PI-113 - PBPK-LED ASSESSMENT OF ANTIMALARIAL DRUG CONCENTRATIONS IN BREASTMILK: A STRATEGY FOR OPTIMAL USE OF PREDICTION METHODS TO GUIDE DECISION MAKING IN AN UNDERSTUDIED POPULATION

L. Almond¹, K. Abduljalil², A. Pansari², B. Kusmider³, H. Jones⁴, K. Rowland-Yeo¹, I. Gardner², M. Faisal¹, A. Marrast³, M. El Gaaloul³, J. Moehrle⁵, N. Abla³; ¹Certara UK, N/A, UK, ²Certara, Sheffield, England, United Kingdom, ³MMV, N/A, Switzerland, ⁴Certara, MA, USA, ⁵University of Basel, N/A, Switzerland.

Background: Treatment of breastfeeding mothers with malaria is challenging due to the lack of information describing drug exposure in milk and the daily dose to the breastfed infant. The aim of this work was to develop a PBPK-led strategy to evaluate whether clinical lactation studies are warranted for the most commonly used antimalarials.

Methods: Published physiologically based pharmacokinetic (PBPK) models [1] were used with QSAR models [2, 3] to predict milk-to-plasma ratios (M/P), infant daily doses (IDD) and relative infant doses (RID) for five drugs with clinical lactation data (chloroquine, pyrimethamine, piperaquine, mefloquine and primaquine) and seven without (amodiaquine, atovaquone, dihydroartemisinin, proguanil, pyronaridine, lumefantrine and tafenoquine). Sensitivity analyses were used to assess the impact of drug and milk properties on the predicted M/P.

Results: RID was correctly categorised as > or < the WHO cut-off of 10% using both models. M/P prediction accuracy had a bias (AFE and AAFE) and a precision (RMSE) of 1.04, 2.28 and 2.14, using the phase distribution model (Model 1), and 1.42, 1.73 and 1.41, using the log-transformed model (Model 2). Predictions of M/P were within 3-fold of observed values for 75% and 100% of studies for Model 1 and Model 2, respectively. For the drugs without clinical lactation data, RID was < 10% for amodiaquine, dihydroartemisinin, proguanil, and pyronaridine, and >10% for lumefantrine and tafenoquine. For atovaquone, RID was >10% when Model 1 but not Model 2 was used. Predicted IDD were significantly lower than licensed infant doses for all cases except lumefantrine (Model 2) and tafenoquine (not licensed in < 2 years). Predictions were sensitive to fu in plasma, LogD, milk creamatocrit and pH.

Conclusion: This analysis demonstrates the utility of PBPK to predict milk exposure in the absence of clinical lactation information. These prediction methods can then be used, alongside any licensed dosing information for < 1 year-olds, to evaluate whether a clinical lactation study is deemed necessary and to better inform drug label or policy recommendations. The ultimate goal is to better guide optimal treatment for lactating women supporting malaria eradication.
[1] Abla et al., CPT:PSP. 2023;12(9):1335–46.
[2] Fleishaker et al., J Pharm Sci. 1987;76(3):189–93.
[3] Atkinson & Begg, Clin PK. 1990;18(2):151–67