Pharmacokinetics of multiple oral doses of acetaminophen in equine neonates

Cosette Faivre Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA

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David M. Wong Department of Veterinary Clinical Sciences, Iowa State University, Ames, IA

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Nicolas F. Villarino Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA

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 Vet Med DVSc, PhD, DACVCP
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Michael Court Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA

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Jenifer R. Gold Wisconsin Equine Clinic and Hospital, Oconomowoc, WI

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Abstract

OBJECTIVE

To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days.

ANIMALS

12 healthy light-breed neonatal foals.

PROCEDURES

6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis.

RESULTS

No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 μg/mL (22–32) than the 40 mg/kg dose at 23 μg/mL (19–27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0–8 hour [range]) was 100 h•µg/mL (82–100) at 40 mg/kg and 128 h•µg/mL (120–168) for 60 mg/kg. Trough concentrations decreased over time for both regimens.

CLINICAL RELEVANCE

Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.

Abstract

OBJECTIVE

To determine the pharmacokinetics and clinical safety of acetaminophen after oral administration of 40 mg/kg q 12 hours or 60 mg/kg q 24 hours for 14 days.

ANIMALS

12 healthy light-breed neonatal foals.

PROCEDURES

6 foals received acetaminophen at 40 mg/kg q 12 hours and 6 foals received 60 mg/kg q 24 hours for 14 days. The study dates were January 31 to April 15, 2023. Physical examinations were performed daily. Plasma disposition of acetaminophen was determined after the first, mid-point drug administration. Hematology and biochemistry analysis was performed before the study, day 7, and the last day of drug administration. Plasma acetaminophen concentrations were determined by high-performance liquid chromatography. Plasma pharmacokinetic parameters were estimated using noncompartmental analysis.

RESULTS

No statistically significant changes occurred on hematology or biochemistry profiles. Elevations in γ-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were noted in 4 foals at various time points. The maximum plasma concentration (Cmax) occurred within 2 hours for both doses. The 60 mg/kg dose resulted in a larger median Cmax (range) at 28 μg/mL (22–32) than the 40 mg/kg dose at 23 μg/mL (19–27). The median area under the concentration-vs-time curve from 0 to 8 hours (AUC0–8 hour [range]) was 100 h•µg/mL (82–100) at 40 mg/kg and 128 h•µg/mL (120–168) for 60 mg/kg. Trough concentrations decreased over time for both regimens.

CLINICAL RELEVANCE

Foals tolerate oral acetaminophen at 40 mg/kg q 12 hours or 60 mg/kg q 24 hours. Further analgesic and antipyretic studies will help to delineate optimal dosage regimens of acetaminophen to treat foals.

Acetaminophen is a COX-inhibitor whose precise mechanism of action is unknown but is believed to inhibit COX by centrally mediated pathways unlike other NSAIDS that tend to act peripherally1 and the gastrointestinal and renal side effects are not observed.2

In human medicine, acetaminophen is one of the most commonly used drugs for the treatment of pain or pyrexia and is also used in infants for similar purposes. 24 Acetaminophen has been studied after both single and multiple doses in healthy adult horses.59 At this time, 2 acetaminophen pharmacokinetic studies have been performed in 1–3 month foals and 1-week-old foals using a single dose administration.10,11 Variability was found in plasma disposition in 1 to 3-month-old foals that is likely related to change of age, as well because the feed was not withheld.10 Acetaminophen appears to have a linear disposition after a single dose per os of 10–40 mg/kg in foals, which differs from adult horses with repeated acetaminophen administration orally the disposition is no longer linear.7 Acetaminophen disposition is nonlinear in multiple oral dosing in humans as well.1216 The disposition and tolerance of repeated administration of acetaminophen is unknown in neonatal foals.

The first objective of this study was to assess the pharmacokinetics of multiple oral doses of acetaminophen administered to neonatal foals with a second objective of evaluating the hematology and biochemistry parameters over the 2-week course of acetaminophen administration. This was not a hypothesis-driven study.

Methods

Animals

This study utilized 12 healthy neonatal foals from a university-owned herd that was 5 to 6 days of age when enrolled (day 0). Breeds represented included Quarter Horse/Paint (n = 4), Thoroughbred (3), Quarter Horse (2), and Appendix Quarter Horse (3); there were 9 fillies and 3 colts with a mean body weight of 61.1 kg (range = 49–71 kg). This was a convenience sample of foals whose dams were not leaving the property for rebreeding.

Farm personnel observed the parturition of all foals and confirmed the appropriate passive transfer of immunity via automated counter (591B Foal IgG Analyzer Kit, Animal Reproduction Systems, Inc) within 24 hours of birth. Foals were considered healthy based on normal physical exam findings, attitude, appetite, and historic adequate transfer of passive immunity as well as hematology and biochemistry profile parameters within reference intervals. Per farm protocol, all foals received metronidazole (Viona Pharmaceuticals Inc) at a dose of 500 mg, orally, every 12 hours for 3 days starting at 18 hours of age. Foals did not receive metronidazole for 24 hours before the start of acetaminophen administration (day 1). Foals remained with their dams before and during the duration of the study period.

Instrumentation

Before the start of the study, each mare-foal pair was brought to the hospital and a 14-gauge 3.5-inch intravenous over-the-wire catheter (Mila International) was placed aseptically in the jugular vein after the catheter insertion site was sterilely prepared using chlorhexidine and alcohol. One mL of 2% lidocaine (Vet One) was administered subcutaneously for local anesthesia. Sedation was used to facilitate catheter placement on an as-needed basis, with foals <2 weeks receiving diazepam (Pfizer Inc) (0.1 mg/kg, IV) and foals >2 weeks old receiving xylazine (AnaSed, Vet One) (0.6 mg/kg, IV). Intravenous catheters were maintained from day 0 through day 2 and then immediately removed after the 24-hour sampling point. Foals and their mares were subsequently returned to the university farm until returning to the hospital on day 14 for the final sampling period. A second intravenous catheter was placed on day 14 in the opposite jugular vein as described above and maintained through the 48-hour sampling point on day 17, after which the catheter was removed.

Drug administration

Each foal was assigned a number (1–12) based on birth date and randomly assigned to a group (to receive acetaminophen per os at either 40 mg/kg q 12 hours or 60 mg/kg q 24 hours administered for 14 consecutive days) using a random number generator (Random.org). Six foals received the 40 mg/kg dose q 12 hours, and 6 foals received the 60 mg/kg dose q 24 hours. Of the 12 foals, 4 fillies and 2 colts received the 40 mg/kg dosing regimen, and 5 fillies and 1 colt received the 60 mg/kg dosing regimen. These doses were selected based on previous research by Gold et al, which demonstrated no adverse effects at the 40 mg/kg dose in 7- to 9-day-old foals.11 The acetaminophen (Better Living Brands) dose was ground up in a coffee grinder, and the grinder was cleaned out into a cup to get all the acetaminophen. The drug was mixed with water and Karo Syrup Lite (ACH FOOD CO. Inc) a 12 cc syringe before administration and labeled with the foal’s number. The acetaminophen tablets used for the study were 500 mg tablets; thus, the dose the foals received were close to the calculated dose, with the number of tablets varying per dose allotted and the foal’s weight. The foals were given the acetaminophen dose as close to their calculated dose as possible (within 20 mg, maximum 160 mg) utilizing 500 mg or 1/2 tablets (250 mg). The same investigator (CF) was responsible for mixing and administering all medications. The foals were not separated from their dams nor were feed, water, or nursing withheld at any point during the study. Foals were medicated at the same times daily both in the hospital and at the university farm.

Sample collection

Blood samples were collected through the catheter except on day 7. Briefly, after flushing the catheter with 1 mL of 10 units/mL of heparin (4MD Medical) in 0.9% sodium chloride (physiologic saline solution, 4MD Medical), 5 mL of blood was withdrawn and retained, a new syringe was used to collect an additional 5 mL of blood and placed into a heparin blood collection tube (Fisher Scientific), and the initial 5 mL of blood was returned to the foal and the catheter was flushed with 5 mL of physiologic saline solution. Irrespective of the sampling schedule, the jugular catheter was flushed every 6 hours with either 5 mL of heparinized saline (as described earlier) or 5 mL of 0.9% physiologic saline solution every 12 hours for the first 24 hours. Blood was collected once before administration of acetaminophen and 9 additional times over the 2-week study period that included time 0 before acetaminophen administration and then 30 minutes, 1, 2, 4, 8, 16, and 24 hours postacetaminophen administration, once on day 7 before acetaminophen administration and then once on day 15, 12 hours after the last dose of acetaminophen. All samples were centrifuged at 1,800 X g for 5 minutes, plasma was placed in plastic storage vials, and stored at −80 °C within 4 hours of collection until analysis was conducted.

Monitoring

At each sampling time, all foals received a physical exam including, heart rate, respiratory rate, body temperature, mucous membrane color, capillary refill time, gastrointestinal sounds, and observation or presence of feces/urine and nursing behavior. If any heat, swelling, pain, or discharge was noted from any of the catheters, the catheter was removed immediately, the site monitored for improvement, and a new catheter was placed in the opposite jugular vein. The foals received once-daily physical exams on the farm before daily drug administration. The foals were weighed throughout the study and the acetaminophen dose was adjusted according to the weight change. If an updated weight was not available daily weight gain was estimated at 1.25 kg per day which is the typical weight gain in foals.17

Quantification of acetaminophen

Quantification of acetaminophen in plasma was performed as previously described.10,11

The acetaminophen assays were performed within 6 months of collection. A preliminary study using horse plasma samples from our prior study11 stored under the same conditions showed good stability of acetaminophen concentrations (105 ± 6% of the original value) over a year after the original assay. This is consistent with stability studies of acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in humans plasma, which showed minimal change after 6 months of storage at −80 °C.18

Serum biochemistry profile and hematology

Six milliliters of blood was collected for hematology and serum biochemistry profile via direct jugular venipuncture on day 0. On day 7, blood was collected before drug administration via direct jugular venipuncture for CBC, serum biochemistry profile, and plasma acetaminophen levels. Blood was collected on day 14 for CBC and serum biochemistry profile through an intravenous catheter. The CBC and serum biochemistry profile were performed immediately (Vitros 4600, Advia 2120i Ortho Clinical Diagnostics) during regular business hours, or by 1 investigator (CF) (Abaxis VetScan VS2, Zoetis Services LLC; Heska Element HT5, Heska Corp) after-hours with cytological evaluation and fibrinogen performed by laboratory staff on the next business day.

Estimation of pharmacokinetic parameters

Noncompartmental analysis was used to estimate pharmacokinetic parameters19 as implemented by WinNonlin® v8.0.k (Phoenix, Cetara). Estimated pharmacokinetic parameters included the area under the plasma concentration-time curve from 0 hours to 4 and 8 hours after the first dose. (AUC0-4h ours, AUC0-8-hours), maximum plasma concentration (Cmax), time to maximum concentration (Tmax), and plasma concentration before next administration at 1, 7, and 14 days after the first administration of acetaminophen (CTrough-1day, CTrough-7day, and CTrough-14day). Time points used in the pharmacokinetic analysis included: day 0 at 0, 0.5, 1, 2, 4, 8, and 24 hours, day 7, and day 15 at 0 hours. The results were reported as median and range.

Statistical analysis

Hematology and biochemistry profile parameters were assessed statistically using the Wilcoxon matched-pairs signed-rank test. Dose proportionality was evaluated as dose-normalized AUC0-8 (AUC0-8 dose) and Cmax (Cmax/dose).19,20 The median ratios across dose levels were compared statistically using the Kruskal-Wallis test. All statistical comparisons were made using GraphPad (Prism v7.4 for Windows). The level of significance was set at P < .05.

Results

No adverse effects were observed in any of the foals on physical exam during the study period. Many foals experienced handling-related stress (tachypnea, tachycardia) that improved or resolved over the course of the study period, presumably due to increased handling and acclimatization.

No statistically significant hematologic differences were noted during the study period (Table 1); 1 foal had elevated fibrinogen at the end of the study; however, that was presumed to be due to concurrent omphalitis. Likewise, no statistically significant differences were detected in measured biochemistry parameters (Table 2) and all parameters were within normal limits except for mild elevations in GGT, SDH, and total bilirubin. One foal (60 mg/kg group) had an elevated GGT at 7 days but returned to normal at the end of the study. Another foal (60 mg/kg group) started the study with a normal GGT, but it was above the reference interval at 7 and 15 days. Total bilirubin was outside the reference interval in foals (40 and 60 mg/kg) but all decreased over the course of the study. SDH was also elevated (40 mg/kg group) at 7 days but returned to normal by the end of the study. Two foals (60 mg/kg group) had SDH elevations, 1 foal at the 7-day sample returned to normal at the end of the study and the other was mildly elevated at the end of the study. None of these changes were statistically significant.

Table 1

Mean (range) hematologic results for 12, 5- to 6-day-old university-owned foals immediately before (day 0) and 7 and 14 days after initiation of treatment with acetaminophen 40 mg/kg, PO, every 12 hours (n = 6) or 60 mg/kg, PO, every 24 hours (6) for 14 days in a study conducted between January 31 and April 15, 2023.

Regimen-time PCV% White Cell X 103/μL Red Cell X 106/μL Hemoglobin g/dL Plasma Protein g/dL Fibrinogen mg/dL
40 mg/kg-day 0 34.8 (29.5–40.3) 7.8 (5.6–9.5) 8.8 (7.8–10.4) 12.3 (10.0–14.3) 5.5 (5.0–6.8) 266 (100–400)
40 mg/kg-day 7 36.9 (33.8–40.1) 6.8 (4.8–8.6) 8.9 (7.4–10.4) 12.26 (9.4–14.4) 5.98 (5.4–7.2) 420 (400–500)
40 mg/kg-day 14 30.1 (26.8–32.3) 6.2 (4.5–7.4) 7.7 (7.1–8.9) 10.3 (8.1–11.4) 5.8 (5.2–6.7) 400 (400–500)
60 mg/kg day 0 34.7 (33.2–38.4) 7.2 (5.8–9.3) 8.9 (8.2–9.4) 12.3 (11.5–12.8) 5.9 (5.5–6.3) 333 (200–400)
60 mg/kg- day 7 36.3 (32–39.9) 7.1 (6.0–8.9) 9.5 (8.8–10.4) 13 (12.1–14.7) 6.1 (5.8–6.6) 400 (300–500)
60 mg/kg- day 14 33.4 (29.9–37.3) 6.8 (5.3–9.0) 8.5 (7.5–9.5) 11.8 (10.9–12.7) 6.0 (5.8–6.2) 450 (200–900)
Reference range21
1 week 28–43 6.3–13.6 8.9–9.9 10.7–15.8 5.1–7.5 160–418
2 weeks 34–44 7.2–13.5 9.1–10 12.2–13.4 6.2–7.2 330–473

No statistical significance seen in any parameter.

Table 2

Mean (range) biochemical results for the foals described in Table 1 immediately before (day 0) and 7 and 14 days after initiation of treatment with acetaminophen 40 mg/kg, PO, every 12 hours (n = 6) vs 60 mg/kg, PO, every 24 hours (6) for 14 days.

Regimen-time BUN mmoL/L Cr μmoL/L Alk Phos U/L GGT U/L AST U/L SDH U/L TBILI μmoL/L TG mmoL/L
40 mg/kg day 0 3.3 (1.3–3.9) 106.1 (70.7–133) 1,098 (818–1,387) 56 (35–84) 235 (195–260) 5.8 (0.5–13.1) 47.8 (30.8–82.1) 1.58 (0.67–2.5)
40 mg/kg day 7 2.2 (2.1–3.2) 97.3 (79.6–115) 554 (411–662) 67.5 (39–109) 259 (203–294) 8.2 (0.9–32.3) 35.9 (22.2–68.4) 1.04 (0.68–1.4)
40 mg/kg day 14 3.4 (2.1–4.6) 97.3 (88.4–133) 398 (222–499) 60.0 (37–94) 248 (223–268) 2.4 (0.5–4.5) 30.8 (20.5–58.1) 0.57 (0.19–1.2)
60 mg/kg day 0 2.8 (1.8–3.6) 97.3 (79.6–124) 998 (383–1,431) 54.0 (25–74) 204 (163–248) 7.6 (4.7–12.2) 44.5 (32.5–61.5) 1.21 (1.0–2.4)
60 mg/kg day 7 1.9 (1.4–2.5) 97.3 (79.6–124) 616 (382–671) 126 (61–198) 326 (245–449) 7.0 (1.9–16.2) 32.5 (23.9–58.1) 0.94 (0.4–1.2)
60 mg/kg day 14 2.2 (1.8–3.2) 124 (106–168) 570 (535–621) 103 (52–234) 315 (234–429) 4.1 (1.6–10.9) 23.9 (22.2–27.4) 0.7 (0.52–0.9)
Reference range2122
1 week 1.4–7.1 88.4–150.3 861–2671 14–164 237–620 0.1–23.3 1 13.6–51.3 0.35–2.7
2 weeks 2.1–4.6 35.4–185.7 182–859 16–169 240–540 0.6–4.3 11.9–37.6 0.44–2.55

No statistical significance noted in the parameters. Cr = Creatinine. ALK PHOS = Alkaline phosphatase. AST = Aspartate aminotransferase. SDH = Sorbitol dehydrogenase. TBILI = Total bilirubin. TG = Triglyceride.

After the oral administration of acetaminophen, the drug was detected in all foals (Table 3). The maximal concentration was observed within 2 hours in all foals for both dosage regimens. The median trough concentrations at days 1, 7, and 15 after the administration of 40 mg/kg every 12 hours were higher than the administration of 60 mg/kg every 24 hours. The administration of a single 40 mg/kg dose of acetaminophen resulted in a peak plasma concentration of 23 µg/mL within 0.5 to 1 hour of administration (Figure 1). Administration of a single 60 mg/kg dose of acetaminophen resulted in peak plasma concentrations of 28 µg/mL within 0.5 to 2 hours of administration, with peak proportional to dose. For the 40 mg/kg dosage regimen, the median (range) trough plasma concentration was 3.1 ug/mL (1.5 to 6.6) after day 1 (2 drug administrations) and 1.3 µg/mL (0.5 to 2.6) 12 hours after the last administration. For the 60 mg/kg dosage regimen, the median (range) trough plasma concentration was 0.48 µg/mL (0.2 to 1) after day 1 (1 drug administration) and 0.4 µg/mL (0.17 to 0.6) 24 hours after the last administration. The median trough concentrations on days 1, 7, and 15 after the administration of 40 mg/kg every 12 hours were higher than the median trough concentrations after the administration of 60 mg/kg every 24 hours.

Table 3

Mean (range) results for plasma pharmacokinetic parameters for the foals described in Table 1 after initiation of treatment with acetaminophen 40 mg/kg, PO, every 12 hours (n = 6) vs 60 mg/kg, PO, every 24 hours (6) for 14 days.

PK parameter Unit 40 mg/kg (n = 6) 60 mg/kg (n = 6)
Tmax h 0.5 (0.5–1) 0.1 (0.5–2)
Cmax ug/mL 23 (19–27) 28 (22–32)
AUC0-4hours h•ug/mL 64 (56–79) 83 (72–103)
AUC0-8hours h•ug/mL 100 (82–120) 128 (120–168)
AUC0-8 hours/dose h•ug/mL 2.5 (2.05–3.0) 2.1 (2.0–2.8)
Cmax/dose N/a 0.58 (0.48–0.55) 0.46 (0.36–0.53)
CTrough-day 1 ug/mL 3.1 (1.5–6.6) 0.48 (0.2–1)
CTrough-day 7 ug/mL 1.6 (0.4–3.1) 0.26 (0.05–0.5)
CTrough-day 15 ug/mL 1.3 (0.5–2.6) 0.4 (0.17–0.6)

AUC0–4hours and AUC0–8hours = Area under the plasma concentration-time curve from 0 hours 4 and 8 hours after the first drug administration. Cmax = Maximum concentration time to maximum concentration after the first administration. Tmax = Time to maximum concentration after the first administration. CTrough-day correspond to the plasma concentration before next administration at the days indicated in the table. CTrough-day correspond to 12 hours and 24 hours after the administration for the 40 mg/kg and 60 mg/kg, respectively. N/a = Not applicable.

Figure 1
Figure 1

Mean plasma disposition of acetaminophen in 12, 5- to 6-day-old university-owned foals at 0.5, 1, 2, 4, and 8 hours (A) and trough plasma concentration of acetaminophen on days 1, 7, and 15 (B) after initiation of treatment (time and day 0) with acetaminophen 40 mg/kg, PO, every 12 hours (red; n = 6) or 60 mg/kg, PO, every 24 hours (blue; 6) for 14 days in 5 a study conducted between January 31 and April 15, 2023. For each time point, the square or triangle represents the mean and the whiskers represent the range.

Citation: American Journal of Veterinary Research 84, 9; 10.2460/ajvr.23.04.0079

Discussion

This is the first study to describe plasma pharmacokinetics of repeated oral administration of acetaminophen in 5- to 6-day-old foals at 40 mg/kg every 12 hours or 60 mg/kg every 24 hours for 14 days and the effect of acetaminophen administration on physical examination parameters and hematological and serum biochemical parameters. The disposition of acetaminophen after the first dose was comparable with the pharmacokinetic profile reported in a previous study performed in 7- to 9-day-old foals.11 The maximum concentration after the first administration was observed within 2 hours for both dosage regimens, which is comparable with acetaminophen studies in both foals and adult horses.511

In adult humans, the minimum therapeutic levels and the 50% effective dose of acetaminophen (ED50) for pyrexia is between 10 and 20 µg/mL2,3,29 compared with 5 μg/mL in children.25,28 Analgesia has been shown to be effective at a plasma concentration of 10 μg/mL in 50% of children undergoing tonsillectomy.26 Several recent studies have evaluated antipyretic and analgesia in adult horses.8,9 Mercer et al, looked at the effect of acetaminophen on multiple parameters after administration of lipopolysaccharide (LPS).8 Their study found the plasma disposition of acetaminophen to be 13.97 ± 2.74 μg/mL within an hour of administration and a decrease in pyrexia at 4 to 6 hours post-LPS administration.8 Another recent study looked at the effects of codeine and acetaminophen on thermal nociception in horses. They found extensive interindividual variation in the pharmacokinetic parameters of codeine and acetaminophen and the combination of the 2 drugs.9 One of the steps needed next in foals is to find the effective dose to achieve analgesic and antipyretic concentrations.

In this study, dose regimens had a Cmax well above the reported minimum therapeutic levels and ED50 of acetaminophen in people.2,2329 Neither the effectiveness of acetaminophen as an analgesic or antipyretic nor the duration of therapeutic action, were evaluated in this study.

To the authors’ knowledge, this is the first study assessing plasma disposition of acetaminophen after administration of 60 mg/kg, administered every 24 hours, to 5- to 6-day-old foals. The administration of acetaminophen at 60 mg/kg resulted in a relatively larger median Cmax than 40 mg/kg dosage regimen (Table 3). However, the median trough plasma concentrations at days 1, 7, and 15 after administration of 40 mg/kg every 12 hours were higher than administration of 60 mg/kg every 24 hours. This likely reflects the larger cumulative dose of 80 mg/kg per 24 hours vs 60 mg/kg. The 40 mg/kg dose q 12 hours likely also provides a larger drug exposure than the administration of 60 mg/kg every 24 hours. Accumulation of acetaminophen has been reported in infants and young children receiving therapeutic doses for several days which was postulated to be due to reduced clearance in this cohort.28,29 This accumulation was not associated with an increased risk of hepatotoxicity.32,3335

The median terminal half-life of acetaminophen reported in 7- to 9-day-old foals was 6 hours at a dose of 20 mg/kg and approximately 5 hours at the 40 mg/kg dose,11 which is slightly prolonged compared with adult horses at 4 hours.59 Terminal half-life reflects absorption, plasma clearance, and distribution. As absorption of acetaminophen from the proximal small intestine is typically an hour or less, this is likely not a contributing factor.5 The volume of distribution in foals tends to be higher due to increased total body water and this may be contributing to a prolonged terminal half-life. However, plasma clearance may also be decreased in foals.

It is expected that the plasma acetaminophen concentrations would reach a steady state in approximately 60 hours, or 10 terminal half-lives. Attained steady-state plasma concentrations of acetaminophen should be reflected in relatively steady trough plasma concentrations. In this study, foals were 5 to 6 days old when they received the first acetaminophen administration, suggesting that the concentration of acetaminophen tended to decrease as the foals aged. Gold et al suggested that age may influence the plasma disposition of acetaminophen in foals based on prior studies.10,11 In adult horses AUC0-∞ has been shown to decrease after multiple doses of acetaminophen, which is also documented in people28 and is believed to result from decreased drug bioavailability.1417 In adult horses, the half-life is longer for multiple doses compared with single doses of acetaminophen, also suggesting a nonlinear elimination.57

Compared with adult horses, foals have increased total body water, an increased extracellular fluid compartment, lower serum protein concentrations, and reduced drug metabolism.30,31 Thus, age-dependent pharmacokinetics could be the result of temporal changes in drug metabolism and/or excretion. The route of acetaminophen elimination in horses and foals is not clear, but liver enzymatic systems likely biotransform acetaminophen in horses, similarly to humans.8,31 Physiologic changes in the rate and extent of drug biotransformation capacity of enzymatic systems are expected with neonatal development; thus, it is reasonable to speculate that dosage regimens would need to be adjusted by age in growing foals, as is the case for some NSAIDs currently used in neonatal foals.30 Determining the relationship between pharmacokinetic and pharmacodynamic data of acetaminophen in neonatal foals and establishing the maximal analgesic/antipyretic effect and duration of pharmacological effects of acetaminophen would help define the effective doses and dosing intervals.

In most mammals, acetaminophen is biotransformed in the liver via glucuronidation primarily, and to a lesser extent sulfidation, to nontoxic products such as mercapturic acid or cysteine conjugates, which then undergo primarily renal excretion.27 A small amount of acetaminophen may be metabolized via CYP450 2E1, 1A2, and 3A4 to make n-acetyl-para-benzoquinoneimine (NAPQI), which itself undergoes diffuse glutathione conjugation in all tissues. Toxicity occurs in people when these metabolic processes are overloaded, leading to increased presence of NAPQI, which then binds to cellular proteins and membranes leading to cellular dysfunction and death, particularly of hepatocytes.32 Hepatotoxicity with the use of acetaminophen is a known adverse effect in people, with the toxic dose suspected to be higher in children due to a higher likelihood of emesis after ingestion, higher glutathione turnover, and higher oxidative metabolism and sulfidation capacity compared with adults; however, none of these theories are confirmed.34,35 While acetaminophen administration was well-tolerated by foals in this study, with no statistically significant changes in CBC, serum biochemistry, or physical exam parameters noted, a few foals demonstrated elevations in GGT, SDH, and bilirubin. Other markers of hepatic dysfunction, such as bile acids, ammonia, and liver biopsy pre- and postprotocol, might help differentiate if acetaminophen administration results in alterations in liver function, but these tests were not evaluated in this study. More invasive diagnostics such as biopsy may not be indicated to ascertain safety given that there were no statistically significant changes in liver enzymes or function noted in this cohort, however, it would provide a more sensitive indicator of clinical safety. Alternatively, elevations in some of these liver parameters could simply represent normal variations in enzyme activity in healthy, growing neonatal foals.

In adult horses, acetaminophen has been frequently reported as a component of multimodal analgesic therapy.3638 While the development of gastric ulceration has not been reported in adult horses in prior acetaminophen trials,59 increased frequency (but not severity) of gastric ulceration was noted in people receiving combination therapy with acetaminophen and aspirin compared with unimodal therapy, although this data was not statistically significant.35 Thus, future studies of acetaminophen as a component of multimodal therapy might benefit from the assessment of changes in gastric ulceration scores over the course of treatment.

Growing evidence suggests that acetaminophen disposition is nonlinear and is age dependent.39 This study does not provide definitive conclusions about linearity, or lack thereof, or acetaminophen’s age dependency in the body after repeated administration because the study was not designed with that purpose. Limitations of this study include the fact that, per farm protocol, all the foals in the study received a 3-day course of metronidazole, starting at approximately 18 hours of age, before the start of the study to prevent neonatal diarrhea. Due to the hepatic metabolism of metronidazole, the study was not instituted until 24 hours after the last dose of metronidazole. This, however, may have caused some of the initial abnormalities in serum biochemistry parameters. Clinical diseases encountered by foals during this study included mild diarrhea (suspected foal heat diarrhea) and septic omphalitis. Additionally, other treatments including phenylbutazone, Di-Tri-Octahedral Smectite (Bio-Sponge), doxycycline, trimethoprim-sulfamethoxazole, and gentamicin, were administered to foals by farm personnel during the study, which has the potential to confound the data of this study and lead to malabsorption of acetaminophen or alterations in its hepatic metabolism. The purpose of this study was not to examine the effects of acetaminophen when co-administered with other medications or for specific disease conditions, but these variables may be more reflective of real-world pharmacokinetics, as co-administration of other medications is likely in foals requiring acetaminophen.

In conclusion, foals appear to absorb oral acetaminophen quickly, with Cmax that may be above the reported effective therapeutic concentrations for antipyresis in adult horses for both 40 mg/kg q 12 hours and 60 mg/kg q 24 hours. No systemic adverse effects were noted in either group. Further studies of pharmacodynamic profiles and clinical efficacy are needed to define optimal therapeutic regimens.

Acknowledgments

The authors thank Kaitlin Kotfila for her animal handling expertise.

Disclosures

The authors have nothing to disclose. No AI-assisted technologies were used in this generation of this manuscript.

Funding

WSU Intramural Funding-Luella Gottstein Endowment for Equine Research, Stanley L. Alder Research. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript.

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