Maria Menendez

Pharmacokinetics of methylprednisolone acetate after intra-articular administration and subsequent suppression of endogenous hydrocortisone secretion in exercising horses

OBJECTIVE To determine the pharmacokinetics of methylprednisolone (MP) and the relationship between MP and hydrocortisone (HYD) concentrations in plasma and urine after intra-articular (IA) administration of 100 or 200 mg of MP acetate (MPA) to horses. ANIMALS Five 3-year-old Thoroughbred mares. PROCEDURES Horses exercised on a treadmill 3 times/wk during the study. Horses received 100 mg of MPA IA, then 8 weeks later received 200 mg of MPA IA. Plasma and urine samples were obtained at various times for 8 weeks after horses received each dose of MPA; concentrations of MP and HYD were determined. Pharmacokinetic-pharmacodynamic estimates for noncompartmental and compartmental parameters were determined. RESULTS Maximum concentration of MP in plasma was similar for each MPA dose; concentrations remained greater than the lower limit of quantitation for 18 and 7 days after IA administration of 200 and 100 mg of MPA, respectively. Maximum concentration and area under the observed concentration-time curve for MP in urine were significantly higher (approximately 10-and 17-fold, respectively) after administration of 200 versus 100 mg of MPA. Hydrocortisone concentration was below quantifiable limits for ≥ 48 hours in plasma and urine of all horses after administration of each MPA dose. CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetics of MP may differ among IA MPA dosing protocols, and MP may be detected in plasma and urine for a longer time than previously reported. This information may aid veterinarians treating sport horses. Further research is warranted to determine whether plasma HYD concentration can aid identification of horses that received exogenous glucocorticoids.

Influence of exercise on the distribution of technetium Tc 99m medronate following intra-articular injection in horses

OBJECTIVE To determine the effects of exercise on the distribution and pharmacokinetics of technetium Tc 99m medronate ((99m)Tc-MDP) following intra-articular (IA) injection in horses. ANIMALS 5 horses. PROCEDURES 1 antebrachiocarpal joint (ACJ)/horse was assigned to the exercised group (n = 5), and the contralateral ACJ was evaluated in the nonexercised group (5) after a minimum washout period of 7 days. Following IA injection of (99m)Tc-MDP (148 MBq), blood and scintigraphic images of the carpus were obtained at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 240, 360, 480, 600, 720, and 1,440 minutes. Plasma and scintigraphic radioactivity were determined over time, and pharmacokinetic parameters were generated via noncompartmental and compartmental analyses. Each horse was monitored via physical and lameness examination and ACJ synovial fluid analysis before injection and at days 1, 2, 3, and 7. RESULTS Lameness was not observed. Mean ± SD synovial fluid WBC count increased at day 1 (exercised, 721 ± 234 cells/μL; nonexercised, 948 ± 223 cells/μL), but returned to baseline at days 3 and 7 Mean time to maximum plasma radioactivity was earlier in the exercised group (16.00 ± 2.35 minutes) than the nonexercised group (43.75 ± 3.64 minutes). Linear regression of the scintigraphic radioactivity-time curves revealed a greater negative slope in the exercised group within the first 25 minutes. There was no difference in absorption or elimination rate constants in a 2-compartment model. CONCLUSIONS AND CLINICAL RELEVANCE IA injection of (99m)Tc-MDP was safe and effective for evaluating synovial solute distribution. Exercise significantly increased early transfer of (99m)Tc-MDP from the ACJ into plasma, although absorption and elimination rate constants were not affected. Exercise may affect synovial clearance and withdrawal times of medications administered IA.

Pharmacokinetics of intra-articular betamethasone sodium phosphate and betamethasone acetate and endogenous hydrocortisone suppression in exercising horses.

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra-articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration-time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non-compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater Tmax (Tmax 0.8 h) vs. urine (Tmax 7.1 h). Urine BTM concentration (ng/mL) and amount (AUClast ; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (Tlast ; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC-MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine.

Feasibility of Na18F PET/CT and MRI for Noninvasive In Vivo Quantification of Knee Pathophysiological Bone Metabolism in a Canine Model of Post-traumatic Osteoarthritis.

Purpose: To assess and quantify by molecular imaging knee osseous metabolic changes serially in an in vivo canine model of posttraumatic osteoarthritis (PTOA) of the knee utilizing sodium fluoride (Na18F) positron emission tomography (PET)/computed tomography (CT) coregistered with magnetic resonance imaging (MRI). Materials and Methods: Sodium fluoride PET imaging of 5 canines was performed prior to anterior cruciate ligament transection (ACLT) and 2 times post-ACLT (3 and 12 weeks). The PET/CT was coregistered with MRI, enabling serial anatomically guided visual and quantitative three-dimensional (3D) region of interest (ROI) assessment by maximum standardized uptake value. Results: Prior to ACLT, every 3D ROI assessed in both knees showed no Na18F uptake above background. The uptake of Na18F in the bone of the ACLT knees increased exponentially, presenting significantly higher uptake at 12 weeks in every region compared to the ACLT knees at baseline. Furthermore, the uninjured contralateral limb and the ipsilateral distal bones and joints presented Na18F uptake at 3 and 12 weeks post-ACLT. Conclusion: This study demonstrated that Na18F PET/CT coregistered with MRI is a feasible molecular imaging biomarker to assess knee osseous metabolic changes serially in an in vivo canine model of knee PTOA. Moreover, it brings a novel musculoskeletal preclinical imaging methodology that can provide unique insights into PTOA pathophysiology.

Pharmacokinetics and bone resorption evaluation of a novel Cathepsin K inhibitor (VEL-0230) in healthy adult horses.

Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1)] analyses were performed following single and multiple oral dose protocols of a Cathepsin K inhibitor (VEL-0230) in horses. Outcomes included plasma and urine drug and CTX-1 concentrations. In the dose range study, 2, 4, and 8 mg/kg body weight (b.w.) doses were administered in a Latin square design to three mares and evaluated for 1 week. Based on the PK characteristics of VEL-0230, 4 mg/kg b.w. was selected for the dose interval study in which 3.25 days (d) and 7 days dose intervals were evaluated over three administrations using four exercising horses in a Latin square design. The 3.25 days and 7 days dose intervals provided a rapid inhibition of bone resorption based on plasma CTX-1. CTX-1 inhibition prior to next dose administration was not different from baseline in the 3.25 days and 7 days protocols, and for the first 3 days but the sustained CTX-1 inhibition in the 7 days protocol along with the cost and logistic benefits for weekly administration made the 7 days protocol preferable. Weekly administration of VEL-0230 may provide effective inhibition of bone resorption in young exercising horses that returns to baseline within 7 days after drug withdrawal even after multiple doses.

Preclinical Multimodal Molecular Imaging Using 18F-FDG PET/CT and MRI in a Phase I Study of a Knee Osteoarthritis in In Vivo Canine Model

The aim of this study was to use a multimodal molecular imaging approach to serially assess regional metabolic changes in the knee in an in vivo anterior cruciate ligament transection (ACLT) canine model of osteoarthritis (OA). Five canine underwent ACLT in one knee and the contralateral knee served as uninjured control. Prior, 3, 6, and 12 weeks post-ACLT, the dogs underwent 18F-fluoro-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging (MRI). The MRI was coregistered with the PET/CT, and 3-dimensional regions of interest (ROIs) were traced manually and maximum standardized uptake values (SUVmax) were evaluated. 18F-fluoro-d-glucose SUVmax in the ACLT knee ROIs was significantly higher compared to the uninjured contralateral knees at 3, 6, and 12 weeks. Higher 18F-FDG uptake observed in ACLT knees compared to the uninjured knees reflects greater metabolic changes in the injured knees over time. Knee 18F-FDG uptake in an in vivo ACLT canine model using combined PET/CT and MRI demonstrated to be highly sensitive in the detection of metabolic alterations in osseous and nonosteochondral structures comprising the knee joint. 18F-fluoro-d-glucose appeared to be a capable potential imaging biomarker for early human knee OA diagnosis, prognosis, and management.