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Antibody-drug conjugates (ADCs) represent a promising therapeutic modality for the clinical management of cancer. Here we discuss the clinical pharmacology and safety of ADCs that are either approved or in late stages of clinical development. We have taken examples of ADCs employing either DNA damaging payloads (such as calicheamicin) or tubulin depolymerizing agents (such as auristatins and maytansinoids) to discuss the impact of dose and dosage intervals on pharmacokinetics/pharmacodynamics (PK/PD) and safety of ADCs. We also discuss the development of PK/PD models that were validated using preclinical and clinical data from two approved ADCs (ado-trastuzumab emtansine (T-DM1, Kadcyla™) and brentuximab vedotin (SGN-35, Adcetris™). These models could be used to predict clinical efficacious doses of ADCs. [ABSTRACT FROM AUTHOR]

The Zhunge'er (Junggar) Basin in northern Xinjiang was a key crossroads in antiquity for the dispersal of ideas and technological innovations from the Eurasian steppe into the heartland of central China. The Bronze Age chronology of the Zhunge'er Basin is chiefly based on relative dating and little is known about subsistence strategies, although the strong tradition of nomadic and transhumant pastoralism among modern populations suggests that there may have been a high degree of mobility. The visibility of ancient cemeteries and the need to salvage graves before they are looted have resulted in a lack of focus on settlements, with a consequent assumption that in antiquity agriculture played a limited role. This assumption has been challenged by rescue excavations at the Jimusa'er (Jimsar) Luanzagangzi site, which indicate that agriculture may have been a significant component of Bronze Age subsistence strategies. Small-scale soundings at settlement sites provide well-stratified sequences of material for absolute dating which can be used to place the artifacts recovered from graves in a more secure chronological context. [ABSTRACT FROM AUTHOR]

1. PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction. 2. In vivo, PF-592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. 3. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N-glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N-glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. 4. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing. [ABSTRACT FROM AUTHOR]

The article describes the physical attributes and examines the chronology of flint implements excavated from several prehistoric sites. The excavations are housed by the Institute of Archaeology, University of London. Among the sources of excavated flints are Naqb Ashtar, El Barsa and Mashshashar. The discussion encompasses the physical dimensions of the implements and their historical background.