Deconvolution Analysis of the Interaction between Tacrolimus and Ketoconazole

Objective. To improve the precision of the point estimate and develop predictors of tacrolimus bioavailability, alone and when administered concomitantly with CYP3A and P-gp inhibitors. Background. Tacrolimus (TAC) has been used for immunosuppresion after solid organ transplant for over ten years. Despite numerous pharmacokinetic studies of TAC the absolute bioavailability (F) remains poorly defined. Methods. Subjects were 19 adult renal transplant recipients receiving TAC as part of an immunosuppression regimen. TAC was administered by intravenous (IV) infusion after a 24-hr washout period; a single oral (po) dose of KT (400 mg) was administered followed by the same IV dose of TAC. Whole blood was drawn to provide pharmacokinetic (PK) profiles after IV administration. Steady state oral TAC PK profiles with and without KT were similarly obtained. A two-compartment model for intermittent IV infusion and po dosing at steady state were simultaneously fit and deconvolution analysis was performed using WinNonLin Professional V 5.2. Percent change in F and the Ln transformed KT/TAC po dose ratio were fit to a sigmoid Emax model. Results. Systemic clearance of TAC was not altered by 400 mg of oral KT (control 0.102 L/h/kg (0.089-0.114) Vs keto 0.088 L/H/kg (0.072-0.103) p = 0.15). TAC F was altered by KT (14 %(11-17) ctrl; 35% (26-44) KT; p=0.0006) in a dose dependent fashion (Emax 350 %, EC50 = 4.2 mg keto /mg TAC, γ = 15). Conclusion. TAC F is altered by KT, not by changing systemic clearance, but rather by increasing absorption from jejunal and ileal sites

AN IMPROVED NONLINEAR MIXED EFFECTS PHARMACOKINETIC MODELOF INTRAVENOUS D9TETRAHYDROCANNABINOL (THC) AND METABOLITES IN VOLUNTEERS

Objective. To develop and evaluate a nonlinear mixed effect model of d9-THC and its two major metabolites. Background. Marijuana use is increasingly becoming more prevalent due to the rise of medical use. A nonlinear mixed effects model to predict plasma concentrations of the major active constituents of marijauna, D9-THC and its two metabolites does not exist. This model could be used in health care and by law enforcement. Methods. Data from 25 subjects administered d9-THC intravenously over 5 minutes and sampled from arterial line in serial fashion from time of dosing to 48 hours was available. Of the 975 available plasma concentrations, analyzed with LC/MS/MS API 4000, 75 were BLQ and not used in the model. Nonlinear mixed effect modeling using Phoenix® NLME 1.2 was applied to the data to determine the typical values of a 3 compartment pharmacokinetic model for the parent THC that provides input to a second 3 compartment model for the first and active metabolite THC-OH, which in turn provides input to the 2 compartment model for the second and inactive metabolite THC-COOH. The model was parameterized using CL and V, residual error was log-additive, the omega matrix was diagonal, initial estimates were taken from NCA analysis of the data. The FOCE-extended least squares algorithm performed best with this data set, standard errors were determined using the central difference Hessian method. The model was optimized in several steps, using traditional assessment techniques: -2LL, AIC, BIC, Conditional WRES Vs pred, ipred, time and observed dose/volume. The model employs actual body weight as a covariate. The “final” model was evaluated using the predictive check option in Phoenix. Results. The data was successfully fit to a 3 stage metabolite model. The model parameters follow: tvV thc 6.05939 L tvV thc2 29.7352 L tvCLd12 thc 51.5397 L tvV thc3 325.58 L tvCLd13 thc 19.0989 L tvV thc-oh 88.6359 L tvCL metabolic thc49.9912L/h tvV thc-cooh 6.51545 L tvCL metabolic thc-oh153.778 L/h tvV thc-oh2 14.4936 L tvCLd12 thcoh 0.725483L/h tvV thc-cooh2 405.939 L tvCLd12 thc-cooh 25.7877 L/h tvCL renal thc-cooh 7.86533 L/h tvV thcoh3 371.384 L/h tvCLd13 thc-oh 109.992 L/h Conclusion. This model could be used to predict THC, THC-OH or THCCOOH concentrations over time. Grants. non

Tendencies in Clinical Pharmacy Journal Publications Over the Past Twenty Years

Objective. The objective of the study is to evaluate pharmacy specific journals to determine publishing rates between original research, case reports, and review articles over the previous twenty years. Background. In the past 20 years, numbers of pharmacy faculty have dramatically increased. Additionally, scholarship requirements of pharmacy faculty have increased. It is unknown, however, to what degree research articles have increased. Methods. Pharmacy journals in print for at least 20 years, indexed in Medline, and authored primarily by pharmacists were evaluated. All publications were categorized either as research, case reports, reviews, letters/editorials, or other based on the publication types classification system used by PubMed. Descriptive statistics were described. Additionally, data were analyzed for statistical significance utilizing ANOVA with significance at p \u3c 0.05. Results. Three journals meeting inclusion criteria were the American Journal of Health-Systems Pharmacy (AJHP), Annals of Pharmacotherapy, and Pharmacotherapy. The total publication rate from 1988-1989 to 2008- 2009 increased from 1201 to 2096 (74%) (p \u3c 0.05). The rate of original research articles increased from 15% to 19% (NS). The rate of case reports decreased from 13% to 11% (NS). The rate of review articles increased from 12% to 18% (NS). However, individually AJHP and Pharmacotherapy decreased in terms of research publications while Annals of Pharmacotherapy increased. Annals of Pharmacotherapy also decreased the total number of review articles published whereas AJHP and Pharmacotherapy increased. Conclusion. Despite significant increase in publications in pharmacy specific journals, there appears to be minimal increases in original research, case reports, and review articles published. Grants. N/

Anticoagulation strategies in COVID-19 infected patients receiving ECMO support

Background: Hospitalized COVID-19 patients with hypoxemic respiratory failure may deteriorate despite invasive mechanical ventilation and thus require extracorporeal membrane oxygenation (ECMO) support. Unfractionated heparin (UFH) is the antithrombotic of choice, however, bivalirudin may offer more predictable pharmacokinetics resulting in consistent anticoagulant effects with lower bleeding and thrombotic occurrences. The aim of this study was to evaluate efficacy and safety outcomes in patients undergoing venovenous (VV) ECMO receiving bivalirudin or UFH-based anticoagulation. Methods: This retrospective, single-center, observational cohort study included patients with confirmed COVID-19 infection requiring VV ECMO support receiving anticoagulation with UFH or bivalirudin. Primary endpoints were time to reach therapeutic aPTT, percent time spent in aPTT range, and the occurrence of thrombotic events over the entire course of ECMO support. Secondary endpoints included the incidence of major/minor bleeding, the ability to wean off ECMO support, in-hospital mortality, and length of stay. Results: Twenty-two patients were included in the study (n = 10 UFH, n = 12 bivalirudin). Time to therapeutic aPTT was achieved faster with UFH (10 h vs. 20 h). The percentage time spent within the goal aPTT range was similar between UFH and bivalirudin (50% vs. 52%). Thrombotic events were significantly higher in the UFH group (40% DVT, 40% PE, 80% oxygenator thrombus in ECMO machine, 10% ischemic stroke) versus bivalirudin (8% DVT, 17% PE, 33% oxygenator thrombus, no ischemic strokes) (CI 95%, p = 0.04). The overall bleeding incidence was higher in the UFH arm (90% vs. 75%). The mortality rate was 90% in the UFH group and 58% in the bivalirudin group. The length of stay was similar between the two study arms. Conclusion: In hospitalized patients with COVID-19-associated acute respiratory distress syndrome (ARDS) on VV ECMO support, the use of bivalirudin showed to be a viable anticoagulation alternative in terms of efficacy compared to UFH and resulted in a favorable safety profile with lower rates of bleeding and thrombotic events