Evaluation of Clinical and Safety Outcomes Following Uncontrolled Tacrolimus Conversion in Adult Transplant Recipients.

PURPOSE: To compare clinical and safety outcomes of transplant recipients converted between different tacrolimus formulations to those patients who remained on a single formulation in an outpatient environment. METHODOLOGY: This was a single-center, retrospective cohort study at a large tertiary care medical center with an associated institutional outpatient pharmacy system. Adult transplant recipients with institutional pharmacy refill from August 1, 2009, to May 31, 2016, were assessed. Patients were allocated into four separate groups: Group (A) innovator tacrolimus (no conversion), Group (B) generic tacrolimus (no conversion), Group (C) single conversion (from innovator to single generic or from generic to innovator tacrolimus), and Group (D) multiple conversions. Index date was either the date of first tacrolimus product conversion (Groups C and D) or a pre-specified post-transplant time (Groups A and B). RESULTS: Overall, 100 patients were included in the analysis, 63% were male, 62% were Caucasian, and 59% were renal transplant recipients. When compared between groups, linear trends in dose-normalized tacrolimus levels were similar in the pre-index date period (p=0.52) and in the post-index date period (p=0.08). When groups were compared individually, linear trends in dose-normalized tacrolimus levels were significantly different pre- versus post-index date for Group B (p=0.008). There were no differences in the linear trends of dose-normalized tacrolimus levels across the other groups (p>0.05 for all). After the index date, 43% of patients across all groups required tacrolimus dose modification with no differences by group (p=0.32). Allograft function and hospitalizations were similar across all groups. CONCLUSIONS: Conversion between tacrolimus generic formulations has been suggested to be unsafe. This study demonstrates that switching tacrolimus products in post-transplant recipients does not alter dose-normalized tacrolimus trough concentrations, renal or hepatic function, pathology, or hospitalizations.

Differential behavioral sensitivity to carbon dioxide (CO2) inhalation in rats.

Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine ß hydroxylase (DßH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2-positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal gray (VLPAG) subdivision in CO2-sensitive strains. Conversely, DßH-positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.