Aysenur Yaliniz1,2, Christopher Scala3, Amélie Marsot1,2,4
1Laboratoire de Suivi Thérapeutique Pharmacologique et Pharmacocinétique, Faculty of Pharmacy, Université de Montréal, 2Faculty of Pharmacy, Université de Montréal, 3Marineland Parks Côte d’Azur, 4Research Center, Centre Hospitalier Universitaire Sainte-Justine
Introduction/Objective: Antibiotic administration in penguins is often performed empirically due to this species’ lack of pharmacokinetic (PK) data on drug dosing regimens. [1] Dosage recommendations are typically extrapolated from data on other avian species, poultry, or even mammals, which can lead to subtherapeutic or supratherapeutic drug concentrations. [1] Consequently, this may result in treatment failure, antimicrobial resistance, and toxicity. Amoxicillin, a ß-lactam penicillin antibiotic, is used in avians for its broad-spectrum antimicrobial activity against infections. [1, 2, 3] However, PK data on amoxicillin in penguins are scarce in the literature, leaving uncertainty regarding the optimal dose required to reach target drug concentrations in this species. This study aims to characterize the PK parameters of amoxicillin in penguins. Methods: The data were collected from a prospective study conducted on penguins at Marineland Parks, France. Each penguin received a single intramuscular amoxicillin dose of 600 mg. Blood samples were collected between 15 minutes and 96 hours post-administration to assess drug concentration over time. Amoxicillin plasma levels were determined using a liquid chromatography – tandem mass spectrometry (LC-MS/MS) method developed on-site on a Triple Quad 4500 system (SCIEX, Saint-Germain-en-Laye, France). Since PK parameter values for amoxicillin in penguins are not documented, a non-compartmental analysis (NCA) was performed using the Sparse NCA function in PKanalix (v2024R1, Lixoft). This provided initial parameter estimates to guide the development of a population pharmacokinetic (popPK) model. The popPK analysis was performed using a nonlinear mixed-effects approach in NONMEM (v7.6, ICON Development Solutions) using the Pirana v23.10.1 interface. One- and two-compartment models were tested, along with proportional, additive, and combined error models, to determine the structural model that best fits the data. The effect of body weight and sex on PK parameters was assessed, primarily based on reductions in the objective function value (OFV) and interindividual variability (IIV) compared to the base model, as well as relative standard errors (RSE%). From the final model, a bootstrap analysis (n=1000) was performed. Data visualization and statistical analyses were conducted in R v4.4.2 (R Project for Statistical Computing) using the RStudio v2024.09.1 interface. Results: Data were collected from 18 penguins (7 males, 11 females) with a median [range] body weight of 4.00 [3.65, 4.84] kg. These data included 23 unique occasions and 45 concentration measurements, with each penguin providing one to three samples. A one-compartment model with proportional error best described the data. Population predictions were performed using the NONMEM subroutine ADVAN1 TRANS2, given the high absorption observed and the sparse data per penguin for estimating the absorption rate constant. Sex was identified as a significant covariate for apparent clearance (CL/F), while body weight was significant for apparent volume of distribution (V/F), together resulting in an 11.7-point reduction in the OFV. Population typical value estimates for CL/F were 2.49 and 1.30 L/h for males and females, respectively, while V/F was 17.6 L. The corresponding RSE% were 10.1% and 13.9% for CL/F and V/F, respectively. IIV was 23.3% for CL/F and 47.6% for V/F, with a residual error of 0.389. Conclusions: This is the first popPK model to describe the PK profile of amoxicillin in penguins. The administered doses, standardized by body weight, are generally higher than those reported in the literature for other avian species. [2, 3, 4] Furthermore, the rapid absorption observed in penguins aligns with findings in birds. However, the PK parameters appear to differ, potentially due to anatomical and physiological differences in penguins. [2, 3, 5] Although classified as avians, penguins are distinct from other bird species, highlighting the need for popPK studies to allow personalized treatment.
[1] Soh HY, Tan PXY, Ng TTM, Chng HT, Xie S. A Critical Review of the Pharmacokinetics, Pharmacodynamics, and Safety Data of Antibiotics in Avian Species. Antibiotics (Basel). 2022 May 31;11(6):741. doi: 10.3390/antibiotics11060741. PMID: 35740148; PMCID: PMC9219738. [2] Sartini I, Lebkowska-Wieruszewska B, Fadel C, Lisowski A, Poapolathep A, Giorgi M. Single and multiple oral amoxicillin treatment in geese: a pharmacokinetic evaluation. Br Poult Sci. 2022 Aug;63(4):493-498. doi: 10.1080/00071668.2022.2036699. Epub 2022 Feb 23. PMID: 35118922. [3] Anadón A, Martinez-Larrañaga MR, Diaz MJ, Bringas P, Fernandez MC, Martinez MA, Fernandez-Cruz ML. Pharmacokinetics of amoxicillin in broiler chickens. Avian Pathol. 1996 Sep;25(3):449-58. doi: 10.1080/03079459608419154. PMID: 18645871. [4] Pozniak B, Paslawska U, Motykiewicz-Pers K, Switala M. The influence of growth and E. coli endotoxaemia on amoxicillin pharmacokinetics in turkeys. Br Poult Sci. 2017 Aug;58(4):462-468. doi: 10.1080/00071668.2017.1304531. Epub 2017 Apr 21. PMID: 28290713. [5] Kandeel M. Pharmacokinetics and oral bioavailability of amoxicillin in chicken infected with caecal coccidiosis. J Vet Pharmacol Ther. 2015 Oct;38(5):504-7. doi: 10.1111/jvp.12205. Epub 2015 Jan 27. PMID: 25623275.
Reference: PAGE 33 (2025) Abstr 11757 [www.page-meeting.org/?abstract=11757]
Poster: Drug/Disease Modelling - Infection