Informing the risk assessment related to lactation and drug exposure: A physiologically based pharmacokinetic lactation model for pregabalin

Abstract

Breastfeeding is important in childhood development, and medications are often necessary for lactating individuals, yet information on the potential risk of infant drug exposure through human milk is limited. Establishing a lactation modeling framework can advance our understanding of this topic and potentiate clinical decision making. We expanded the modeling framework previously developed for sotalol using pregabalin as a second prototypical probe compound with similar absorption, distribution, metabolism, and elimination (ADME) properties. Adult oral models were developed in PK-Sim® and used to build a lactation model in MoBi® to simulate drug transfer into human milk. The adult model was applied to breastfeeding pediatrics (ages 1 to 23 months) and subsequently integrated with the lactation model to simulate infant drug exposure according to age, size, and breastfeeding frequency. Physiologically based pharmacokinetic (PBPK) model simulations captured the data used for verification both in adults and pediatrics. Lactation simulations captured observed milk and plasma data corresponding to doses of 150 mg administered twice daily to lactating individuals, and estimated a relative infant dose (RID) of approximately 7% of the maternal dose. The infant drug exposure simulations showed peak plasma concentrations of 0.44 μg/mL occurring within the first 2 weeks of life, followed by gradual decline with age after week four. The modeling framework performs well for this second prototypical drug and warrants expansion to other drugs for further validation. PBPK modeling and simulation approaches together with clinical lactation data could ultimately help inform infant drug exposure risk assessments to guide clinical decision making.

FIGURE 1

Physiologically based pharmacokinetic (PBPK) modeling workflow (a) and stepwise process for randomly splitting internal adult data (b).

FIGURE 2

Lactation PBPK model schematic and basic structure of the breast tissue and milk compartment (The lactation PBPK model structure as well as the structure of the breast tissue and milk compartments were informed by Job et al. ⁴⁰ ). The basic PBPK model structure illustrates oral drug administration into the stomach with absorption occurring in the small intestine, followed by distribution into venous and arterial blood. Pregabalin then distributes into breast tissue and subsequently into human milk, in addition to other tissues including its primary site of pharmacological action in the brain. The net flux from plasma into human milk is illustrated by the larger half arrow (red) in the breast tissue compartment (center of figure). Transfer between interstitial fluid (ISF) and milk is also illustrated, but with thin black arrows as this pathway is thought to be of minor significance. On the far right is a simplified depiction of the actual anatomical structure of the barrier separating plasma from human milk that resides in the lumen of the alveoli. The lumen of the alveoli is lined with milk‐producing lactocytes on the apical side and is layered with myoepithelial cells along with a basement membrane through which the drug occurs. The equations listed are those incorporated into the MoBi® template by Job et al. to calculate the number of lobules per lobe in the breast, the volume of milk produced per day (V _milk) as a function of baby weight (W _baby), baby weight according to sex (W _baby,girl, W _baby,boy) and age (t), and the milk‐to‐plasma partition coefficient (K _milk/plasma) set equal to the milk‐to‐plasma AUC ratio. The equation for V _milk was not used in the lactation PBPK model discussed here because observed values were input into the model instead; therefore, W _baby also had no impact on the model. K _milk/plasma, milk‐to‐plasma partition coefficient; K _{milku/plasmau}, milk‐to‐plasma partition coefficient for unbound drug; f _u, fraction unbound in plasma; f _u,milk, fraction unbound in milk; AUC_τ,milk, area under the milk concentration‐time curve for dosing interval (τ); AUC_τ, area under the plasma concentration‐time curve for dosing interval (τ); θ ₁, θ ₂, θ ₃, fitted parameters (160.39, 0.232, and 0.00252, respectively); t, time after delivery (days); W _baby, calculated weight of baby (kg); V _milk, daily milk volume (mL/day); V _exp, fraction of V _milk expressed per feeding.

FIGURE 3

Lactation PO PBPK model performance with visual predictive check and simulated populations. Evaluation of lactation PBPK model predictive performance in plasma (red and orange simulation curves and corresponding shaded regions) and human milk (blue and cyan simulation curves and corresponding shaded regions) for fasted (a) and fed (b) state simulations, and for virtual populations in the fasted (c) and fed (d) states. Solid lines represent the simulated mean concentration and the respective shaded regions represent the 95% confidence interval (CI, 2.5%–97.5% range) of the simulated value. For the fasted‐state simulations (a) and (c), mean plasma concentration is shown in red with corresponding observed data overlain as red squares (mean ± standard deviation [SD]), and mean milk concentration is shown in blue with corresponding data as blue circle (mean ± SD). For the fed‐state simulations (b) and (d), mean plasma and milk concentrations are shown in orange and cyan, respectively, with corresponding data overlain as red squares and blue circles as with the fasted‐state simulations. Semi‐log plots of simulation means are shown in the inset plots in the upper right corners. The observed data correspond to all individuals from the Lockwood et al. study.

FIGURE 4

Infant drug exposure simulations. Simulation showing the infant drug exposure expected from milk consumption over 2 weeks for an infant 0 weeks old, 2 weeks old, 4.5 months old, 8 months old, and 16 months old, with a maternal dose of 150 mg administered twice daily. “Toxicity Threshold” (dark red horizontal line) corresponds to the observed C _max for the highest dose tested in pediatric clinical trials (i.e., 15 mg/kg/day in two divided doses, or 7.5 mg/kg twice daily), which was ~16 μg/mL. “Therapeutic Threshold” (blue horizontal line) corresponds to the observed C _max for the lowest dose tested in pediatric clinical trials (i.e., 2.5 mg/kg/day in two divided doses, or 1.25 mg/kg twice daily), which was ~1.5 μg/mL.