Volume replacement strategies do not impair the binding of dabigatran to idarucizumab: Porcine model of hemodilution.

BACKGROUND: Idarucizumab is a humanized Fab fragment that specifically reverses dabigatran anticoagulation. In trauma, volume expanders are used for resuscitation to compensate for blood loss and hemorrhagic shock, but it is unknown whether volume expanders influence the binding of dabigatran to its antidote. Using a porcine dilutional coagulopathy model, this study investigated whether volume replacement strategies affect binding of dabigatran to idarucizumab. METHODS: Twenty-five male pigs were treated orally with dabigatran etexilate (30 mg/kg bid) for 3 days. The following day, animals were anesthetized, infused with dabigatran (total dose 0.645 mg/kg) to achieve supratherapeutic concentrations, and randomized 1:1:1:1:1 (n = 5 per group) to control (no hemodilution) or hemodilution where ~50% of blood volume was substituted with Ringer's solution, 6% hydroxyethyl starch 130/0.4, 6% hydroxyethyl starch 200/0.5 or 4% gelatin. Idarucizumab was then administered intravenously (30 mg/kg) and serial blood samples were taken for up to 24 hours to measure diluted thrombin time (corresponding with dabigatran activity), total dabigatran (bound to antidote and free drug) and a panel of coagulation parameters. RESULTS: Mean plasma dabigatran levels were 617 ± 16 ng/mL after infusion and 600 ± 114 ng/mL after ~50% hemodilution with no significant differences between groups. Following treatment with idarucizumab, plasma concentrations of unbound dabigatran decreased markedly, with similar reductions in all groups. Dabigatran-induced prolongation of coagulation parameters was rapidly reversed in all groups. CONCLUSION: This study indicates that several volume expanders used for resuscitation in trauma do not interfere with the binding of idarucizumab to dabigatran.

The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.

Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways.

Correlation between net water flux and absorptive clearance determined from in situ intestinal perfusion studies does not necessarily indicate a solvent drag effect.

Estimation of absorptive clearance (PeA) of drugs from in situ perfusion studies, based on the disappearance of drugs from the intestinal lumen, involves correcting outflow perfusate drug concentration with net water flux (Jw). However, as demonstrated through both theoretical derivations and simulations, the PeA estimated from a nonlinear equation approximates a linear relationship with Jw for a low permeability drug, regardless of whether or not Jw has a real effect on PeA. As such, a correlation between Jw and PeA is less meaningful as an indicator of a solvent drag effect. Moreover, from the linear relationship, the slope of the Jw-PeA correlation plot (defined as the sieving coefficient) equals the ratio of outflow versus inflow perfusate drug concentrations and can be greater than unity when more water than drug is absorbed during perfusion studies. The intercept of the correlation plot can be below zero if this occurs.

Microdialysis evaluation of the brain distribution of stavudine following intranasal and intravenous administration to rats.

Intranasal (IN) administration as a potential route of enhancing brain delivery of stavudine (d4T) was investigated in rats using microdialysis as a sampling technique. Sprague-Dawley rats were divided into two groups (n = 7 per group). One group of animals received IN administration of 5 mg/kg d4T (50 microL); the other group was dosed intravenously (IV) at the same dose. Following IN administration, d4T was rapidly and completely absorbed into the systemic circulation with a T(max) of 14 min and an IN bioavailability of 105%. The brain/plasma AUC ratios in the lateral ventricle, caudate putamen, and frontal cortex in the anesthetized and nasal surgery-operated rats were 0.36 +/- 0.090, 0.47 +/- 0.089, and 0.41 +/- 0.087, respectively, whereas they were 0.63 +/- 0.077, 0.62 +/- 0.17, 0.60 +/- 0.13, respectively, following IV dosing to sham animals. The half-life of d4T in the various brain regions was significantly longer than that in plasma (p < 0.05). Moreover, the systemic clearance of d4T was significantly reduced in these anesthetized and nasal surgery-operated animals. Further studies of the effect of anesthesia suggest the additive role of anesthesia, possibly in additional to nasal surgery, in decreasing the systemic clearance. The extent of the brain distribution, however, was not significantly affected by anesthesia. Lack of enhancement of the brain delivery of d4T following IN administration over systemic dosing cannot be attributed to its absorption into systemic circulation, since direct nose-brain transport, if fully functional and effective, should be a parallel and competing process with systemic absorption. The current study results along with several physiological considerations raise a question regarding the overall effectiveness of IN administration for direct delivery of small molecules into brain tissues, particularly where passive diffusion predominates.

Intestinal absorption and presystemic elimination of the prokinetic agent, EM574, in the rabbit.

The purpose of this study was to characterize the pharmacokinetics and dose proportionality of the prokinetic macrolide, EM574, in rabbits following intravenous dosing, and to determine the intestinal absorption and intestinal and hepatic first-pass elimination of EM574 in rabbits. Two doses (0.05 and 0.25 mg/kg) of EM574 were given to rabbits intravenously in a crossover study. In a separate gut perfusion study, rabbit duodenal or jejunal segments were perfused with EM574 solution at 0.2 mL/min for 130 min. Plasma levels of EM574 were determined by a validated LC-MS/MS assay, and concentrations in perfusate were determined by HPLC with UV detection. The absorptive clearance (PeA) of EM574 was calculated from the steady-state rate of disappearance from the gut lumen during perfusion. The cumulative amount (A(app)) of drug appearing in the systemic circulation was calculated by deconvolution, where the input response was the plasma concentration-time profile during intestinal perfusion and the unit impulse response was the mean profile following intravenous bolus dosing to sham-operated rabbits in a separate experiment. F(g)F(h) was calculated from the ratio of A(app) to the total amount disappeared from gut lumen during perfusion. Hepatic first-pass elimination was measured by intraportal venous infusion. EM574 exhibits linear kinetics over the dose range studied. CL, V(ss), and terminal half-life (mean +/- SD) of EM574 were 68.6 +/- 15.5 mL/min/kg, 13.4 +/- 3.0 L/kg, and 2.7 +/- 0.8 h, respectively. EM574 is expected to be absorbed completely from the rabbit small intestine based on its high jejunal PeA values (8.1 +/- 2.2, and 5.5 +/- 1.5 microL/min/cm following low and high dose perfusion, respectively). The first-pass extraction of EM574 was substantial and dose independent. Mean F(g) and F(h) were 0.14 and 0.20, respectively, suggesting that the intestinal and hepatic first-pass elimination of EM574 were comparable. Deconvolution was successfully applied in the determination of gut wall and hepatic first-pass elimination of EM574.