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Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs.

ABSTRACT: Thrombosis is common in critically ill dogs and causes considerable morbidity and mortality. The direct factor Xa inhibitor apixaban is safe, efficacious, and convenient in humans. This study aimed to determine the pharmacokinetics (PK), bioactivity, protein binding, and bioavailability of apixaban following intravenous (IV) and oral (PO) administration to healthy dogs. Six healthy, adult, mixed-breed dogs were administered apixaban 0.18 mg/kg IV and then following a minimum 2-week washout period administered apixaban 0.2 mg/kg PO. Dogs were monitored using an apixaban-calibrated anti-Xa bioassay, prothrombin time (PT) and activated partial thromboplastin time (aPTT) and tissue-factor thromboelastography (TF-TEG). Plasma apixaban concentrations were measured using liquid chromatography-tandem mass spectrometry. Concentration-time plots were constructed, and PK modeling performed using compartmental methods. Administration of IV and PO apixaban was well-tolerated. Following IV administration, mean half-life was 4.1 h, and volume of distribution was 177 ml/kg. Apixaban was highly protein bound (98.6%). Apixaban concentrations and anti-Xa activity were highly correlated (R² 0.994, P < 0.0001). Intravenous apixaban significantly prolonged PT at time points up to 1 h, and aPTT at time points up to 0.25 h post-administration. Coagulation times were positively correlated with apixaban concentrations (PT R² 0.599, P < 0.0001; aPTT R² 0.430, P < 0.0001) and TF-TEG R-time was significantly prolonged 0.25 h post-administration. Following oral administration, mean bioavailability was 28.4%, lag time was 2 h, time to C_max was 5 h and the apparent elimination half-life was 3.1 h. Oral apixaban significantly prolonged PT at 4, 6, and 8 h but aPTT and TF-TEG were not consistently affected by oral apixaban. Apixaban concentrations are best monitored using anti-Xa activity. Future studies should determine PK and bioactivity of other doses using commercial tablets and following multidose administration and establish safe, effective dosing ranges in sick dogs.

SUBMITTER: Herrera ND

PROVIDER: S-EPMC8287028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin-clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations. Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure. Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose. Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.

Project description:Torasemide is a loop diuretic licensed in dogs for cardiogenic pulmonary oedema. The aim of this pharmacokinetic-pharmacodynamic (PK/PD) study was to define an optimally effective dosage regimen based on preclinical data. In a first study, 5 dogs received once-daily oral torasemide (0, 0.1, 0.2, 0.4, 0.8 mg/kg/day) for 14 days. A second study compared once-daily oral torasemide (0, 0.1, 0.2, 0.3, 0.4 mg/kg/day) to twice-daily furosemide (1, 2, 4, 8 mg/kg/day). For all doses of the second study, 11 dogs received a first day of treatment, followed by a 3 day washout and resumed daily treatment for 10 days (until Day 14). Blood and urine were collected to measure urinary torasemide excretion and plasma torasemide concentrations and daily diuresis and natriuresis. Torasemide PK was linear. After rapid absorption (Tmax 0.5-1 h), 61% of the bioavailable torasemide was eliminated unchanged in urine. Diuresis and natriuresis observed with torasemide were similar to the ones obtained after furosemide (daily dose-ratios: 1/20 to 1/10). The average diuresis increased from baseline (220 ± 53 mL/day for 10 kg dogs) to 730 ±120 mL after the first torasemide administration and up to 1150 ± 252 mL after 10 administrations at the highest dose. At higher doses (≥0.3 mg/kg/day), daily diureses after 10 diuretic treatment-days were higher than Day 1 and variable between dogs; in contrast, diureses remained constant over time and less variable for doses up to 0.2 mg/kg/day. Natriuresis peaked after the first day and decreased dramatically after the 2nd treatment-day then stabilized to a value close to baseline, except for 0.4 mg/kg/day. Urinary torasemide excretion predicted pharmacodynamics better than plasma concentrations. The decrease in natriuresis observed was successfully modeled using a resistance mechanism; this is likely due to a reabsorption of sodium which did not seem however to affect the volume of urine excreted. For a daily target diuresis of 460 mL/dog/day in severe pulmonary oedema (net fluid loss 240 mL/dog/day), a computed dose of 0.26 mg/kg/day (3.5 mg/kg/day furosemide-equivalent) was selected for clinical studies. Due to high inter-individual variability in diureses at doses ≥0.3 mg/kg, higher doses should be limited to 3-5 days to avoid supra-clinical effects in high responders.

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Project description:BACKGROUND:Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. OBJECTIVE:Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. METHODS:In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ?4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. RESULTS:Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0-24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0-24, Cmax, Cmin) was 20%-24% for apixaban versus 29%-46% for rivaroxaban. Peak AXA, AXA AUC(0-24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration-AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). CONCLUSION:Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined.

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Pharmacokinetics and Biologic Activity of Apixaban in Healthy Dogs.

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