Christine M Walko

Julphar School of Pharmacy, North Carolina, United States

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Publications (48)263.66 Total impact

  • Cancer Research 05/2015; 75(9 Supplement):P1-03-02-P1-03-02. DOI:10.1158/1538-7445.SABCS14-P1-03-02 · 9.28 Impact Factor
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    ABSTRACT: A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. 355 patients receiving tamoxifen 20 mg/day were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen/N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned; 2, 1, 0.5, and 0, respectively. Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each p < 0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM, and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (p < 0.0001), with the CYP2D6*2 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (p = 0.014). The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs. This article is protected by copyright. All rights reserved.
    British Journal of Clinical Pharmacology 04/2015; DOI:10.1111/bcp.12665 · 3.69 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2015; 21(2):S310. DOI:10.1016/j.bbmt.2014.11.494 · 3.35 Impact Factor
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    ABSTRACT: Background. Pharmacokinetically guided (PK-guided) versus body surface area-based 5-fluorouracil (5-FU) dosing results in higher response rates and better tolerability. A paucity of data exists on PK-guided 5-FU dosing in the community setting. Patients and Methods. Seventy colorectal cancer patients, from one academic and five community cancer centers, received the mFOLFOX6 regimen (5-FU 2,400 mg/m(2) over 46 hours every 2 weeks) with or without bevacizumab at cycle 1. The 5-FU continuous-infusion dose was adjusted for cycles 2-4 using a PK-guided algorithm to achieve a literature-based target area under the concentration-time curve (AUC). The primary objective was to demonstrate that PK-guided 5-FU dosing improves the ability to achieve a target AUC within four cycles of therapy. The secondary objective was to demonstrate reduced incidence of 5-FU-related toxicities. Results. At cycles 1 and 4, 27.7% and 46.8% of patients achieved the target AUC (20-25 mg 3 hour/L), respectively (odds ratio [OR]: 2.20; p 5.046). Significantly more patients were within range at cycle 4 compared with a literature rate of 20% (p < .0001). Patients had significantly higher odds of not being underdosed at cycle 4 versus cycle 1 (OR: 2.29; p = .037). The odds of a patient being within range increased by 30% at each subsequent cycle (OR: 1.30; p = 5.03). Less grade 3/4 mucositis and diarrhea were observed compared with historical data(1.9% vs16% and 5.6% vs 12%, respectively); however, rates of grade 3/4 neutropenia were similar (33% vs 25%-50%). Conclusion. PK-guided 5-FU dosing resulted in significantly fewer underdosed patients and less gastrointestinal toxicity and allows for the application of personalized colorectal cancer therapy in the community setting.
    The Oncologist 08/2014; 19(9). DOI:10.1634/theoncologist.2014-0132 · 4.54 Impact Factor
  • Christine M Walko, Howard L McLeod
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    ABSTRACT: Minimizing toxicity while maximizing efficacy is a common goal in the treatment of any condition but its importance is underscored in the discipline of oncology because of the serious nature of many chemotherapeutic toxicities and the risk of cancer recurrence or disease progression. The challenge of achieving an optimal therapeutic index is especially augmented in the elderly population because of age-related metabolism changes and interacting concurrent medications. Additional factors, such as germline mutations in drug-metabolizing enzymes and other pharmacogenomic alterations, may have more pronounced effects in elderly patients, given their predisposition to altered pharmacokinetics and pharmacodynamics with resulting increased risk of toxicity. Examples of the possible interplay of these factors will be discussed using tamoxifen, paclitaxel, codeine, and fluorouracil as starting points. Limited participation of the elderly in many cancer trials, especially trials assessing drug exposure, makes much knowledge on the interaction of these patient and environmental factors speculative in nature but presents an opportunity for future research to achieve better optimization of chemotherapeutic agents in the elderly.
    Journal of Clinical Oncology 07/2014; 32(24). DOI:10.1200/JCO.2014.55.9047 · 17.88 Impact Factor
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    ABSTRACT: This pilot study examined the feasibility of outpatient screening and clopidogrel dose adjustment for patients with previous percutaneous coronary intervention and at least one CYP2C19 loss-of-function allele. After screening a total of 211 outpatients, 50 patients were enrolled in a crossover study comparing 30 days of standard dose (75 mg) to 30 days of high-dose clopidogrel (150 mg). Platelet function was assessed with the VerifyNow P2Y12 assay. In patients with CYP2C19*2, 150 mg daily of clopidogrel was associated with improved ADP-specific platelet inhibition (217 vs 258 P2Y12 reaction units, p = 0.01). Outpatient screening for CYP2C19 loss-of-function polymorphisms is feasible, and a strategy of clopidogrel dose escalation may improve platelet inhibition in appropriately selected patients.
    Pharmacogenomics 05/2014; 15(7):915-923. DOI:10.2217/pgs.14.17 · 3.43 Impact Factor
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    ABSTRACT: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without mannitol. This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol.
    Annals of Pharmacotherapy 04/2014; 48(7). DOI:10.1177/1060028014533303 · 2.92 Impact Factor
  • Christine M Walko, Carolyn Grande
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    ABSTRACT: Sorafenib, a tyrosine kinase inhibitor, is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). Sorafenib is currently being evaluated in phase II and III trials in various malignancies as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapies (metastatic breast cancer). Grade 1 and 2 adverse events (AEs) that commonly occur during treatment (ie, dermatologic manifestations, diarrhea, fatigue, and hypertension) should be proactively managed. The goal is to allow patients to remain on their full dose of sorafenib for as long as their treatment is indicated. A combination of early recognition of and intervention for AEs, patient education, and an open dialogue between patients and their multidisciplinary healthcare team, with timely reporting of AEs, will allow for effective management of AEs and minimize the need for sorafenib dose reduction or discontinuation.
    Seminars in Oncology 02/2014; 41S2:S17-S28. DOI:10.1053/j.seminoncol.2014.01.002 · 3.94 Impact Factor
  • Biology of Blood and Marrow Transplantation 02/2014; 20(2):S292. DOI:10.1016/j.bbmt.2013.12.493 · 3.35 Impact Factor
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    ABSTRACT: Background: CYP2D6 is a critical enzyme in the metabolism of tamoxifen and potentially a key determinant in breast cancer outcomes. Our study examined patients' beliefs about how the CYP2D6 genotype would affect their prognoses. Methods: Women enrolled in a pharmacogenomic clinical trial and on tamoxifen for prevention or treatment of breast cancer underwent CYP2D6 genotyping (EM = extensive, IM = intermediate, PM = poor metabolizing alleles). The informed consent said that the purpose of the trial was to examine effects of dose adjustment based on genotype, but that clinical benefits were uncertain. Our embedded sub-study surveyed 320 patients prior to receiving their genotypes. We experimentally manipulated 6 vignettes to describe hypothetical tamoxifen treatment (no or yes) and hypothetical genotype (EM, IM or PM). For each vignette, women gave their perceived recurrence risk (RR; 0-100%). Results: Women believed that genotype would not affect their RR if they did not take tamoxifen (p = 0.06). However, women believed that if prescribed tamoxifen, genotype would affect their RR (22% if EM, 30% if IM and 40% if PM, p < 0.001). Conclusion: Women believed that extensive tamoxifen metabolizers had better prognoses, despite study materials stating uncertainty about any benefit. The rapidly changing nature of genomic science calls for caution when communicating clinical utility. © 2014 S. Karger AG, Basel.
    Public Health Genomics 01/2014; 17(1):43-47. DOI:10.1159/000356565 · 2.46 Impact Factor
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    ABSTRACT: PurposeThe primary purpose of this study was to determine the rate of infusion reactions to cetuximab in oncology patients treated at the University of North Carolina Cancer Hospital. Secondarily, we sought to evaluate predictors of grade 3-4 hypersensitivity, including geography. /st>Data were collected by retrospective chart review for patients treated with cetuximab at the University of North Carolina Cancer Hospital between 15 November 2006 and 31 December 2010. Data were analyzed for occurrence of hypersensitivity reaction in 125 patients with various cancer types. /st>Of the 125 subjects, 31 (24.8%) experienced an infusion reaction of any grade. Of 125, 18 (14.4%) experienced a grade 3 or 4 reaction. The odds ratio for patients with an allergy history having a grade 3 or 4 reaction was 2.57 (95% CI 0.93 to 7.09, p = 0.07). Pretreatment with steroids was associated with absence of grade 3 or 4 reaction with an odds ratio of 0.21 (95% CI 0.05 to 0.83, p = 0.04). Mapping of reaction rates by county revealed higher rates in some of the more rural counties of North Carolina, however, statistical power was lacking. /st>Rates of hypersensitivity reaction at UNC are similar to rates seen in other areas of the southeastern United States and higher than in other regions of the United States and Europe. Rates of both hypersensitivity reactions and grade 3 to 4 hypersensitivity reactions have not substantially changed over time. Geography, allergy history, and perhaps smoking or cancer type may help predict who will react to cetuximab. Steroids should be strongly considered as premedication in addition to diphenhydramine.
    Journal of Oncology Pharmacy Practice 11/2013; DOI:10.1177/1078155213510542
  • Daniel J Crona, Meredith D Keisler, Christine M Walko
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    ABSTRACT: To review currently available literature on the oral multikinase inhibitor regorafenib and its role in the treatment of metastatic colorectal cancer (mCRC), and imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GISTs). A comprehensive literature search was performed of PubMed/MEDLINE and American Society of Clinical Oncology (ASCO) abstracts (through August 2013). Preclinical pharmacological and phase I to III trials data analyzing regorafenib efficacy and safety in mCRC or imatinib- and sunitinib-resistant GIST patients were evaluated. All available English-language, peer-reviewed articles and ASCO abstracts with relevant information were reviewed. Regorafenib was approved for mCRC in September 2012 and for imatinib- and sunitinib-resistant GISTs in February 2013. Regorafenib is an inhibitor of stromal, angiogenic, and oncogenic receptor tyrosine kinases, as well as the RAF/MEK/ERK signaling pathway. Phase III CORRECT (Regorafenib Monotherapy for Previously Treated Metastatic Colorectal Cancer) trial data demonstrated an overall survival benefit for mCRC patients treated with regorafenib (6.4 vs 5.0 months; P = .0052). Phase III GRID (Gastrointestinal Stromal Tumors After Failure of Imatinib and Sunitinib) trial data revealed a progression-free survival benefit in imatinib- and sunitinib-resistant GIST patients (4.8 vs 0.9 months; P < .0001). Its adverse event (AE) profile is comparable to that of other multikinase inhibitors. The most commonly observed grade ≥3 AEs included hypertension, hand-foot skin reaction, rash, diarrhea, and fatigue. Regorafenib is a novel oral multikinase inhibitor that has shown promising results for patients with advanced, unresectable or metastatic treatment-refractory CRCs or imatinib- and sunitinib-resistant GISTs.
    Annals of Pharmacotherapy 11/2013; 47(12). DOI:10.1177/1060028013509792 · 2.92 Impact Factor
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    ABSTRACT: A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.
    Anti-cancer drugs 01/2013; DOI:10.1097/CAD.0b013e32835dc7c5 · 1.89 Impact Factor
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    Christine M Walko, Ogechi Ikediobi
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    ABSTRACT: Oncology chemotherapeutics frequently exhibit a narrow therapeutic index, further complicated by the serious nature of dosing either too high (dangerous toxicities) or too low (loss of antitumor benefits). This underscores the need for optimal individualized drug selection and dosing, especially with agents that have wide interpatient variability. Pharmacogenomic assessment of drug metabolizing enzymes can improve the ability to optimally dose patients being treated with certain agents such as 6-mercaptopurine, irinotecan, tamoxifen, and flurouracil. Two of these agents (6-mercaptopurine and irinotecan) already have mention of pharmacogenomic testing in their FDA approved package inserts. Ongoing retrospective and prospective trials will help to further optimize the place in clinical practice for not only performing these pharmacogenomic assessments but, more importantly, how the results should be incorporated into therapy dosing decisions for patients.
    Journal of Pharmacy Practice 08/2012; 25(4):439-46. DOI:10.1177/0897190012448308
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    ABSTRACT: • Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel. • This pilot study demonstrates for the first time that there is an in vivo correlation between paclitaxel and rosiglitazone exposure. The finding, that a single rosiglitazone plasma concentration after oral dosing may explain significant variance in paclitaxel exposure, suggests that rosiglitazone may satisfy the requirements of a clinically useful in vivo probe. However, it is acknowledged that there is a need for further studies evaluating the use of rosiglitazone as a CYP2C8 probe and quantifying the relationship, in order to guide dosing of narrow therapeutic index drugs metabolized primarily by CYP2C8, such as paclitaxel. To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure. The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects. Rosiglitazone concentration was significantly correlated with paclitaxel exposure (P= 0.018) while ERMBT had no predictive value (P= 0.47). The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.
    British Journal of Clinical Pharmacology 07/2012; 74(1):197-200. DOI:10.1111/j.1365-2125.2012.04165.x · 3.69 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):3768-3768. DOI:10.1158/1538-7445.AM2012-3768 · 9.28 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):750-750. DOI:10.1158/1538-7445.AM2012-750 · 9.28 Impact Factor
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    Jai N Patel, Christine M Walko
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    ABSTRACT: To review the currently available literature on peginterferon alfa-2b (pegIFN [Sylatron]), including its role in therapy and toxicity for adjuvant treatment of locally advanced melanoma. A literature search was performed of PubMed and the American Society of Clinical Oncology abstracts from 1976 to February 2012, using the primary search terms peginterferon alfa-2b, interferon, Sylatron, and melanoma. All available English-language articles and trials that described the pharmacology, pharmacokinetics, pharmacodynamics, clinical activity, or safety profile of pegIFN were reviewed. PegIFN was approved in March 2011 for the adjuvant treatment of node-positive melanoma. Interferon (IFN) is commonly used in patients with melanoma who remain at high risk for relapse following surgery; however, the optimal scheduling and dose are not agreed upon. Pegylation of IFN involves conjugation with polyethylene glycol. Following subcutaneous injection of pegIFN, the rate of absorption, renal and cellular clearance, and immunogenicity are reduced. As a result of the extended serum half-life, once-weekly administration is feasible, compared with the daily and/or thrice weekly dosing of IFN. When compared with observation alone in patients with resected stage III melanoma, pegIFN demonstrated a significant increase in relapse-free survival, with a marginal impact on overall survival. The most common adverse events were as expected with IFN and included fatigue, increased liver enzymes, pyrexia, headache, anorexia, myalgia, nausea, chills, depression, and injection site reactions. A large Phase 3 study is underway to further assess outcome and toxicity differences between pegIFN weekly and low-dose IFN thrice weekly. PegIFN is a modified version of the previously approved interferon indicated for the adjuvant treatment of melanoma. Although the safety profile remains similar between the pegylated and non-pegylated forms, once-weekly administration is feasible secondary to an extended serum half-life and may have improved convenience for the patient.
    Annals of Pharmacotherapy 05/2012; 46(6):830-8. DOI:10.1345/aph.1Q791 · 2.92 Impact Factor
  • Christine M Walko, Howard McLeod
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    ABSTRACT: Tamoxifen is a selective estrogen-receptor modulator that is commonly utilized in the treatment and prevention of endocrine receptor-positive breast cancer. Ultimate conversion of the parent drug by the enzyme CYP2D6 to the active metabolite, endoxifen, is required for tamoxifen to exert its anticancer effects. CYP2D6 exists in varying concentrations across individuals due, in part, to genetic variation. Lower concentrations of endoxifen have been associated with inferior breast cancer outcomes in numerous retrospective trials. In an effort to increase the endoxifen concentrations, three prospective trials have assessed different methods of increasing tamoxifen dose based on patient CYP2D6 genotypes. All three demonstrated the ability to increase endoxifen concentrations using tamoxifen at a dose of 30 or 40 mg daily. These positive findings support future investigations to determine, not only the clinical benefit of genotype-guided therapy, but also the optimal dose needed for individual patients.
    Pharmacogenomics 04/2012; 13(6):691-7. DOI:10.2217/pgs.12.27 · 3.43 Impact Factor
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    Journal of the American College of Cardiology 03/2012; 59(13). DOI:10.1016/S0735-1097(12)61407-7 · 15.34 Impact Factor

Publication Stats

493 Citations
263.66 Total Impact Points


  • 2014
    • Julphar School of Pharmacy
      North Carolina, United States
    • University of South Florida
      Tampa, Florida, United States
  • 2004–2014
    • University of North Carolina at Chapel Hill
      • • Institute of Pharmacogenomics and Individualized Therapy
      • • Department of Medicine
      • • Division of Pharmacotherapy and Experimental Therapeutics
      North Carolina, United States