Cefiderocol is a novel parenteral siderophore cephalosporin that shows potent efficacy against various Gram-negative bacteria, including carbapenem-resistant strains, in vitro and in preclinical models of infection. The aim of the present study was to evaluate the pharmacokinetics (PK), safety, and tolerability of cefiderocol after both single and multiple dosing by intravenous infusion over 60 min in healthy adult subjects. A single-ascending-dose study at doses of 100, 250, 500, 1,000, and 2,000 mg was conducted in 40 healthy Japanese males and females (6 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). A multiple-ascending-dose study at doses of 1,000 (two groups) and 2,000 mg every 8 h (q8h) was conducted in 30 healthy Japanese and Caucasian males (8 individuals receiving the active drug and 2 individuals receiving a placebo per cohort). There were no serious or clinically significant adverse events (AEs) observed in either study. A single subject receiving 1,000 mg cefiderocol q8h was withdrawn due to AEs. Dose-proportional increases in the maximum plasma concentration (Cmax), the area under the concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration after dosing, and the area under the concentration-time curve extrapolated from time zero to infinity were observed across the dose range of 100 to 2,000 mg. The mean plasma half-life of cefiderocol was 1.98 to 2.74 h. Cefiderocol was primarily excreted unchanged in the urine (61.5% to 68.4% of the dose). There was little accumulation of Cmax and AUC by dosing q8h, and the PK of cefiderocol did not change with multiple dosing. This study indicates that single and multiple intravenous doses of cefiderocol at up to 2,000 mg are well tolerated in healthy subjects and exhibit linear PK at doses up to 2,000 mg.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • In healthy subjects, GSK2248761 was shown to be safe and well tolerated with single doses up to 1200 mg once daily and with multiple doses up to 800 mg once daily for 7 days. Furthermore, a phase IIa monotherapy study demonstrated that GSK2248761 30 to 800 mg once daily for 7 days was well tolerated in HIV‐1–infected subjects and that doses ≥100 mg once daily were associated with antiviral activity (∼1.8 log10 copies ml−1). However, the potential for drug interactions with co‐administration of GSK2248761 and other antiretroviral medications or supportive medications is not known. WHAT THIS STUDY ADDS • These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated. In addition, these studies indicate that few dosage modifications would be necessary if GSK2248761 were to be administered with most antiretroviral therapies or supportive medications. AIM To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non‐nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV‐1 infection. METHODS A series of phase I drug interaction studies was conducted. RESULTS GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration–time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co‐administration of GSK2248761. Plasma raltegravir AUC(0,τ) and Cmax increased by 18% with no change in Cτ when raltegravir was co‐administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), Cmax and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and Cmax increased following co‐administration with GSK2248761, with the largest changes observed for simvastatin (3.7‐fold and 4.3‐fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co‐administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co‐administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25‐ to ≤2‐fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co‐administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug‐related AEs, and no treatment‐related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.

The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring.

Background: Biliary cystadenomas are rare cystic tumours that arise in the liver or less frequently in the extrahepatic biliary system. They are commoner in middle-aged women, their most favoured site is the right hepatic lobe. Methods: Case report and review of the literature. Results: We present only the second case of an intrahepatic cystadenoma causing luminal obstruction of the common bile duct. Clinical presentation is often non-specific and can prove to be a diagnostic challenge. Conclusion: Wide local excision of biliary cystadenomas is recommended, with regular radiological follow-up.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log 10 copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C max ], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC 0-], and concentration at the end of the dosing interval [C ]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E max ) model using C (E max ‫؍‬ 2.0; 50% effective concentration [EC 50 ] ‫؍‬ 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

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Introduction Although conventional endoscopic techniques for the removal of stones from the biliary tree are highly effective, they fail in up to 10% of patients with choledocholithiasis. With the introduction of single operator peroral cholangioscope (POC), the SpyGlass ® System, stone fragmentation under direct visual control has proven to be highly effective and is now emerging as an important endoscopic therapy. We describe the characteristics and outcomes of patients undergoing POC directed electrohydraulic lithotripsy (POC-EHL) in two tertiary Hepatobiliary units in England. Methods Details of all patients undergoing POC-EHL at Aintree University Hospital and University College London Hospitals were prospectively recorded. Data collected included demographics, number of ERCPs, site of the stone, number of POC-EHL sessions, success of stone clearance and complications. Results A total of 93 patients were referred for POC-EHL. There were 25 males (27%) and 68 females (73%). The median age was 65 (20-92) years. 71 (76%) patients were tertiary referrals. 62 (67%) patients had at least two or more endoscopic attempts at stone removal prior to referral for POC-EHL. In six patients POC-EHL was not required because at ERCP prior to POC, the ducts could be cleared with conventional techniques. In five patients EHL was not attempted due to the size, configuration and quantity of stones. With the knowledge that these patients were fit for cholecystectomy, they were referred for cholecystectomy and bile duct exploration as a one-stage procedure. All POC-EHL sessions were performed under general anaesthesia. Of the 82 patients undergoing POC-EHL 61 (75%) patients needed one POC-EHL session and 10 (12%) required two sessions and 6 (7%) required three sessions for complete stone extraction. In 5/82 (6%) complete stone extraction was not possible despite POC-EHL and these patients were referred for surgery. The sites of stones were common bile duct in 48%, cystic duct and CBD in 20%, cystic duct in 4%, common hepatic duct in 10% and intra-hepatic ducts in 18%. Three patients developed cholangitis post POC-EHL, responding to antimicrobial therapy. Two patients experienced post-procedure bleeding, only one patient required endoscopic intervention. Conclusion On an intention to treat basis, 89% of patients referred for POC-EHL were treated successfully. Successful POC-EHL frequently requires combination with other stone removal techniques including mechanical lithotripsy. POC-EHL appears to be a safe and effective technique in the clearance of refractory biliary stones. Disclosure of Interest None Declared.