Introduction

Phenytoin (brand name Dilantin) is an anticonvulsant medication used for the treatment of seizures (1).

Phenytoin has a narrow therapeutic index—individuals that have supratherapeutic blood concentrations of phenytoin have increased risks of acute side effects. Dosing can be complex due to pharmacokinetic factors, including individual weight, age, gender, concomitant medications, plasma binding protein status, the presence of uremia or hyperbilirubinemia, and specific pharmacogenetic variants. As such, therapeutic drug monitoring is often used to adjust dose and maintain serum concentrations within the therapeutic range (10–20 μg/mL).

The CYP2C9 enzyme is one of the main enzymes involved in the metabolism of phenytoin, and variant CYP2C9 alleles are known to influence phenytoin drug levels. Individuals who have decreased activity CYP2C9 variants may have reduced clearance rates of phenytoin and be at greater risk for dose-related side effects (2).

An individual’s human leukocyte antigen B (HLA-B) genotype is a known risk factor for drug-induced hypersensitivity reactions. The HLA-B protein has an important immunological role in pathogen recognition and response, as well as to non-pathogens such as drugs. Individuals who have the HLA-B*15:02 allele are at high risk of developing potentially life-threatening phenytoin-induced Stevens-Johnson syndrome (SJS) and the related toxic epidermal necrolysis (TEN).

The HLA-B*15:02 allele is most often found among individuals of Southeast Asian descent, where there is a strong association between SJS/TEN and exposure to carbamazepine. Carbamazepine is an antiseizure medication used to treat the same types of seizures as phenytoin, as well as trigeminal neuralgia and bipolar disorder.

The FDA-approved drug label for phenytoin states that consideration should be given to avoiding phenytoin as an alternative for carbamazepine in individuals positive for HLA-B*15:02 (Table 1). The label also mentions that variant CYP2C9 alleles may contribute to unusually high levels of phenytoin (1).

Dosing recommendations for phenytoin based on HLA-B and CYP2C9 genotype have also been published by the Clinical Pharmacogenetics Implementation Consortium (CPIC, Table 2, Figure 1) and the Dutch Pharmacogenetics Working Group (DPWG, Table 3, Table 4). These recommendations include the use of an antiseizure medication other than carbamazepine, phenytoin (or its prodrug fosphenytoin) for any HLA-B*15:02 positive individual regardless of CYP2C9 genotype, individual ancestry, or age. These recommendations also include specific dose reductions of phenytoin for individuals who have low or deficient enzyme activity (2, 3).

Figure 1:

Dosage Guidelines from the CPIC for Phenytoin based on HLA-B and CYP2C9 Genotype. Figure reproduced with permission from the authors.

Drug: Phenytoin

Phenytoin is a generic antiseizure drug that is rarely prescribed to newly diagnosed individuals due to its propensity for long-term side effects. Nevertheless, it continues to be used by many individuals who initiated treatment before the availability of newer medications that have fewer side effects and drug-drug interactions. Phenytoin is used for the control of partial seizures and generalized tonic-clonic convulsions. It is also used in the treatment of status epilepticus and may be used to prevent or treat seizures that occur during and following neurosurgery (1).

Phenytoin belongs to the sodium channel blocker class of antiseizure drugs, which are thought to suppress seizure activity by blocking voltage-gated sodium channels that are responsible for the upstroke of action potentials (6, 7). The block by phenytoin and other members of this class of antiseizure drugs occurs in a state-dependent fashion, with preferential binding and block of the inactivated state of the channel. This results in voltage- and frequency-dependent block in which high frequency action potential firing, which occurs during epileptic activity, is preferentially inhibited. (1, 8)

The dosing of phenytoin can be complex, as treatment is typically initiated at a low starting dose, which considers individual age, weight, and the presence of concomitant medications that may influence phenytoin metabolism or protein binding. The dose is then carefully escalated to obtain the desired therapeutic effect. There is a wide variation in how individuals respond to phenytoin (2). Therapeutic drug monitoring is often used to adjust the dose to ensure that plasma levels are within therapeutic range (10–20 μg/ml in adults). Measurement of plasma levels is useful when adding or discontinuing concomitant medications that effect phenytoin levels. Periodic measurement of plasma phenytoin concentrations may also be valuable in pregnancy because altered phenytoin pharmacokinetics increases the risk of seizures.

Phenytoin use during pregnancy has been associated with an 11% risk of fetal hydantoin syndrome in the offspring, which is characterized by dysmorphism, hypoplasia, and irregular ossification of the distal phalanges. Facial dysmorphism includes epicanthal folds, hypertelorism, broad flat nasal bridges, an upturned nasal tip, wide prominent lips, and, in addition, distal digital hypoplasia, intrauterine growth retardation, and mental retardation. An additional 30% of the in utero-exposed children express fetal hydantoin effects, in which there is a more limited pattern of dysmorphic characteristics. Some studies have found significant associations between in utero exposure to phenytoin and major congenital abnormalities (mainly, cardiac malformations and cleft palate) whereas others have failed to find such associations (9, 10).

The adverse effects of phenytoin fall into 2 categories, types A and B. (11)

Type A adverse drug reactions account for up to 90% of reactions. They are predictable and can occur in any individual if their drug exposure is high enough. Some of these reactions occur rapidly and are reversible when the dose is reduced. These include acute central nervous system adverse effects such as sedation, nystagmus, and ataxia. Other common side effects occur with long-term exposure and include changes to the physical appearance, such as gingival hyperplasia, coarsening of the facial features, hirsutism, and acne.

Type B adverse drug reactions include idiosyncratic hypersensitivity reactions, such as severe cutaneous adverse reaction (SCAR). Such reactions can occur at any dose and develop through a mechanism that is unrelated to the mechanism of action of the drug. A rare but life-threatening hypersensitivity reaction associated with phenytoin treatment is SJS and the related TEN. Both are severe cutaneous reactions to specific drugs, and are characterized by fever and lesions of the skin and mucous membranes, with a mortality rate of up to 30% (12).

It is difficult to predict in whom a drug-induced hypersensitivity reaction is likely to occur. However, for phenytoin individuals who are positive for a specific HLA allele are known to be susceptible to phenytoin-induced SJS/TEN. Human leukocyte antigen testing of individuals can identify at-risk individuals so that an alternative drug can be used.

The HLA Gene Family

The human leukocyte antigen (HLA) genes are members of the major histocompatibility complex (MHC) gene family, which includes more than 200 genes. The MHC family has been subdivided into 3 subgroups based on the structure and function of the encoded proteins: Class I, Class II, and Class III. The class I region contains the genes encoding the HLA molecules HLA-A, HLA-B, and HLA-C. These molecules are expressed on the surfaces of almost all cells and play an important role in processing and presenting antigens. The class I gene region also contains a variety of other genes, many of which are not known to be involved in immune function.

An important role of HLA class I molecules is to present peptide fragments to immune cells (CD8+ T cells). Most of these peptides originate from the breakdown of normal cellular proteins (“self”). However, if foreign peptide fragments are presented, for example, from a pathogen, CD8+T cells will recognize the peptides as “non-self” and will be activated to release inflammatory cytokines and launch an immune response to dispose of the pathogen (or foreign body).

Because HLA molecules need to present such a wide variety of “self” and “non-self” peptides, the HLA genes are both numerous and highly polymorphic. More than 1,500 HLA-B alleles have been identified (13). The HLA allele nomenclature includes the HLA prefix, followed by the gene, an asterisk and a 2 digit number that corresponds to antigen specificity, and the assigned allele number (14). For example, the HLA-B*15:02 allele is composed of:

• HLA: the HLA prefix (the HLA region on chromosome 6)
• B: the B gene (a particular HLA gene in this region)
• 15: the allele group (historically determined by serotyping, namely, a group of alleles that share the same serotype)
• 02: the specific HLA allele (a specific protein sequence; determined by genetic analysis).

Additional digits have recently been added to the nomenclature to discriminate alleles that do not differ in the protein amino acid sequence, but differ in their genetic sequence (namely, due to synonymous and noncoding genetic variants).

Variation in HLA genes plays an important role in the susceptibility to autoimmune disease and infections, and they are also critical in the context of transplant surgery where better outcomes are observed if the donor and recipient are HLA-compatible.

More recently, HLA alleles have been associated with susceptibility to Type B adverse drug reactions. For example, HLA-B alleles have been associated with severe hypersensitivity reactions to abacavir (used to treat HIV), allopurinol (used to treat gout), and the antiepileptic drugs carbamazepine and phenytoin.

Gene: HLA-B*15:02

Individuals who have one or 2 copies of the high-risk HLA-B*15:02 allele are known as HLA-B*15:02 positive (Table 5).

The association between the HLA-B*15:02 allele and SJS/TEN was first reported with the use of carbamazepine in the Han Chinese population. In the initial study, all individuals who had carbamazepine-induced SJS/TEN were found to have HLA-B*15:02 (44/44, 100%), whereas the allele was much less common among carbamazepine-tolerant individuals (3/101, 3%)(15). In subsequent studies, this association was replicated, with an HLA-B*15:02 positivity frequency of 70–100% among cases of carbamazepine-induced SJS/TEN (16).

The HLA-B*15:02 allele was later associated with phenytoin-induced hypersensitivity reactions, including phenytoin-induced SJS in a Thai population and phenytoin-induced SJS/TEN in Chinese Asians (17, 18).

There are fewer studies on phenytoin-induced hypersensitivity than carbamazepine, and the strength of association between phenytoin and SJS/TEN is weaker than that of carbamazepine and SJS/TEN. However, from the evidence available, the FDA recommends consideration of avoiding phenytoin as an alternative treatment to carbamazepine in individuals who have HLA-B*15:02 (2).

The prevalence of carbamazepine-induced SJS/TEN is higher in populations where HLA-B*15:02 is more common. Of note, the HLA-B*15:02 allele frequency is highest in Southeast Asia, as populations from Hong Kong, Thailand, Malaysia, Vietnam, and parts of the Philippines have an allele frequency >15%. It is slightly lower (~10–13%) in Taiwan and Singapore, and around 4% in North China. South Asians, including Indians, appear to have an HLA-B*15:02 allele frequency of ~2–4%, with higher frequencies in some subpopulations. (15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The HLA-B*15:02 allele is rare (<1%) in East Asia (Japan and Korea) and among individuals who are not of Asian descent. For example, the allele is rare in Europeans, Hispanics, Africans, African Americans, and Native Americans. (16, 21)

Gene: CYP2C9

The cytochrome P450 superfamily (CYP450) is a large and diverse group of hepatic enzymes that form the major system for metabolizing lipids, hormones, toxins, and drugs. The CYP450 genes are very polymorphic and can result in reduced, absent, or increased enzyme activity.

The CYP2C9 enzyme metabolizes approximately 15% of clinically used drugs, and atypical metabolic activity caused by genetic variants in the CYP2C9 gene can play a major role in adverse drug reactions (31, 32).

The CYP2C9 gene is polymorphic, with more than 50 known alleles. Variation in CYP2C9 is thought to contribute to the pharmacogenetic variability in phenytoin metabolism. CYP2C9*1 is considered the wild-type allele when no variants are detected and is categorized as normal enzyme activity (2). Individuals who have 2 normal-function alleles (for example, CYP2C9 *1/*1) are classified as “normal metabolizers” (Table 6).

For individuals who are CYP2C9 normal metabolizers, the recommended starting maintenance dose of phenytoin does not need to be adjusted based on genotype (2).

Two common allelic variants associated with reduced enzyme activity are CYP2C9*2 (p.Arg144Cys) and CYP2C9*3 (p.Ile359Leu). The *2 allele is more common in Caucasian (10–20%), than Asian (1–3%) or African (0–6%) populations. The *3 allele is less common (<10% in most populations) and is extremely rare in African populations. In African Americans, the CYP2C9*5, *6, *8 and *11 alleles are more common (33, 34, 35).

Linking HLA-B and CYP2C9 Genetic Variation with the Risk of Side Effects and Treatment Response

Reduced activity CYP2C9 alleles, in particular CYP2C9*3, influence phenytoin dosage, individual response, and predict adverse drug reactions (36, 37, 38, 39, 40). Individuals with reduced-function CYP2C9 alleles have reduced clearance of phenytoin and have an increased risk of side effects.

Specific HLA alleles, namely, HLA-B*15:02, are also strongly associated with SCAR (41).

To guide the optimal dose of phenytoin and reduce the risk, both genetic factors (CYP2C9 and HLA alleles) and non-genetic factors (for example, omeprazole co-medication) need to be considered (41, 42, 43, 44, 45).

The HLA-B and CYP2C9 Gene Interactions with Medications Used for Additional Indications

Other medications with multiple indications are known to interact with the HLA-B alleles or to be metabolized by CYP2C9.

• Other seizure medications—Carbamazepine has similar interactions with HLA variation and hypersensitivity reactions: individuals with one or more copies of HLA-B*15:02 are at risk of SJS/TEN and the HLA-A*31:01 is strongly associated with a potentially life-threatening condition known as drug reaction with eosinophilia and systemic symptoms (DRESS) and a milder reaction maculopapular exanthema (MPE).
• Uric acid reduction medications—Allopurinol is a xanthine oxidase inhibitor to treat high uric acid levels seen in gout, tumor lysis syndrome, and cases of symptomatic hyperuricemia. The HLA-B*58:01 allele is associated with SCAR during allopurinol treatment. Lesinurad is a urate transport inhibitor, also used in the treatment of gout and it is metabolized by CYP2C9 to inactive metabolites. Individuals who are CYP2C9 poor metabolizers will have an increased exposure to the active drug and thus have an increased risk of side effects such as kidney stones or cardiovascular events.
• Anti-retroviral medication—Abacavir, a nucleoside/nucleotide reverse transcriptase inhibitor used in the treatment of HIV, is also associated with hypersensitivity reactions, the risk of which increases when an individual has the HLA-B*57:01 allele.
• Non-steroidal anti-inflammatory drugs (NSAIDs)—Celecoxib, Flurbiprofen, and Piroxicam are used for pain management in osteoarthritis, rheumatoid arthritis, and other conditions; they are all metabolized by CYP2C9 and poor metabolizers will experience higher levels of exposure to these NSAIDs and have higher risk of side effects.
• Anti-emetics—Dronabinol, a synthetic cannabinoid, is used in the treatment of chemotherapy-induced nausea and vomiting for individuals who had poor responses to traditional anti-emetics. It also is used to treat anorexia-associated weight loss in individuals with acquired immunodeficiency syndrome. Dronabinol is activated by CYP2C9 metabolism and individuals with poor metabolizer phenotypes will have an increased exposure to dronabinol and increased risk of side effects.

Additional information on gene-drug interactions for HLA-B and CYP2C9 are available from PharmGKB, CPIC, and the FDA (search for “HLA-B” or “CYP2C9”).

Genetic Testing

The NIH’s Genetic Testing Registry provides examples of the genetic tests that are available for the phenytoin drug response, the HLA-B gene, and the CYP2C9 gene.

The genotype results for an HLA allele such as HLA-B*15:02 can either be “positive” or “negative”. There are no intermediate phenotypes because the HLA genes are expressed in a codominant manner.

A positive result indicates the individual is either “heterozygous” or “homozygous” for the variant, depending upon whether they have one or 2 copies of the *15:02 allele.

A negative result indicates that the individual does not have the HLA-B*15:02 allele. However, a negative result does not rule out the possibility of an individual developing phenytoin-induced SJS/TEN. Therefore, clinicians should carefully monitor all individuals according to standard practices.

For CYP2C9, alleles to be included in clinical genotyping assays have been recommended by the Association for Molecular Pathology. (46) Results are typically reported as a diplotype, such as CYP2C9 *1/*2, and may include an interpretation of the individual’s predicted metabolizer phenotype (normal, intermediate, or poor) and an activity score (Table 6).

Therapeutic Recommendations based on Genotype

This section contains excerpted¹ information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.

Nomenclature of Selected HLA-B Alleles

Nomenclature of Selected CYP2C9 Alleles

Acknowledgments

The authors would like to thank Marga Nijenhuis, PhD, Royal Dutch Pharmacists Association (KNMP), The Hague, The Netherlands; Bernard Esquivel MD, PhD, President of the Latin American Association for Personalized Medicine, Vancouver, BC, Canada; and Jason H. Karnes, PharmD, PhD, BCPS, FAHA, Assistant Professor, Department of Pharmacy Practice & Science, University of Arizona College of Pharmacy; Sarver Heart Center, University of Arizona College of Medicine, Tucson, Arizona, USA for reviewing this summary

First edition:

The author would like to thank Mohamed Nagy, Clinical Pharmacist, Head of the Personalised Medication Management Unit, Department of Pharmaceutical Services, Children's Cancer Hospital, Cairo, Egypt; Emily K. Pauli, Director of Research, Clearview Cancer Institute, Huntsville, AL, USA; Michael A. Rogawski, Professor of Neurology, University of California, Davis, CA, USA; and Stuart A. Scott, Assistant Professor of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA for reviewing this summary.

Version History

To view the previous version of this chapter, published on 22 September 2016, please click here.

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