090: Pharmacokinetics of Tetrahydrocannabinol in Infants Exposed to Breastmilk from Recreational Cannabis Users

Statement of Purpose, Innovation or Hypothesis: Multiple studies have shown that breastmilk concentration of tetrahydrocannabinol (THC) among lactating recreational users is multiple folds higher than their corresponding plasma concentrations. However, limited data exist regarding the corresponding THC exposures in breastfed infants and their potential effects. Ethical considerations likely contribute to this lack of information, potentially leading to divergent breastfeeding recommendation among lactation professionals in a recent survey [1]. This research extends our previously developed physiologically based pharmacokinetic model (PBPK) of THC in lactating mothers by incorporating an infant PBPK model. Our aim is to predict THC exposure in infant plasma resulting from the ingestion of THC-containing breastmilk.

Description of Methods & Materials: Our previously developed adult PBPK model, which utilized several relevant system- and drug-specific parameters from literature to describe ADME processes in Pumas v2.3, was extended to an oral inhalation breastmilk (OIBM) PBPK model by incorporating lactation and inhalation characteristics. The adult base model was scaled to an infant PBPK model by accounting for age-dependent changes in organ weights, cardiac output, plasma protein concentration, CYPs 2C9 and 3A4 ontogeny, and other relevant physiological and biochemical parameters. The infant PBPK model was then linked to the maternal OIBM-PBPK model via breastfeeding. Model verification was successful if the predicted and observed values differed by no more than two-fold difference. Finally, the paired maternal-infant model was used to simulate THC exposure in breastmilk and subsequent exposure in the plasma of breastfed infants up to one year of age.

Data & Results: The lactation model successfully predicted THC concentrations within 0.5 – 2 folds of the observed values. Due to a lack of THC data to validate the infant model, an empirical approach of allometrically scaling a published population pharmacokinetics (popPK) model with enzyme maturation incorporation was adopted. Predictions from our infant PBPK model predictions were within 0.5 – 2 folds of the popPK-based predictions across all the infant age groups up to one year. In our simulation, one hundred virtual lactating mothers (mean age: 28 years, body weight: 78 kg) smoked 0.32 g of cannabis containing 14.14% THC, either once or multiple times to capture different use patterns between chronic and frequent cannabis users. Mothers were assumed to breastfeed their babies eight times daily, and infant dose input was obtained by multiplying THC breastmilk concentration and volume of breastmilk ingested at each feeding time. For a mother smoking cannabis once daily and breastfeeding a one-month-old infant, maternal and infant plasma AUC were 273 and 0.59 ng⋅hr/mL, respectively. This exposure increased with higher frequency of maternal cannabis use. Additionally, infant exposure decreased with increasing age, possibly due to increased metabolizing enzyme capacity (Figure 1).

Interpretation, Conclusion or Significance: An infant PBPK model describing the pharmacokinetics of THC in infant plasma was successfully developed and validated. Although the model suggests lower THC exposures in breastfed infants’ plasma, the potential health risks or psychoactive impacts on developing infant organs remain uncertain. Prioritizing research in this area is crucial for the safety and well-being of both mothers and infants.

Disclosures: No disclosures.

Citations/References: Bergeria et al. (2015). Surveying Lactation Professionals Regarding Marijuana Use and Breastfeeding. Breastfeed. Med. 2015, 10, 377–380.

Additional Information/Authors: Babajide Shenkoya (Presenting Author); Venkata Yellepeddi (CoAuthor); Katrina Mark (CoAuthor); Mathangi Gopalakrishnan (CoAuthor)