Incorporating Breastfeeding-Related Variability with Physiologically Based Pharmacokinetic Modeling to Predict Infant Exposure to Maternal Medication Through Breast Milk: a Workflow Applied to Lamotrigine

Abstract

Current methods to assess risk in infants exposed to maternal medication through breast milk do not specifically account for infants most vulnerable to high drug exposure. A workflow applied to lamotrigine incorporated variability in infant anatomy and physiology, milk intake volume, and milk concentration to predict infant exposure. An adult physiologically based pharmacokinetic model of lamotrigine was developed and evaluated. The model was scaled to account for growth and maturation of a virtual infant population (n=100). Daily infant doses were simulated using milk intake volume and concentration models described by a nonlinear equation of weight-normalized intake across infant age and a linear function on the relationship of observed milk concentrations and maternal doses, respectively. Average infant plasma concentration at steady state was obtained through simulation. Models were evaluated by comparing observed to simulated infant plasma concentrations from breastfeeding infants based on a 90% prediction interval (PI). Upper AUC ratio (UAR) was defined as a novel risk metric. Twenty-five paired (milk concentrations measured) and 18 unpaired (milk concentrations unknown) infant plasma samples were retrieved from the literature. Forty-four percent and 11% of the paired and unpaired infant plasma concentrations were outside of the 90% PI, respectively. Over all ages (0-7 months), unpaired predictions captured more observed infant plasma concentrations within 90% PI than paired. UAR was 0.18-0.44 when mothers received 200 mg lamotrigine, suggesting that infants can receive 18-44% of the exposure per dose as compared to adults. UARs determined for further medications could reveal trends to better classify at-risk mother-infant pairs.

Ornidazole Transfer into Colostrum and Assessment of Exposure Risk for Breastfeeding Infant: A Population Pharmacokinetic Analysis

“…Of note, the volume of colostrum was obtained using the following equation describing the weight-normalized human milk intake (WHMI) [24]:…”

“…An RID criterion of less than 10% was used to estimate the safety threshold for ornidazole concentration in breast milk, which was subsequently used to assess the potential risk of drug exposure to breastfed newborns. Of note, the volume of colostrum was obtained using the following equation describing the weight-normalized human milk intake (WHMI) [24]:…”

Addressing maternal medication use during breastfeeding using clinical resources and a novel physiologically based pharmacokinetic model-derived metric: A qualitative study

“…The approach is mechanistic and "bottom up", with physicochemical properties of the compound and system parameters (anatomy and physiology) being the two main inputs. At minimum, a daily bodyweight-normalized infant volume of milk intake model (17) and information about drug concentration in breast milk, together with the drug's pediatric PBPK model that translates dose via breast milk into exposure in neonates, are needed to produce the UAR. Applying these components, we pioneered the UAR to measure relative infant exposure risk using validated lamotrigine PBPK models as a first case example in a previous publication (18).…”

“…If data are available (e.g., a few infant plasma drug concentrations), they are used only for confirmatory rather than exploratory purposes. Increasing work that validates pediatric PBPK models to accurately predict breastfeeding infant exposures gives confidence in our workflow and UAR determination ( 18 ). With more drugs assessed with our workflow, eventually we can rank the drugs according to their potential risk and focus resources on those with significant risk (i.e., highest UAR).…”

“…Although the UAR was created in an effort to improve available clinical resources, how it is perceived and potentially used in practice by healthcare providers has not been formally assessed. To further understand healthcare provider perspectives, it is important to gather information on how resources are currently being used, whether there is a need for the UAR in addition to current resources, how the UAR could be used in current practice, whether the UAR would confer benefits, which healthcare providers would particularly benefit from use of the UAR, and how the UAR could be further improved for clinical practice [e.g., approaches to disseminate the UAR beyond its publication in Yeung ( 18 )]. Thus, the objective for this study was to understand existing resource use and UAR use in practice, their advantages and disadvantages, and areas of improvement for the UAR through one-on-one semi-structured interviews with healthcare providers.…”