Dose rationale for the use of meropenem/vaborbactam combination in paediatric patients with Gram-negative bacterial infections.

AIMS: Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients. METHODS: Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA). RESULTS: Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months). CONCLUSIONS: An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).

Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study.

PURPOSE: To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. PATIENTS AND METHODS: Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. RESULTS: Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. CONCLUSION: Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

Clinical and pharmacologic study of the novel prodrug delimotecan (MEN 4901/T-0128) in patients with solid tumors.

PURPOSE: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites. EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m2, followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity. RESULTS: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m2 (n = 1), 3,600 mg/m2 (n = 1), and 2,400 mg/m2 (n = 2). The dose level of 1,800 mg/m2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m2) and head and neck cancer (2400 mg/m2). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan. CONCLUSIONS: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m2 in a phase II study.

Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human.

Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be sufficient to disrupt physiological motor and, possibly, secretory activity at the colonic level. Available evidence indicates that, in healthy volunteers, the infusion of NKA (25 pmol/kg/min i.v.) stimulated small intestine motility and precipitated a series of intestinal and non-intestinal adverse events. Nepadutant (8 mg i.v.), a selective NK2 receptor antagonist, antagonised small intestine motility induced by NKA and prevented associated intestinal adverse events. In another study, the same dose of nepadutant increased colo-rectal compliance during isobaric balloon distension in healthy volunteers pretreated with a glycerol enema, disclosing a NK2 receptor-mediated component in the regulation of colonic smooth muscle tone. However, the prolonged blockade of NK2 receptors by nepadutant (16 mg i.v. b.i.d. for 8 days) did not affect bowel habits, neither in term of movements nor of stool consistency. Altogether, these results indicate that, even when there is a significant redundance in the effects of TKs and in the role of their receptors, the selective blockade of tachykinin NK2 receptors can have functional consequences on human intestinal motility and perception, but this can occur without the disruption of the physiological functions.

Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy.

AIMS: The SENIORS trial recently demonstrated that nebivolol reduces the composite risk of all-cause mortality and cardiovascular hospital admission in elderly patients with chronic heart failure and, importantly, that ejection fraction does not influence the clinical effects of nebivolol. An echocardiographic substudy was designed to evaluate the effects of nebivolol on systolic and diastolic left ventricular (LV) function in patients stratified according to the presence or absence of systolic LV dysfunction. METHODS AND RESULTS: The substudy randomized 112 patients in 29 European centres, of whom 104 were evaluable for the study; 43 had an ejection fraction (EF) 35%. LV end-systolic volume (ESV), EF, mitral valve E/A ratio, and E-wave deceleration time were assessed at baseline and after 12 months. Echocardiograms were submitted to a core laboratory to perform quantitative analysis in blinded condition. In the group with EF35% group, no significant changes in either systolic or diastolic parameters were observed. CONCLUSION: In patients with heart failure and advanced systolic LV dysfunction, nebivolol reduces ventricular size and improves EF. The absence of detectable changes with standard echocardiography in patients with predominant diastolic heart failure questions the mechanism of benefit on morbidity/mortality in such patients.

A phase II study of sabarubicin (MEN-10755) as second line therapy in patients with locally advanced or metastatic platinum/taxane resistant ovarian cancer.

BACKGROUND: Sabarubicin (MEN-10755) is a third generation anthracycline, with a remarkable antitumor activity in human tumor xenografts, including doxorubicin-resistant tumors. Phase I studies have shown that myelosuppression is the main toxicity of sabarubicin, while its cumulative cardiotoxicity is mild. METHODS: The aim of the study was to evaluate the activity and safety profile of sabarubicin in patients with locally advanced or metastatic ovarian cancer failing 1st line platinum and/or taxane based chemotherapy, and relapsing earlier than 6 months after the last chemotherapy. Eligible patients received sabarubicin at the dose of 80 mg/m2 (dose level 0) every 3 weeks over 30 minutes. Dose was to be escalated to 90 mg/m2 (dose level +1) after the 1st cycle in case of grade 0-1 toxicity, while it was to be reduced to 60 mg/m2 (dose level -1) in case of toxicity. Response was assessed every 2 courses according to WHO criteria. Toxicity was graded according to Common Toxicity Criteria version 2.0. Gehan's design was used for sample size determination. RESULTS: Nineteen patients were enrolled and received 65 courses. One patient had a confirmed partial response, 9 patients had stable disease, 5 patients had disease progression, 3 patients were not evaluable for response, while one patient had an early progressive disease. The duration of response was 88 days. Mean time to disease progression was 125 days (range 56-188). Median survival was 62 days (range 36-202). Hematologic toxicity was moderate, since grade 3-4 neutropenia was observed in 25 out of 52 courses at 80 mg/m2, and grade 4 neutropenia occurred in one out of 12 courses at 90 mg/m2. Other grade 3-4 toxicities were: fatigue (five cases), nausea (two cases), stomatitis, general health deterioration, anorexia, vomiting, abdominal pain, hyponatremia (one case each). Cardiac toxicity was observed in the study; in fact, left ventricular ejection fraction (LVEF) fell below 50% in 2 patients, and 3 patients had a >15% decrease of LVEF from baseline, but there were no signs/symptoms of congestive heart failure. CONCLUSIONS: Sabarubicin showed limited activity in patients with resistant ovarian cancer. However, the observed data on disease stabilization, together with the drug's overall manageable toxicity profile, may prompt to its further investigation in advanced ovarian cancer.

Tachykinin NK2 receptor antagonists for the treatment of irritable bowel syndrome.

Tachykinin NK2 receptors are expressed in the gastrointestinal tract of both laboratory animals and humans. Experimental data indicate a role for these receptors in the regulation of intestinal motor functions (both excitatory and inhibitory), secretions, inflammation and visceral sensitivity. In particular, NK2 receptor stimulation inhibits intestinal motility by activating sympathetic extrinsic pathways or NANC intramural inhibitory components, whereas a modulatory effect on cholinergic nerves or a direct effect on smooth muscle account for the NK2 receptor-mediated increase in intestinal motility. Accordingly, selective NK2 receptor antagonists can reactivate inhibited motility or decrease inflammation- or stress-associated hypermotility. Intraluminal secretion of water is increased by NK2 receptor agonists via a direct effect on epithelial cells, and this mechanism is active in models of diarrhoea since selective antagonists reverse the increase in faecal water content in these models. Hyperalgesia in response to intraluminal volume signals is possibly mediated through the stimulation of NK2 receptors located on peripheral branches of primary afferent neurones. NK2 receptor antagonists reduce the hyper-responsiveness that occurs following intestinal inflammation or application of stressful stimuli to animals. Likewise, NK2 receptor antagonists reduce intestinal tissue damage induced by chemical irritation of the intestinal wall or lumen. In healthy volunteers, the selective NK2 antagonist nepadutant reduced the motility-stimulating effects and irritable bowel syndrome-like symptoms triggered by intravenous infusion of neurokinin A, and displayed other characteristics that could support its use in patients. It is concluded that blockade of peripheral tachykinin NK2 receptors should be considered as a viable mechanism for decreasing the painful symptoms and altered bowel habits of irritable bowel syndrome patients.