Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

AIMS: To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. PATIENTS AND METHODS: Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (ΔSUVmax) after 1 cycle using [18F]-fluorodeoxyglucose (FDG) PET. Early poor responders (ΔSUVmax < 70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. RESULTS: A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (~14 days) than previously reported (~26-28 days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k10) was positively correlated with ΔSUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. CONCLUSION: Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system.

Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.

Mortality risk score for Klebsiella pneumoniae bacteraemia.

BACKGROUND: Klebsiella pneumoniae bacteraemia (KPB) has been associated with multiple risk factors. However association of these risk factors with mortality secondary to KPB has been poorly documented. OBJECTIVES: To assess underlying co-morbidities in patients with KPB and any associated presentations. These findings were then used to devise a score to estimate the risk of in-hospital mortality in patients with underlying KPB. METHODS: A retrospective analysis of all patients diagnosed with KPB between November 2007 and March 2012 at Mater Dei hospital in Malta was carried out. Using the odds ratios of risk factors for mortality associated with KPB, a mortality risk score was then prepared. RESULTS: 186 patients (mean age 62 years; mean hospital stay 22.6 days) were included. 51 patients died as inpatients. Being admitted to intensive care (Overall risk (OR): 9, p<0.0001), having a solid organ tumour (OR 3, p<0.005), and having an underlying pneumonia (OR 3, p<0.021) were statistically significant risk factors associated with mortality. There were 0% mortality in patients with a score of 0, and progressively increasing mortalities with increasing scores up to a 100% mortality in patients with scores of >15. This translated into a validated risk score where an increasing score reflected an increasing mortality. CONCLUSIONS: Klebsiella pneumoniae bacteraemia is associated with high in-patient mortality. ICU admission, underlying solid tumours, and co-existent pneumonias are among the factors used in our mortality risk score. This needs to be further validated in larger populations.

Streptococcus gallolyticus bacteraemia in hepatobiliary-pancreatic and colonic pathologies.

BACKGROUND: Streptococcus gallolyticus bacteraemia has been associated with several pathologies, including bacterial endocarditis and colorectal cancer. AIMS: In this study, we have analysed whether Streptococcus gallolyticus bacteraemia is associated with an increased risk of hepatobiliary and colonic pathology. The association with other pathologies and the antibiotic sensitivities of Streptococcus gallolyticus were also analysed. DESIGN: Observational retrospective study. METHODS: The case notes of patients with documented Streptococcus gallolyticus bacteraemia between 2007 and 2012 at Mater Dei hospital (Malta) were reviewed. Demographic and clinical data, including co-morbidities, clinical investigations, antibiotic sensitivities and mortality were analysed. RESULTS: A total of 42 patients (33 males, 9 females) were recruited. Two patients were pre-term infants and were therefore excluded from the study. Mean age of the cohort population studied was 72 years (SD ± 14). One-year survival rate was 62%. Gastrointestinal (colonic and hepatobiliary-pancreatic) pathologies were present in 59.5% of patients with 16% of this group having more than one gastrointestinal pathology. High incidence rates of underlying diabetes mellitus (28.6%), valvular heart disease (21.4%) and malignancies (21.4%) were noted in this study. Furthermore, we observed that 14.3% of patients had an underlying respiratory pathology. Streptococcus gallolyticus was 100% sensitive to cefotaxime and vancomycin but was highly resistant to clindamycin, erythromycin and tetracycline. CONCLUSION: Streptococcus gallolyticus bacteraemia is commoner in the elderly and in those with multiple underlying co-morbidities. The high incidence of gastrointestinal pathologies among patients with Streptococcus gallolyticus bacteraemia (59.5%) suggests that a thorough work-up for colonic and hepatobiliary/pancreatic pathology should be carried out in these patients.

Neonatal anesthesia in Malta. A 4-year study (1980-1983).

Out of 21,090 live births registered in the Maltese Archipelago between 1st January 1980 and 31st December, 1983 there were 31 cases of congenital abnormalities that needed emergency surgery in the first few hours of life. The final results obtained locally compare favourably to those registered in larger centres abroad.