SummaryThe poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 ± 12.1 gm thick) with t1,2 values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-,-en-a-ol (EO9) and doxorubicin through multicell layers was significantly slower (t1,2 = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of E09 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that E09 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (tl,2 < 10 min), suggests that E09 is unlikely to penetrate more than a few ,um from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of E09 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo.

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Care management efforts focused on patients not achieving quality goals can improve performance in value-based care quality programs, but may pose challenges for integration into routine clinical care. We evaluated a 12-month NP-led care management pilot program (CMPP) to improve outcomes for adults with T2DM and A1c&gt;9% (N=62, 40% male) covered under a value-based care quality program and receiving care at a diabetes center. Visits were scheduled as billable encounters between routine clinical visits. Diabetes quality outcomes (A1c≤9%, BP&lt;140/90, and annual retinal screening) were assessed by CMPP participation. For this pilot program, p&lt;0.05 and p&lt;0.10 defined significance and trend, respectively. The CMPP began in November 2020 with 43% (n=27) participation; participants and non-participants had no baseline differences in age, diabetes duration, or baseline attainment of diabetes quality metrics. CMPP participants had more visits compared to non-participants over the 12 month pilot period (10.4 vs. 4.0, p&lt;.001); 62% of participant visits were virtual vs 47% among non-participants (p=.01). At 12 months, CMPP participants had a significant improvement in % A1c≤9% and trended towards improved annual retinal screening. This integrated NP-led CMPP leveraging virtual care may improve diabetes quality outcomes. Future efforts will focus on scaling and implementation in primary care. Disclosure L.J.Tinsley: None. K.D.Ariyabuddhiphongs: None. E.Halprin: None. J.Beaulieu: None. M.Moreau: None. A.Millan-ferro: None. J.Rizzotto: None. B.Cronin: None. S.N.Mehta: None.

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