The optimal measurement method and clinical application of the therapeutic drug monitoring of cyclosporine remain uncertain (1,2). At a workshop held at Hawks Cay, FL, from January 14 to January 17, 1990, 57 scientists presented their latest research findings, either in formal papers or as discussants. Lively debate and discussion followed presentation of extant and new methodologies for drug measurements as well as multicenter validation studies; applications of trough-concentration monitoring in renal, hepatic, and bone-marrow transplants as well as in autoimmune disease; and alternative pharmacokinetic approaches to guide cyclosporine therapy. The process of inducing and maintaining optimal immunosuppression to facilitate graft success is a complex and often challenging task, requiring the combined expertise of multiple disciplines. Thus, the assembly of four of the groups essential to the transplant process—clinicians, laboratory scientists, the pharmaceutical company, and the manufacturers of cyclosporine measurement kits—provided a unique opportunity to evaluate therapeutic drug monitoring issues facing the transplant field. Here we present the major conclusions reached at the meeting, brief discussions of the study data on which they are based, and a summary of unresolved problems that will require further rigorous investigations. The Consensus Document was reviewed by all the workshop participants before we submitted this final manuscript.
The PI3K inhibitor copanlisib has efficacy and manageable safety in patients with indolent lymphoma and solid tumors. Pharmacodynamic effects relative to copanlisib dose and plasma exposure were evaluated. Patients with lymphoma or solid tumors received copanlisib 0.4 or 0.8 mg/kg on days 1, 8, and 15 of a 28-day cycle. Primary variables were maximum changes in phosphorylated AKT (pAKT) levels in platelet-rich plasma (PRP) and plasma glucose. Other evaluations included PI3K signaling markers and Tlymphocytes in paired tumor biopsies, the relationship between estimated plasma exposure and pharmacodynamic markers, response, and safety. Sixty-three patients received copanlisib. PRP pAKT levels showed sustained reductions from baseline following copanlisib [median inhibition: 0.4 mg/kg, 73.8% (range À94.9 to 144.0); 0.8 mg/kg, 79.6% (range À96.0 to 408.0)]. Tumor pAKT was reduced versus baseline with copanlisib 0.8 mg/kg in paired biopsy samples (P < 0.05). Dose-related transient plasma glucose elevations were observed. Estimated copanlisib plasma exposure significantly correlated with changes in plasma pAKT and glucose metabolism markers. There were two complete responses and six partial responses; seven of eight responders received copanlisib 0.8 mg/kg. Adverse events (all grade) included hyperglycemia (52.4%), fatigue (46.0%), and hypertension (41.3%). Copanlisib demonstrated dosedependent pharmacodynamic evidence of target engagement and PI3K pathway modulation/inhibition in tumor and immune cells. Results support the use of copanlisib 0.8 mg/kg (or flat-dose equivalent of 60 mg) in solid tumors and lymphoma, and provide a biomarker hypothesis for studies of copanlisib combined with immune checkpoint inhibitors (NCT03711058).
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