Comparison of a thymine challenge test and endogenous uracil-dihydrouracil levels for assessment of fluoropyrimidine toxicity risk.

PURPOSE: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity. METHODS: Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC-MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases. RESULTS: There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), Unorm p = 0.0004; U/DHUnorm p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%). CONCLUSIONS: The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

Literature based drug interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions.

Drug-drug interactions (DDIs) are a common cause of adverse drug events. In this paper, we combined a literature discovery approach with analysis of a large electronic medical record database method to predict and evaluate novel DDIs. We predicted an initial set of 13197 potential DDIs based on substrates and inhibitors of cytochrome P450 (CYP) metabolism enzymes identified from published in vitro pharmacology experiments. Using a clinical repository of over 800,000 patients, we narrowed this theoretical set of DDIs to 3670 drug pairs actually taken by patients. Finally, we sought to identify novel combinations that synergistically increased the risk of myopathy. Five pairs were identified with their p-values less than 1E-06: loratadine and simvastatin (relative risk or RR = 1.69); loratadine and alprazolam (RR = 1.86); loratadine and duloxetine (RR = 1.94); loratadine and ropinirole (RR = 3.21); and promethazine and tegaserod (RR = 3.00). When taken together, each drug pair showed a significantly increased risk of myopathy when compared to the expected additive myopathy risk from taking either of the drugs alone. Based on additional literature data on in vitro drug metabolism and inhibition potency, loratadine and simvastatin and tegaserod and promethazine were predicted to have a strong DDI through the CYP3A4 and CYP2D6 enzymes, respectively. This new translational biomedical informatics approach supports not only detection of new clinically significant DDI signals, but also evaluation of their potential molecular mechanisms.

Assessment of the face validity of two pain scales in Kenya: a validation study using cognitive interviewing.

BACKGROUND: Patients in sub-Saharan Africa commonly experience pain, which often is un-assessed and undertreated. One hindrance to routine pain assessment in these settings is the lack of a single-item pain rating scale validated for the particular context. The goal of this study was to examine the face validity and cultural acceptability of two single-item pain scales, the Numerical Rating Scale (NRS) and the Faces Pain Scale-Revised (FPS-R), in a population of patients on the medical, surgical, and pediatric wards of Moi Teaching and Referral Hospital in Kenya. METHODS: Swahili versions of the NRS and FPS-R were developed by standard translation and back-translation. Cognitive interviews were performed with 15 patients at Moi Teaching and Referral Hospital in Eldoret, Kenya. Interview transcripts were analyzed on a question-by-question basis to identify major themes revealed through the cognitive interviewing process and to uncover any significant problems participants encountered with understanding and using the pain scales. RESULTS: Cognitive interview analysis demonstrated that participants had good comprehension of both the NRS and the FPS-R and showed rational decision-making processes in choosing their responses. Participants felt that both scales were easy to use. The FPS-R was preferred almost unanimously to the NRS. CONCLUSIONS: The face validity and acceptability of the Swahili versions of the NRS and FPS-R has been demonstrated for use in Kenyan patients. The broader application of these scales should be evaluated and may benefit patients who currently suffer from pain.

The oncology pharmacy in cancer care delivery in a resource-constrained setting in western Kenya.

The movement to deliver cancer care in resource-limited settings is gaining momentum, with particular emphasis on the creation of cost-effective, rational algorithms utilizing affordable chemotherapeutics to treat curable disease. The delivery of cancer care in resource-replete settings is a concerted effort by a team of multidisciplinary care providers. The oncology pharmacy, which is now considered integral to cancer care in resourced medical practice, developed over the last several decades in an effort to limit healthcare provider exposure to workplace hazards and to limit risk to patients. In developing cancer care services in resource-constrained settings, creation of oncology pharmacies can help to both mitigate the risks to practitioners and patients, and also limit the costs of cancer care and the environmental impact of chemotherapeutics. This article describes the experience and lessons learned in establishing a chemotherapy pharmacy in western Kenya.