137: Application of Lactation Physiologically-based Pharmacokinetic Modeling to Predict Exposure of Select Compounds

Statement of Purpose, Innovation or Hypothesis: One in four mothers are reported to take medications while breastfeeding. Drugs can pass to an infant through human milk and can potentially cause toxicity depending on the drug and resulting exposure level. Therefore, it is important to estimate the drug excretion in human milk and understand the potential exposure in infants. Recently, physiologically-based pharmacokinetic (PBPK) models have gained interest as a tool to predict drug excretion in milk and assess the exposure level in infants. The current study aims to develop and assess the predictive performance of PBPK models to simulate the atenolol, alprazolam, and escitalopram concentration profiles in maternal plasma and human milk as compared to clinical data.

Description of Methods & Materials: PBPK models for adult healthy subjects were developed using physicochemical and physiological parameters of atenolol and escitalopram using the Simcyp v23. For alprazolam PBPK model, the default compound file in Simcyp v23 was used. The in-built lactation compartment in the Simcyp was utilized. To develop a lactation PBPK model, milk-to-plasma ratio (M/P) and unbound fraction (f_u,skimmed) in skimmed milk were incorporated in the model. M/P ratio and f_u,skimmed used for atenolol, escitalopram and alprazolam were reported in the literature as 4.7, 2.2, 0.46 and 0.96, 0.96, 0.74, respectively. Using those values in the lactation PBPK models, concentration profiles in milk and plasma were simulated and compared to clinical data. Atenolol and escitalopram concentrations were measured at steady state with a dose of 25mg twice daily and 10mg once a day, respectively. Alprazolam concentrations were obtained after a single dose of 0.5mg. In the simulation the same dosage regimens were applied.

Data & Results: Atenolol, alprazolam, escitalopram PBPK models showed good agreement of plasma concentration time profiles with respective clinical data through a wide variety of doses and populations. The lactation PBPK model predicted milk concentration profiles with reasonably good agreement, as well (Figure 1).  The predicted AUC and C_max in the milk and the M/P ratio for atenolol, alprazolam and escitalopram were found to be 6533, 57.86 and 1335 ηg/ml*h; 807.49, 4.01 and 48.1 ηg/ml; and 4.71, 0.46 and 2.22, respectively. The predicted AUC, C_max and M/P ratio were within 1.37-fold of the reported values suggesting a good agreement between simulation and clinical data. The relative infant daily doses (RID) were found to be 10.56%, 6.51% and 3.98% for atenolol, alprazolam and escitalopram, respectively.

Interpretation, Conclusion or Significance: Current work shows the potential of lactation PBPK models to predict the drug exposure in human milk for 3 drugs that are not P-gp/BCRP substrates. The approach will be further evaluated for drugs that are substrates for these active transporters known to be present in mammary tissues.

Disclosures: Authors declare no conflict of interest.

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