This article examines the case of a patient who developed toxic levels of voriconazole while taking the antifungal prophylactically as part of her treatment regimen in addition to standard chemotherapy for a leukocyte neoplasm. The usefulness of molecular diagnostic testing as an aid in voriconazole dosing is discussed.
by S. Rezaei, L. Collier and Dr S. Taylor
The patient was a 14-year-old female who was referred to the emergency department with a 10-day history of generalized bone pain and progressively worsening fatigue. An initial complete blood count (CBC) revealed a white blood cell (WBC) count that was well within the normal range, and only slight anemia and thrombocytopenia. However, because marked neutropenia and elevated numbers of leukemic blasts were noted in the differential, a bone marrow (BM) examination was performed. Marrow aspiration was markedly hypercellular with diffuse clusters of blasts (Fig. 1). Flow cytometry on the aspirate disclosed a significant (50% of total sample) blast population that exhibited CD33, CD13 (partial, dim), CD34 (partial), CD15 (heterogeneous), CD19 (dim), CD10 (dim), HLA-DR, CD64 (partial, dim), CD71 (dim), CD117, CD123, CD58, CD38, cytoplasmic CD79a, CD45 (dim), Tdt, and myeloperoxidase markers. These same markers were exhibited by the circulating blasts in her peripheral blood. The co-expression of B-lymphoid and myeloid antigens prompted an initial diagnosis of biphenotypic acute leukemia. After multiple expert consultations, it was decided to model the patient’s treatment on therapy for acute lymphocytic leukemia (ALL). Thus, the patient received prednisone, vincristine, daunorubicin and PEG asparaginase as induction chemotherapy, with vincristine and daunorubicin administered again 7 days later.
Cytogenetic test results that were returned on day 8, revealed a chromosomal translocation of (8;21)(q22;q22); RUNX1-RUNX1T1, which changed the patient’s diagnosis to an atypical form of acute myelogenous leukemia (AML). Accordingly, the patient’s chemotherapy regimen was changed so that the ALL-type therapy was discontinued and standard AML therapy that included cytarabine, daunorubicin, and etoposide was begun. To address other specific issues, this patient was treated with multiple medications along with her chemotherapy drugs, including Ambien, Bactrim, Benadryl, cefepime, cyproheptadine, hydroxyzine, meropenem, vancomycin, and voriconazole.
On day 16, 8 days after the start of her new pharmacology regimen, the patient began to experience fluctuating confusion and auditory/visual hallucinations. Screening tests revealed no abnormalities that could explain her altered mental status, so attention turned to the medications that she was receiving. All medications that seemed likely to contribute to her neurologic problems were suspended and then reintroduced gradually with no adverse effect. Voriconazole was not suspected of being contributory to her altered mental status, and was not interrupted. This antifungal was first administered to the patient on day 8 of her ordeal, at 200 mg/twice daily. She continued to receive this dose from day 8 onwards, until 4 days after her initial neurological trouble (day 20). At this time, her plasma voriconazole level was determined to be >10.0 μg/mL [normal range (NR): 1.0–6.0 μg/mL]. The patient’s 200 mg twice a day dosing regimen was reduced to 100 mg twice a day. Her plasma concentration of voriconazole was monitored regularly until its level plateaued at 2 μg/mL (Fig. 2).
Voriconazole is an efficient triazole agent used as an antifungal prophylactic in this patient as she was receiving immunosuppressive chemotherapy. Patients with hematologic malignancies are at high risk of aspergillosis and candidiasis infections, because of the neutropenia that is often caused by their chemotherapy regimens [1–3].
Voriconazole is extensively metabolized in the liver, primarily by CYP2C19 and, to a lesser extent, by CYP2C9 and CYP3A4 liver enzymes. The CYP2C19 genotype is generally accepted as the key determinant in voriconazole clearance [4–6]. Variants of the CYP2C19 genotype have been identified and assigned enzyme activity. Thus the CYP2C19*1 variant is the wild-type variant and exhibits normal enzyme activity. CYP2C19 *2, *3, *4, *5, *6, and *8 isotypes display loss of functionality as they possess little or no activity, and the CYP2C19*17 variant is assigned gain-of-function status because of its robust enzyme activity (Table 1) [7, 8].
Individuals who possess a normal or wild-type drug metabolizing phenotype inherit two copies of the normal CYP2C19 genotype (*1/*1), and are designated as extensive metabolizers (EM). Intermediate metabolizers (IM) have any one of the *2–*8 alleles coupled with a normally functioning (*1) allele. Poor metabolizers (PM) are individuals with an enzyme activity phenotype that is less than optimal, caused by a genotype consisting of loss-of-function alleles (*2–*8/*2–*8 ). Ultrarapid metabolizers (UM) are at the other end of the enzyme activity spectrum, they may either be heterozygous ultrarapid metabolizers with a wild-type allele combined with an gain-of-function allele (*1/*17 genotype), or they may be homozygous ultrarapid metabolizers with only gain-of-function alleles (*17/*17) (Table 1) [7, 8]. The drug metabolizing phenotype of individuals with the gain-of-function allele (*17) combined with a loss-of-function allele (*2–*8) is less clear. There is a certain amount of dissention in the literature as to how these individuals should be classified, that is, various researchers classify them as ultrarapid, extensive, intermediate, or unknown metabolizers [7, 9].
It is intuitive that an individual’s CYP2C19 genotype fundamentally contributes to voriconazole metabolism, elimination, and therefore bioavailability of the drug [4–6].
Systemic exposure to voriconazole is generally higher in individuals with reduced ability to metabolize and eliminate the drug. Trough plasma concentrations of voriconazole have been significantly higher in people possessing PM phenotypes followed by individuals with an IM phenotype, with the lowest bioavailability of the drug detected in individuals with an EM or UM phenotype [4–6, 8]. However, higher trough levels of voriconazole are not universally higher in individuals with reduced CYP2C19 activity [8, 10]. Voriconazole displays expected pharmacokinetic behaviour according to genotype in healthy volunteers, but there is often a marked departure from the customary dose/response relationship in patients. Presumably this deviation from expected pharmacokinetic behaviour is due to drug–drug interactions and/or the pathological circumstances of the patient [5, 6]. Generally, it is expected that disease circumstances or drug side effects that reduce liver enzyme activity (especially of CYP2C19, CYP2C9 and CYP3A4) will decrease metabolism and clearance of voriconazole, and thus increase patient exposure to the drug.
Therapeutic drug monitoring
The United States Food and Drug Administration and the Infectious Diseases Society of America recommend therapeutic drug monitoring (TDM) for patients receiving voriconazole . Numerous studies indicate that voriconazole trough values should be maintained above 1.0 μg/mL for fungal prophylaxis. Moreover, some studies indicate that voriconazole is more efficacious when trough levels are maintained at 2.0 μg/mL or higher [11, 12].
It is important to dose voriconazole accurately, as voriconazole efficacy is dependent on adequate exposure to the drug; however, increased trough levels are associated with numerous severe adverse effects (SAE). Voriconazole has been linked to several adverse events including abnormal liver function tests, gastrointestinal disturbances, rash and vomiting. Neurotoxicity (visual disturbances, hallucinations) is somewhat infrequently observed [1, 2]. Since CYP2C19 is a key metabolizer of voriconazole, it seems reasonable to predict a patient’s drug metabolizing phenotype based on their CYP2C19 genotype, and to use this information to guide dosing. In practice, the drug metabolizing genotype alone is not sufficient to predict the metabolizing phenotype. Confounding variables include the fact that voriconazole has a high propensity for drug–drug interactions, a narrow therapeutic index, it exhibits non-linear pharmacokinetics, and its clearance is affected by circumstances such as patient sex, age, disease state, liver function, obesity and the presence of inflammation [11, 13, 14].
The pharmacodynamic behaviour of voriconazole remains difficult to predict as it displays considerable interpatient and intrapatient variablility. Although TDM for patients receiving voriconazole is recommended, establishing a patient’s pharmacogenomic profile can provide clinicians with valuable information to aid in appropriate voriconazole dosing, especially in the initial stages of therapy. Pharmacogenomic information is likely to contribute to the goal of rapidly attaining a therapeutic concentration while avoiding toxicity. It is possible that our patient has a PM phenotype for voriconazole and that pharmacogenomic testing might have minimized her exposure to toxic levels of voriconazole that arose from standard voriconazole dosing.
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Sahar Rezaei BS; Laura Collier MLS(ASCP); Sara Taylor* PhD, MLS(ASCP)MB
Tarleton State University, Fort Worth, TX, USA