Population pharmacokinetic analysis of amoxicillin in postpartum Göttingen Minipig plasma and milk: a contribution from the ConcePTION project
Miao-Chan Huang (1), Julia Macente (1), Nina Nauwelaerts (1), Yeghig Armoudjian (2), Rodolfo Hernandes Bonan (2), Domenico Ventrella (3), Pieter Annaert (1,2)
(1) KU Leuven, Leuven, Belgium; (2) BioNotus, Niel, Belgium; (3) University of Bologna, Bologna, Italy.
Objectives: The knowledge gap of whether a drug would transfer into milk has existed for most medicines since their drug license was approved[1-2]. However, the amount of the drug in milk an infant is exposed to via breastfeeding is crucial information for assessing the safety of medicines used in lactating women. The Göttingen Minipig (GMP) was considered bio-relevant to humans regarding studying the milk transfer of medicine(s)[3]. Since amoxicillin (AMX) is a broad-spectrum antibiotic prescribed in humans and GMPs, it can be an example for developing a lactation/milk-transfer study framework. This study aimed to characterize AMX pharmacokinetics (PK) in plasma and milk in postpartum GMPs by population pharmacokinetic (popPK) analysis.
Methods: Three GMPs at their first week postpartum received once-daily intramuscular administration of 7 mg/kg AMX (Clamoxyl® RTU) for 3 weeks. The plasma and milk levels of AMX in GMP, determined by a validated liquid chromatography-tandem mass spectrometry method (10-10000 ng/mL), were provided by the research team at University of Bologna under the IMI ConcePTION project[4]. PopPK analysis was conducted by nonlinear mixed-effects modeling using Monolix® version 2021R1 with stochastic approximation expectation-maximization algorithm. Stepwise covariate analysis was performed with the following acceptance criteria: a decrease in objective function value (OFV) of >3.84 (p<0.05) in the forward addition; an increase in OFV of >6.63 (p<0.01) in the backward elimination. The final model was evaluated with goodness-of-fit plots and visual predictive checks. A virtual population (n=1000) was simulated with the final model, and the median simulated AMX plasma and milk profiles were used to calculate the milk-to-plasma (M/P) ratio, daily infant dose (DID), and relative infant dose (RID) with the following equations, where 1072 mL/kg was the assumed daily milk intake volume for a GMP piglet based on literature[5].
M/P ratio = AUCτ,milk/AUCτ,plasma
DID = (AUCτ,milk/τ)*1072
RID = (infant dose/maternal dose)*100%
Results: 123 plasma and 85 milk samples were available from 3 GMPs, where 3 plasma and 4 milk samples below the lower limit of quantification (10 ng/mL) were excluded. All the quantifiable measurements were included in the analysis except the Day 1 data in one animal, which developed a fever and was resolved the same day.
The data were best described by a 2-compartment model with 0-order absorption and linear elimination. The central compartment was linked to the milk compartment by 1st-order transfer. To describe the observed changes in plasma level over time, inter-occasional variability was introduced to Tk0, volume of distribution in plasma compartment (V), and clearance (CL) considering physiologically plausible postpartum changes. Due to the limited amount of data, the absorption duration (Tk0) and the volume of the distribution in the milk compartment (VBM) were fixed to allow identifiability of other parameters. Tk0 was set to 1, and VBM was fixed to 1.33-fold of the value of the daily milk intake volume per litter piglets (5.89 L, assuming 75% of the breast milk volume emptied during breastfeeding). Bodyweight was found to have a significant effect on V.
More than 90% of the observations fell within the 5-95% simulated interval in the virtual population. In the median simulated PK profiles, the highest AUCτ at steady-state in plasma and milk was 17880 and 3598 ng⋅h/mL, respectively. The calculated M/P ratio was 0.140 (0.9-fold of the observed value) and was comparable to the predicted value (0.15) by the physiologically-based PK (PBPK) model for AMX in humans[6]. The DID (RID) was 0.111 mg/kg⋅day (2.30%) and was nearly 0.7-fold of the observed values in the GMPs.
Conclusions: With the current dataset, the developed final PopPK model not only described the AMX plasma and milk levels in GMPs well but also simulated an M/P ratio close to the observed value in GMPs and the predicted value by human PBPK model. The precision of this popPK model is anticipated to improve when more data are available to be included in the future.
Acknowledgment: This work is supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ConcePTION grant No. 821520, Taiwan Scholarship Programme, and Research Foundation—Flanders (1S50721N). The research leading to these results was conducted as part of the ConcePTION consortium. This abstract only reflects the personal views of the stated authors.
References:
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