Effect of varying amounts of a liquid nutritional supplement on the pharmacokinetics of posaconazole in healthy volunteers.

The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables--area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUC(tf)), maximum observed plasma concentration (C(max)), time to C(max) (T(max)), and relative bioavailability--were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereas T(max) was unaffected. Compared with the levels reached under fasting conditions, posaconazole C(max) and AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.

Antibacterial research and development in the 21(st) Century--an industry perspective of the challenges.

The continued evolution of resistance to antibiotics has led to wide ranging consultation at National and International levels as to how to address this issue. In addition to attempting to limit the spread of resistance there is growing consensus that a cornerstone requirement is the development of new antibiotics to help redress the balance of resistance versus available antibiotics. The availability of new technologies such as genomics has opened up new approaches for antibacterial research. It would appear that from an industry perspective, the research and development of antibiotics should be an attractive option. However, this is not the current perception at the majority of large pharmaceutical companies. In addition, the perceived failure of new technologies to create another golden age of new antibacterial classes has led many companies to prioritise other areas of research and, in some cases, to exit antibacterial research. In response, a plethora of small biotech companies have emerged with an interest in antibacterial discovery and large pharmaceutical companies may look to these as a source of development candidates although, to date, these have contributed a very low number of truly novel antibiotic lead compounds. As a reaction to these changes several initiatives are ongoing to examine ways to incentivise antibacterial research and development and ensure a healthy pipeline of compounds in the 21st Century.

A current and historical perspective on disparities in US childhood pneumococcal conjugate vaccine adherence and in rates of invasive pneumococcal disease: Considerations for the routinely-recommended, pediatric PCV dosing schedule in the United States.

Previous research has suggested that reducing the US 4-dose PCV13 schedule to a 3-dose schedule may provide cost savings, despite more childhood pneumococcal disease. The study also stressed that dose reduction should be coupled with improved PCV adherence, however, US PCV uptake has leveled-off since 2008. An estimated 24-36% of US children aged 5-19 months are already receiving a reduced PCV schedule (i.e., missing ≥1 dose). This raises a practical concern that, under a reduced, 3-dose schedule, a similar proportion of children may receive ≤2 doses. It is also unknown if a reduced, 3-dose PCV schedule in the United States will afford the same disease protection as 3-dose schedules used elsewhere, given lower US PCV adherence. Finally, more assurance is needed that, under a reduced schedule, racial, socioeconomic, and geographic disparities in PCV adherence will not correspond with disproportionately higher rates of pneumococcal disease among poor or minority children.

Lack of pharmacokinetic drug interaction between oral posaconazole and caspofungin or micafungin.

The objective of this phase 1, open-label, parallel, randomized study was to determine the effect of posaconazole on the pharmacokinetics of caspofungin and micafungin in 67 healthy subjects. Caspofungin (70 mg on day 1, 50 mg on days 2-14 once daily; 1-hour intravenous infusion) (cohort 1) or micafungin (150 mg once daily days 1-7; 1-hour IV infusion) (cohort 2) was administered alone or with posaconazole oral suspension 400 mg twice daily, on days 1 to 14 (cohort 1) or days 1 to 7 (cohort 2). Pharmacokinetic parameters, maximum plasma concentration (C(max)), steady-state area under the plasma concentration-time curve over the dosing interval (AUC[τ]), and time to C(max) (T(max)) were assessed. Safety assessments included adverse events, clinical laboratory tests, vital signs, and electrocardiograms. Repeated posaconazole dosing did not affect caspofungin or micafungin pharmacokinetics. Log-transformed ratio estimates of caspofungin with posaconazole C(max) and AUC(τ) were 90% and 98%, respectively, of those with caspofungin alone at day 14; ratio estimates of micafungin with posaconazole C(max) and AUC(τ) were 104% and 109%, respectively, of those with micafungin alone at day 7. Median T(max) (1 hour) did not change. Coadministration of posaconazole with caspofungin or micafungin was generally well tolerated and did not affect the pharmacokinetics of either echinocandin.