individual is difficult because this drug has non-linear pharmacokinetics, which together with the possible genetic variations in each patient does not make it easily predictable. This directly impacts the adjustment to achieve the proper dosage and thus the final toxicity and efficacy.²⁰ However, it has been determined that the therapeutic range for 5-FU to be effective and safe is included in an area below the curve (ABC), ranging from 20 to 30 mg/h/L.^21-25 Pharmacokinetic studies have identified that the standard dose does not reach these levels, and doctors commonly underdose (Table I). This inadequate dosing impacts both efficiency and safety. The analysis of the studies listed in Table I indicates the following:

• The ineffectiveness of the dosing by standard body surface was shown in the study by Saam et al., which analyzed several FOLFOX regimens of infusion doses calculated with the formula mg/m², where the majority of patients achieved only suboptimal concentrations of the drug.³²
• The results of the controlled study by Gamelin et al. showed that individual dosing based on pharmacokinetic monitoring of 5-FU results in a higher objective response rate that is statistically significant compared with the group in which the dose was calculated with the formula mg/m². The authors concluded that dosing guided by pharmacokinetic monitoring is necessary to maintain the desired concentrations, since in the same study greater toxicity was observed in patients who were dosed by body surface area.²⁴
• The importance of 5-FU dosing guided by pharmacokinetics was confirmed in the study by Blaschke et al., whose group of patients with appropriate serum concentrations of the medication had better antitumor reponses.²⁶ The frequency of adverse events was the same for patients with low and high drug concentrations, although the frequency of grade 3-4 events was higher for patients who reached doses higher than 25 mg/h/L.²⁶
• The recent study by Kaldate et al. revealed that drug concentrations varied according to the time of infusion, and that dosing guided by pharmacokinetics enabled a suitable ABC (18-25 mg/h/L for this study) over the infusion time and independently of it.³³ The authors concluded that 5-FU is an ideal drug to be pharmacokinetically adjusted, despite the ABC’s dependence on time of infusion.
• Pharmacokinetic studies by Gamelin et al.,²⁴ confirmed Samm et al.,³² showed that long duration infusions of 5-FU (44 versus 8 hours) do not lessen the variability observed in the ABC with a single dose based on body surface.

 

Pharmacological therapeutic monitoring

From the above it is concluded that personalized and pharmacokinetically guided dosing for each patient ensures adequate concentrations for treatment. In agreement with the results discussed above, some authors suggest that the main reason for treatment failure for these conditions is inadequate and low doses, not resistance to the medication.²⁰ The clear relationship between systemic exposure to the antineoplastic, and toxicity, is the main reason for pharmacological therapeutic monitoring (PTM) of these medications.20 With the determination of the ABC, PTM provides the oncologist with valuable information to adjust the dose and keep the concentrations of 5-FU within the therapeutic window, obtaining the expected clinical benefit with the least possible toxicity.²⁰ Other methods of adjusting cytotoxic dosage schedules are a posteriori, which use plasma concentrations of the drug obtained by PTM to adjust subsequent doses. These methods include nomograms, multilinear regression (evaluating ABC of the drug obtained from data from blood samples) and Bayesian methods requiring a population pharmacokinetic model.²⁰  

There are also a priori adjustment methods that estimate the required dose using morphological, biological, genetic, and physiological data, such as body weight, age, gender, detection of relevant alleles, serum creatinine, and glomerular filtration rate.²⁰

The actual concentration of 5-FU (estimated with determination of ABC) is the most important pharmacokinetic parameter for the survival of patients with head and neck cancer, along with the tumor stage;³⁴ thus the majority of successful treatments are achieved by monitoring and adjusting the serum concentrations of 5-FU.^26,35 Therefore, we can say that the implementation of PTM for 5-FU can ensure proper dosing, with the desirable efficacy and safety in this treatment.^24-31 Lack of response to 5-FU may be related to inadequate drug serum concentrations,^22,24,32 largely due to large variations in plasma concentrations of 5-FU.^22,24,32 Indeed, up to 36% of patients are underdosed by 20%, which explains that only a small percentage of patients reach the therapeutic goal.³⁰ The same studies that have found that a large portion of patients are underdosed, have concluded that the best responses are obtained by reaching the highest recommended doses.^22,24,30,32   

Conclusion

To do rational prescribing, adequate knowledge of the patient's pathology and of the pharmacokinetic and pharmacodynamic properties of the selected drug are needed. The approach of personalized medicine to oncology conditions allows the inclusion of unique individual parameters which, in the experience of every doctor, obviously influence the response to treatment and evolution of the disease. Pharmacogenomics offers tools to detect a priori metabolic deficiencies that make drug metabolism, transport, or excretion impossible or inappropriate; however, there are highly valuable tools such as PTM to assess whether the drug stays in the therapeutic window in each case, which helps to individualize the dose, ensuring efficiency and safety.

The ABC has proven to be the pharmacokinetic parameter most closely associated with efficacy and toxicity, and in 5-FU therapy the best response is observed in patients with ABC measures in the range of 20-30 mg/h/L. Outside these parameters, a patient is at risk of lack of efficacy or toxicity from receiving suboptimal therapeutic doses, or toxic doses.

The literature analyzed in this review supports the proposal that 5-FU is an ideal place to customize the dose, using individual pharmacogenomics and pharmacokinetics parameters as a guide to optimize treatment: current molecular and biochemical tools help the doctor detect the population that expresses enzymes unable to metabolize the drug. Additionally, the use of PTM for this drug ensures proper treatment. Applying this knowledge and using these new techniques contributes to therapeutic success by achieving desired efficacy and decreasing the risk of toxicity in our patients.

Acknowledgments

We thank Dr. Isabel Pérez Cruz for her contribution to the development and editing of this manuscript.

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