Re-thinking the possible interaction between proton pump inhibitors and capecitabine.

Proton Pump Inhibitors (PPI) rank within the top ten most prescribed medications in Europe and USA. A high frequency of PPI use has been reported amongst patients undergoing chemotherapy, to mitigate treatment-induced gastritis or gastro-oesophageal reflux. Several recent, mostly retrospective, observational studies have reported inferior survival outcomes among patients on capecitabine who concomitantly use PPI. Whilst this association is yet to be definitively established, given the prominence of capecitabine as an anti-cancer treatment with multiple indications, these reports have raised concern within the oncological community and drug regulatory bodies worldwide. Currently, the leading mechanism of interaction postulated in these reports has focussed on the pH altering effects of PPI and how this could diminish capecitabine absorption, leading to a decrease in its bioavailability. In this discourse, we endeavour to summarise plausible pharmacokinetic interactions between PPI and capecitabine. We provide a basis for our argument against the currently proposed mechanism of interaction. We also highlight the long-term effects of PPI on health outcomes, and how PPI use itself could lead to poorer outcomes, independent of capecitabine.

Sinonasal and gastrointestinal bacterial composition and abundance are stable after 1 week of once-daily oral antibiotic treatment for chronic rhinosinusitis.

BACKGROUND: Despite the widespread prescription of antibiotics for the treatment of chronic rhinosinusitis (CRS), their efficacy remains uncertain. Limited penetration of systemic antibiotics into the sinonasal mucosa has been reported previously by this group. This study aimed to investigate the short-term effects of antibiotics on the sinus and gut microbiota as well as any relationships these had with drug distribution. METHODS: Thirty subjects undergoing functional endoscopic sinus surgery for CRS were randomized to one of three groups: (1) doxycycline (100 mg daily for 7 days); (2) roxithromycin (300 mg daily for 7 days); and (3) control (no antibiotics given). Sinonasal and stool samples collected before and after treatment were analyzed using 16S ribosomal RNA (rRNA) gene-targeted amplicon sequencing and Droplet Digital polymerase chain reaction (PCR) for bacterial community composition and the quantification of bacterial DNA, respectively. RESULTS: There were no significant major bacterial community shifts or changes to bacterial diversity and load following the treatment period in all patient groups. Non-significant trend reductions were observed in gut microbial diversity with antibiotics. For the roxithromycin group, sinonasal bacterial diversity was negatively correlated with serum drug levels and reduced overall compared to controls (p < 0.05). The relative abundance of Staphylococcus ASV129 in sinonasal samples reduced with increasing mucus doxycycline levels (p = 0.01). CONCLUSION: Antibiotic prescription for CRS should be further investigated because of preliminary evidence of poor sinonasal drug penetration, unproven efficacy, and the potential impact of dysbiosis in the sinuses and off-target sites. Further studies should consider distinguishing the presence of DNA from viable and nonviable bacteria.

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.

Oral antibiotics used in the treatment of chronic rhinosinusitis have limited penetration into the sinonasal mucosa: a randomized trial.

Despite the widespread prescription of antibiotics for patients with chronic rhinosinusitis (CRS), the extent to which drug distribution to the sinonasal mucosa occurs remains largely undefined. Twenty subjects undergoing functional endoscopic sinus surgery (FESS) for CRS were randomized to one of two groups: 1) doxycycline (100 mg daily for seven days) 2) roxithromycin (300 mg daily for seven days). Drug levels were measured using liquid chromatography-tandem mass spectrometry in sinonasal mucus, sinonasal tissues and serum at steady state. Doxycycline concentrations measured in the mucus were significantly lower compared to that in the serum (mean mucus/serum ratio = 0.16, p < 0.001) and the tissue (mean mucus/tissue ratio = 0.18, p < 0.0001). Roxithromycin concentrations in the mucus were also significantly lower compared to that in the serum (mean mucus/serum ratio = 0.37, p = 0.002) and the tissue (mean mucus/tissue ratio = 0.60, p < 0.001). Although the efficacy of doxycycline and roxithromycin in sinonasal mucus in vivo cannot be predicted solely from reported minimum inhibitory concentrations, given the added complexity of bacterial biofilm antimicrobial tolerance, these results suggest that low mucosal penetration of antibiotics may be one of the factors contributing to the limited efficacy of these agents in the treatment of CRS.

A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity.

AIMS: A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case-control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5-fluorouracil or capecitabine. METHODS: Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0-4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events. RESULTS: The median THY/DHT ratios were 6.2 (interquartile range 2.9-6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8-4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72-1.00). CONCLUSIONS: The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life-threatening fluoropyrimidine gastrointestinal toxicity.

Subcutaneous nicotine delivery via needle-free jet injection: A porcine model.

Subcutaneous delivery of nicotine was performed using a novel electrically-operated needle-free jet injector, and compared to hypodermic needle delivery in a porcine model. Nicotine was delivered as a single, one-milligram dose into the abdominal skin, formulated as a 50 microliter aqueous solution. Plasma levels of nicotine and cotinine, its main metabolite, were then monitored over 2 h, following which the injection site was excised for histological examination. No irritation or tissue damage were found at the injection sites, and the jet-injected nicotine exhibited comparable absorption into the systemic circulation to that injected using a conventional needle and syringe. The needle-free jet injection of nicotine is a promising and well tolerated method. The data presented from this porcine model will support a first in human trial towards a new promising nicotine replacement therapy.

Ascending single dose pharmacokinetics of cytisine in healthy adult smokers.

1. Cytisine, a partial agonist for the α4ß2-nAChR, is used as a smoking cessation medication. Cytisine's current dosing is complex and involves taking 1.5 mg several times a day. The aim of this study was to explore the effect of dose on the pharmacokinetics and safety of cytisine after a single dose in healthy adult smokers. 2. Participants were assigned to one of three groups (n = 6 in each group) to receive a single oral dose of 1.5, 3 or 4.5 mg of cytisine. Blood samples were collected up to 24 h post dose. Pulse, blood pressure and respiratory rate were measured. Adverse effects were recorded. 3. Cytisine reached peak plasma concentration 1-2 h post dose in all participants irrespective of dose, with no dose-dependent changes in the elimination phase. Mean (SD) cytisine exposure (AUC0-24h) were 81.9 (15.8), 181.9 (40.8) and 254.5 (48.1) ng.h/mL following 1.5, 3 and 4.5 mg, respectively. 4. Cytisine appears to have predictable pharmacokinetics following a single dose of up to 4.5 mg and may be safe given as a single 4.5 mg dose, which is threefold greater than the recommended dose taken at one time. This study is registered in ClinicalTrials.gov (ID:NCT02585024).

Plasma concentrations of cytisine, a commercially available plant-based alkaloid, in healthy adult smokers taking recommended doses for smoking cessation.

1. Cytisine is a plant alkaloid that is a partial agonist for the α4ß2 -nAChRs and is used as an aid to smoking cessation. To date, there are no published data on cytisine concentrations in humans following multiple dosing. The aim of this study was to determine cytisine plasma concentrations after taking recommended doses for smoking cessation and to report on adverse effects. 2. Subjects (n=10) were instructed to follow the 25-day standard dosing regimen of cytisine. Blood was collected at 0, 2, 4, 8 and 10 hours on day 1 then on subsequent visits (days 2, 3, 4, 6, 13, 14, 17, 18, 21, 22, 25 and 26) to measure plasma cytisine concentrations. Plasma concentrations were determined using a validated LC-MS method. 3. Accumulation of cytisine was observed with repeated dosing of cytisine on day 1. Mean ± SEM plasma cytisine concentration measured at 10 hours was 50.8 ± 4.7 ng/mL. Due to dose tapering, there was an overall decrease in plasma cytisine concentration over the whole treatment period. 4. Overall, cytisine was well-tolerated and adverse effects reported were minor, indicating that cytisine is safe at concentrations measured in this study. This study is registered in the Australia and New Zealand Clinical Trials Registry (ACTRN12613000002785).

Pharmacokinetics of cytisine, an α4 ß2 nicotinic receptor partial agonist, in healthy smokers following a single dose.

Cytisine, an α4 ß2 nicotinic receptor partial agonist, is a plant alkaloid that is commercially extracted for use as a smoking cessation medication. Despite its long history of use, there is very little understanding of the pharmacokinetics of cytisine. To date, no previous studies have reported cytisine concentrations in humans following its use as a smoking cessation agent. A high performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for analysis of Tabex® and nicotine-free oral strips, two commercial products containing cytisine. A sensitive liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for the quantification of cytisine in human plasma and for the detection of cytisine in urine. Single-dose pharmacokinetics of cytisine was studied in healthy smokers. Subjects received a single 3 mg oral dose administration of cytisine. Cytisine was detected in all plasma samples collected after administration, including 15 min post-dose and at 24 h. Cytisine was renally excreted and detected as an unchanged drug. No metabolites were detected in plasma or urine collected in the study. No adverse reactions were reported.