Objectives To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). Methods This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5–14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31–50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. Results Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). Conclusions Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

We evaluated the pharmacokinetics and safety of the antimicrobial agent triclosan after dermal application of a 2% triclosan-containing cream to six volunteers. Percutaneous absorption calculated from urinary excretion was 5.9% ؎ 2.1% of the dose (mean ؎ standard deviation). The amount absorbed suggests that daily application of a standard adult dose would result in a systemic exposure 890 times lower than the relevant no-observed-adverse-effect level. Triclosan can be considered safe for use in hydrophobic creams.Triclosan is an antimicrobial agent with broad-spectrum activity against Gram-positive and Gram-negative bacteria as well as some molds and yeasts. It is bacteriostatic at low concentrations as it blocks lipid synthesis, whereas at higher concentrations (as reached in dermatological preparations) membrane destabilization and triclosan-induced K ϩ leakage lead to a rapid bactericidal effect (9, 16). Furthermore, triclosan potently inhibits the growth of Toxoplasma gondii and Plasmodium (13,20) and shows anti-inflammatory effects after topical administration (11,19).For more than 20 years, triclosan has been used widely worldwide in medical and consumer products (5, 21). In dermatological preparations, it is an effective topical antiseptic to reduce colonization with Staphylococcus aureus and to treat superinfected atopic dermatitis (2,8,10,22). Despite the almost-ubiquitous occurrence of the substance, pharmacokinetic studies are sparse.We evaluated the pharmacokinetics and safety of triclosan in a clinical study in six healthy Caucasians. The study was approved by the Ethics Committee of the University of Cologne and by the competent German authorities, and all participants gave their written informed consent. Demographic baseline characteristics are shown in Table 1. The study medication (provided by Infectopharm) was a hydrophobic cream containing 2% triclosan. Its composition corresponds to a dermatological standard preparation (NRF 11.122) which is listed in the Neues Rezeptur Formularium (German List of Recommended Standard Formulations). Approximately 60 g of the cream was massaged into the skin of the whole body except for the head and genitals. Exposure was ended by taking a shower 12 h after administration. The subjects were confined to the clinical ward under standardized conditions from 10 h prior until 48 h after study drug administration.Urinary excretion during individual sampling intervals up to 168 h postdose was used for pharmacokinetic calculations (WinNonlin version 5.01). For quantification, the sum of free triclosan and its glucuronide and sulfate metabolites (after enzymatic hydrolysis) was determined using a specific and sensitive high-performance liquid chromatographymass spectrometry approach based on published methods (15, 18). The lower and upper limits of quantification were 4.5 and 800 g/ml, respectively. Quality control samples showed good precision and accuracy throughout the measurement of study samples.In all individuals, the major fraction of absorbed triclosan was exc...

The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

Posaconazole is a new antifungal drug used in prophylaxis and therapy of fungal infections in patients with immunodeficiency. In the clinical development, posaconazole exhibits variable oral bioavailability. Hence drug monitoring is recommended. For this purpose, a rapid and a convenient high-performance liquid chromatography (HPLC) method has been developed. To 200 mul serum, 50 mul internal standard (itraconazole) was added. After precipitation of the proteins with acetonitrile, the clear supernatant was evaporated in a centrifugal evaporator, and the residue was dissolved in the HPLC elution. Separation was done on a chromatography performed by injecting a 50 mul aliquot of the resuspended sample onto a Multohyp C18 BDS column (250 x 4 mm). Column temperature was maintained at 50 degrees C. The flow rate was 1 ml min(-1). Retention time of posaconazole was about 9 min and those of itraconazole was 17 min. The limit of quantification was 50 mug l(-1) and the limit of detection about 10 mug l(-1). Until now the concentration of posaconazole was measured in 14 patients (64 samples). After a daily dosage of 600-800 mg posaconazole the serum concentrations varied between 100 and 3000 mug l(-1) (582 +/- 579 mug l(-1)). Oral bioavailability was especially low in patients with cytostatic therapy and/or bone marrow transplantation. Further studies are needed to establish the therapeutic range of the posaconazole concentrations.