Cyclosporine inhibition of hepatic and intestinal CYP3A4, uptake and efflux transporters: application of PBPK modeling in the assessment of drug-drug interaction potential.

PURPOSE: To apply physiologically-based pharmacokinetic (PBPK) modeling to investigate the consequences of reduction in activity of hepatic and intestinal uptake and efflux transporters by cyclosporine and its metabolite AM1. METHODS: Inhibitory potencies of cyclosporine and AM1 against OATP1B1, OATP1B3 and OATP2B1 were investigated in HEK293 cells +/- pre-incubation. Cyclosporine PBPK model implemented in Matlab was used to assess interaction potential (+/- metabolite) against different processes (uptake, efflux and metabolism) in liver and intestine and to predict quantitatively drug-drug interaction with repaglinide. RESULTS: Cyclosporine and AM1 were potent inhibitors of OATP1B1 and OATP1B3, IC(50) ranging from 0.019-0.093 µM following pre-incubation. Cyclosporine PBPK model predicted the highest interaction potential against liver uptake transporters, with a maximal reduction of >70% in OATP1B1 activity; the effect on hepatic efflux and metabolism was minimal. In contrast, 80-97% of intestinal P-gp and CYP3A4 activity was reduced due to the 50-fold higher cyclosporine enterocytic concentrations relative to unbound hepatic inlet. The inclusion of AM1 resulted in a minor increase in the predicted maximal reduction of OATP1B1/1B3 activity. Good predictability of cyclosporine-repaglinide DDI and the impact of dose staggering are illustrated. CONCLUSIONS: This study highlights the application of PBPK modeling for quantitative prediction of transporter-mediated DDIs with concomitant consideration of P450 inhibition.

Patient Advisory Committee for a Chronic Opioid Therapy Risk Reduction Evaluation: Engaging Diverse Patients.

BACKGROUND: Active patient engagement in research is critically important, but can be difficult in controversial areas where patients have conflicting perspectives. OBJECTIVES: In this Lesson's Learned report, we describe engagement of patients with divergent views in guiding a controlled interrupted time series evaluation of chronic opioid therapy risk reduction initiatives implemented by a large health plan. METHODS: A nine-person Patient Advisory Committee (PAC) advised the scientific team on the evaluation and reporting of results on diverse outcomes important to patients, including pain and function, opioid use disorder, overdose, motor vehicle accidents, and medically attended injuries. Patients were selected with varied perspectives on opioid prescribing for chronic pain. Multiple strategies facilitated PAC engagement: making room for personal experience; investing upfront in setting the stage for working together including an initial face to face meeting; clarifying shared values; and including individuals skilled in group process and collaboration. PAC meetings were organized separately from regular meetings of the scientific team. RESULTS: Shared values identified to guide the research were: Safety, respect, autonomy, compassion, knowledge and teamwork. PAC guidance altered key scientific decisions regarding assessment of patient outcomes, doctor-patient collaboration, and analytic approaches. CONCLUSIONS: Separate meetings of the PAC and scientific team enhanced opportunities for patients to influence the study design, analyses and interpretation of evaluation results. Convening a large group of patients with diverse perspectives and experiences was productive and influential in guiding the evaluation. Patient selection and building rapport allowed PAC members with divergent perspectives to work together effectively.

Clinical and functional outcomes of anterior cervical discectomy without fusion.

Anterior cervical discectomy without fusion is an effective treatment for myeloradiculopathy arising from a medial disc prolapse. However, the long-term clinical results are not well known. Between 2000 and 2006, 38 patients with persistent radiculopathy and medial disc prolapse or myelopathy due to acute disc prolapse underwent subtotal anterior cervical discectomy without fusion. Patients were evaluated with respect to pain, myelopathy and functional outcome. Thirty-four patients were followed up for an average of 48.6 months. Following surgery, neck pain improved by 69% in 88% of patients, arm pain improved by 76% in 91% of patients and 76% of the patients were able to resume working in their previous occupation. We conclude anterior cervical decompression without fusion can be associated with good clinical results that are sustained in patients with predominant acute soft disc prolapse generating medial nerve root compression or cord compression.