Abdominal tissue concentrations and penetration of carboplatin in a HIPEC procedure ‒ assessment in a novel porcine model.

Objectives: Peritoneal dissemination from intraabdominal cancers is associated with poor prognosis and rapid disease progression. Hyperthermic intraperitoneal chemotherapy (HIPEC) is an antineoplastic treatment, which has improved survival and recurrence-free survival, but little is known about the acquired chemotherapy concentrations in local tissues. The aim of this study was to assess concentrations of carboplatin during and after HIPEC treatment dynamically and simultaneously in various abdominal organ tissues by means of microdialysis in a novel porcine model. Methods: Eight pigs underwent imitation cytoreductive surgery followed by HIPEC (90 min) using a carboplatin dosage of 800 mg/m2. Microdialysis catheters were placed for sampling of drug concentrations in various solid tissues: peritoneum, liver, bladder wall, mesentery and in different depths of one mm and four mm in the hepatoduodenal ligament and rectum. During and after HIPEC, dialysates and blood samples were collected over 8 h. Results: No statistically significant differences in mean AUC0-last (range: 2,657-5,176 min·µg/mL), mean Cmax (range: 10.6-26.0 µg/mL) and mean Tmax (range: 105-206 min) were found between the compartments. In plasma there was a tendency towards lower measures. No difference between compartments was found for tissue penetration. At the last samples obtained (450 min) the mean carboplatin concentrations were 4.9-9.9 µg/mL across the investigated solid tissues. Conclusions: Equal carboplatin distribution in abdominal organ tissues, detectable concentrations for at least 6 h after HIPEC completion, and a carboplatin penetration depth of minimum four mm were found. The present study proposes a new HIPEC porcine model for future research.

joineRML: a joint model and software package for time-to-event and multivariate longitudinal outcomes.

BACKGROUND: Joint modelling of longitudinal and time-to-event outcomes has received considerable attention over recent years. Commensurate with this has been a rise in statistical software options for fitting these models. However, these tools have generally been limited to a single longitudinal outcome. Here, we describe the classical joint model to the case of multiple longitudinal outcomes, propose a practical algorithm for fitting the models, and demonstrate how to fit the models using a new package for the statistical software platform R, joineRML. RESULTS: A multivariate linear mixed sub-model is specified for the longitudinal outcomes, and a Cox proportional hazards regression model with time-varying covariates is specified for the event time sub-model. The association between models is captured through a zero-mean multivariate latent Gaussian process. The models are fitted using a Monte Carlo Expectation-Maximisation algorithm, and inferences are based on approximate standard errors from the empirical profile information matrix, which are contrasted to an alternative bootstrap estimation approach. We illustrate the model and software on a real data example for patients with primary biliary cirrhosis with three repeatedly measured biomarkers. CONCLUSIONS: An open-source software package capable of fitting multivariate joint models is available. The underlying algorithm and source code makes use of several methods to increase computational speed.

Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.

BACKGROUND: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. OBJECTIVES: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. DESIGN: FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. SETTINGS: Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool. PARTICIPANTS: Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. INTERVENTIONS: Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. MAIN OUTCOME MEASURES: Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use. RESULTS: Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%). CONCLUSIONS: The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37558856. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.

Adherence and variability in warfarin dose requirements: assessment in a prospective cohort.

AIM: Although several genetic and nongenetic factors are associated with warfarin dose, approximately 40% of variability remains unexplained. An as yet unexplored factor is medication adherence. Here, we investigate the influence of adherence on response to warfarin and on pharmacogenetic analyses of association. PATIENTS & METHODS: A total of 311 patients starting warfarin were followed-up prospectively, and adherence was measured at 1, 8 and 26 weeks. The association between adherence and warfarin response was tested, and the additional proportion of variability in response explained by adherence was assessed. RESULTS: Significant associations were found between adherence and achievement of stable dose and time taken to achieve it, with nonadherers taking longer. Adjusting for adherence increased the proportion of explained variability in treatment response by up to 8%. CONCLUSION: Given the significant contribution of adherence to drug response, we recommend that consideration is given to the value of assessing adherence when designing future pharmacogenetic studies of warfarin and other drugs.

Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.

OBJECTIVE: Carbonic anhydrase (CA) inhibitors topiramate and zonisamide can induce metabolic acidosis in some patients. Our aims were to assess the prevalence and severity of this acidosis and to determine its predictors. METHODS: For 70 patients established on treatment with topiramate (n=55) or zonisamide (n=14) or both (n=1), we measured electrolytes, and genotyped single nucleotide polymorphisms (SNPs) in the main renal CA isoenzymes (II, IV and XII). RESULTS: Twenty-six percent of patients had a metabolic acidosis (serum bicarbonate <20 mmol/l). The mean serum bicarbonate of patients taking topiramate was significantly lower than those taking zonisamide (P=0.002). We found no association between serum bicarbonate and the dose of drug or the duration of treatment. Serum bicarbonate levels were associated with the CA type XII SNPs rs2306719 (P=0.006 by one-way analysis of variance) and rs4984241 (P=0.015), but this association was not strong enough to survive correction for multiple testing. CONCLUSION: The development of acidosis with topiramate and zonisamide is not determined by drug dose or by treatment duration, but may be influenced by polymorphisms in the gene for CA type XII. The aforementioned SNPs lie 9.8 kb apart in intron 1 of the CA type XII gene, and deserve further study in a larger cohort of patients.

Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study.

BACKGROUND: In this prospective cohort study, we have undertaken a comprehensive evaluation of clinical parameters along with variation in 29 genes (including CYP2C9 and VKORC1) to identify factors determining interindividual variability in warfarin response. METHODS: Consecutive patients (n=311) were followed up prospectively for 26 weeks. Several outcomes chosen to capture both warfarin efficacy and toxicity were assessed. Univariate and multiple regression analyses were undertaken to assess the combined effect of clinical and genetic factors. RESULTS: CYP2C9 was the most important gene determining initial anticoagulant control, whereas VKORC1 was more important for stable anticoagulation. Novel associations with some clinical outcomes were found with single nucleotide polymorphisms in the cytochrome 450 genes CYP2C18 and CYP2C19, which were independent of the associations observed with CYP2C9 and in genes encoding CYP3A5, protein S and clotting factor V, although the variability explained by these genes was small. On the basis of the results of microcosting, adverse events were shown to be a significant predictor of total cost. CONCLUSION: Accurate prediction of warfarin dose requirement needs to take into account multiple genetic and environmental factors, the contributions of which vary in the induction and maintenance phases of treatment.