Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study.

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.

Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring.

RATIONALE: Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. OBJECTIVES: To characterize GER (acid and nonacid) in patients with SSc with and without ILD. METHODS: Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). MEASUREMENTS AND MAIN RESULTS: Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. CONCLUSIONS: Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.

Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication.

OBJECTIVES: After the skin, the gastrointestinal tract is the second most common target of systemic sclerosis (SSc). AIM: Our aims were to investigate orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO) in SSc as a cause of intestinal symptoms. METHODS: Fifty-five SSc patients and 60 healthy controls, sex and age matched, entered the study. Enrolled subjects completed a questionnaire for intestinal symptoms and a global symptomatic score (GSS) was calculated. OCTT and the presence of SIBO were assessed by a lactulose breath test (LBT). Patients with SIBO were treated with rifaximin 1,200 mg/day for 10 days. Finally, a second questionnaire and LBT were performed 1 month after the end of therapy. RESULTS: The prevalence of SIBO was higher in SSc patients compared with controls (30/54 vs 4/60, respectively, P < 0.001). OCTT was significantly slower in SSc patients compared with controls (150 min, 25-75th percentile 142.5-165 vs 105 min, 25-75th percentile 90-135, respectively, P < 0.001). In patients with SIBO, the median GSS score was 8 (25-75th percentile 3.25-10.75). Eradication of SIBO was achieved in 73.3% of patients, with a significant reduction of symptoms in 72.7% of them (GSS score 2, 25-75th percentile 1-3, P < 0.05). CONCLUSIONS: These data suggest that SIBO occurs more frequently in SSc patients than in controls. Intestinal symptoms in these patients may be related to this syndrome and its eradication seems useful to improve clinical features. OCTT is significantly delayed in SSc patients, suggesting an impairment of intestinal motility, a further risk factor for the development of SIBO.