Institutional care paths: Development, implementation, and evaluation.

PURPOSE: The Cleveland Clinic experience with care paths, including their creation and implementation, challenges overcome during development and testing, and outcomes of selected care path evaluations, is described. SUMMARY: Care paths are tools to assist healthcare professionals in practicing evidence-based medicine. The Cleveland Clinic health system has implemented or is developing approximately 100 care paths, including care paths designed to optimize management of sepsis and septic shock and to promote timely use of i.v. tissue plasminogen activator and correct dosing of antithrombotics and statins in patients with stroke. Key steps in successful care path initiatives include (1) identifying key stakeholders, (2) achieving stakeholder consensus on a standardized approach to disease or condition management, (3) cultivating provider awareness of care paths, (4) incorporating care path tools into the electronic health record and workflow processes, and (5) securing the resources to develop, implement, and maintain care paths. Electronic health records facilitate the use of and adherence to care paths. After care path implementation, revisions are typically needed due to unexpected issues not initially identified and to optimize care path features and support resources for clinical practice. Ongoing evaluation is required to determine whether an implemented care path is producing the intended patient and quality performance outcomes. CONCLUSION: Care paths provide a standardized approach to treatment or prevention of a disease or condition, reducing unnecessary variability and expense while promoting optimal, cost-effective patient care.

Assessment of the renal toxicity of novel anti-inflammatory compounds using cynomolgus monkey and human kidney cells.

PF1, an anti-inflammatory drug candidate, was nephrotoxic in cynomolgus monkeys in a manner that was qualitatively comparable to that observed with the two previous exploratory drug candidates (PF2and PF3). Based on the severity of nephrotoxicity, PF1 ranked between the other two compounds, withPF2 inducing mortality at all doses and PF3 eliciting only mild nephrotoxicity. To further characterize nephrotoxicity in monkeys and enable direct comparisons with humans, primary cultures of proximal tubular (PT) cells from monkey and human kidneys were used as in vitro tools, using lactate dehydrogenase release as the biomarker of cytotoxicity. In both human and monkey PT cells, PF2was by far the most cytotoxic compound of the three drugs. PF1 exhibited modest cytotoxicity at the highest concentration tested in human PT cells but none in monkey kidney cells whereas PF3 exhibited the reverse pattern.Because these drugs are organic anions, mechanistic studies using human organic anion transporters 1 and 3 (hOAT1 andhOAT3) transfected cell lines were pursued to evaluate the potential of these compounds to interact with these transporters. All three drugs exhibited high affinity for hOAT3 (PF1 exhibited the lowest IC50 of 6M) but only weakly interacted with hOAT1 (with no interaction found for PF2). PF2 was a strong hOAT3 (not hOAT1) substrate, whereas PF1 and PF3 were substrates for both hOAT1 and hOAT3.Upon pretreatment of monkeys with the OAT substrate probenecid, PF3 systemic exposure (AUC) and half-life (t1/2) increased approximately 2-fold whereas clearance (CL) and volume of distribution (Vdss) decreased, as compared to naïve monkeys. This indicated that PF3 competed with probenecid for hOAT1 and/or hOAT3mediated elimination of PF3. Thus, hOAT1 and/or hOAT3 may be responsible for the uptake of this series of drugs in renal PT cells, which may directly or indirectly lead to the observed nephrotoxicity in vivo.

Evaluation of an integrated in vitro-in silico PBPK (physiologically based pharmacokinetic) model to provide estimates of human bioavailability.

PK express module is a physiologically based model of first pass metabolism, which integrates in vitro data with an in silico physiologically based pharmacokinetic (PBPK) model to predict human bioavailability (F(H)). There are three required inputs: FDp (Fraction dose absorbed, final parameter from iDEA absorption module), protein binding (fu) and disappearance kinetics in human hepatocytes. Caco-2 permeability, aqueous solubility (at multiple pH's), estimated dose and chemical structure are inputs required for the estimation of FDp (Norris et al., 2000; Stoner et al., 2004) and were determined for all compounds in our laboratory or obtained from literature. Protein binding data was collected from literature references and/or Pfizer database. Human hepatocyte data was generated in-house using an automated human hepatocyte method (using Tecan Genesis Workstation) as described previously (). Sixteen compounds (commercial and Pfizer compounds) were chosen to evaluate the PK express model and the bioavailability predicted from the module was compared with known clinical endpoints. For majority of the 16 compounds (approximately 80%), the PK express model F(H) values were comparable to the known human bioavailability (F(H)) (within 23.7 units of the known human (true) F, except for PF 3, PF 4, PF 6). In conclusion, the PK express model integrates a number of key readily available discovery parameters and provides estimates of human performance by integrating in silico and experimental variables built on a physiological based pharmacokinetic model. Information from this model in conjunction with other ADME data (e.g., P450 inhibition) will enable progression of most promising compounds for further in vivo PK and/or efficacy studies.

Validation of a semi-automated human hepatocyte assay for the determination and prediction of intrinsic clearance in discovery.

An automated high throughput human hepatocyte assay has been established with a 96-well format using a Tecan Genesistrade mark Workstation. Validation of this assay was performed with nine commercially available compounds and an additional 10 Pfizer compounds with varying hepatic extraction ratios (E(H)) ranging from 0.02 to approximately 1. The incubation conditions in the automated assay are readily and precisely controlled and cell viability of over 80% was achieved in the automated assay further confirming its utility for absorption, distribution, metabolism, and excretion (toxicity) (ADME (T)) screening. The results of the nine commercial compounds correlate with both manually executed (R(2)=0.97) and literature reported experimental results (R(2)=0.93). Overall, measured E(H)s were within two-fold of the literature values for approximately 90% of the 19 compounds tested. Additionally, good inter- and intra-day reproducibility was observed for all the 19 compounds. In conclusion, an automated and robust assay suitable for simultaneously testing up to 48 compounds with multiple time points has been validated. Throughput of 192 compounds per run can be achieved using 384-well plates to meet increasing needs in drug discovery. Currently, this automated assay is used to support early discovery profiling towards lead optimization of various discovery targets/programs.