Developing an In Vitro to In Vivo Extrapolation (IVIVE) Model to Predict Human Milk-to-Plasma Drug Concentration Ratios

Abstract

Determining the amount of drug transferred into human milk is critical for benefit–risk analysis of taking medication while breastfeeding. In this study, we developed an in vitro and in vivo extrapolation (IVIVE) model to predict human milk/plasma (M/P) drug concentration ratios. Drug unionized fractions at pH 7.0 (F ni,7.0) and 7.4 (F ni,7.4), drug fractions unbound in human plasma (f up) and milk (f um), and in vitro cell permeability in both directions (efflux ratio, ER) were incorporated into the IVIVE model. A multiple regression E max model was chosen to predict f um from f up and polar surface area (PSA). A total of 97 drugs with experimental ER from Caco-2 cells were used to test the IVIVE model. The M/P ratios predicted by the IVIVE model had a 1.93-fold geometric mean fold error (GMFE) and 72% of predictions were within two-fold error (Pw2FE), which were superior to the performance of previously reported five models. The IVIVE model showed a reasonable prediction accuracy for passive diffusion drugs (GMFE = 1.71-fold, Pw2FE = 82%, N = 50), BCRP substrates (BCRP: GMFE = 1.91-fold, Pw2FE = 60%, N = 5), and substrates of P-gp and BCRP (GMFE = 1.74-fold, Pw2FE = 75%, N = 8) and a lower prediction performance for P-gp substrates (GMFE = 2.51-fold, Pw2FE = 55%, N = 22). By fitting the observed M/P ratios of 39 P-gp substrates, an optimized ER (1.61) was generated to predict the M/P ratio of P-gp substrates using the developed IVIVE model. Compared with currently available in vitro models, the developed IVIVE model provides a more accurate prediction of the drug M/P ratio, especially for passive diffusion drugs. The model performance is expected to be further improved when more experimental f um and ER data are available.

A perspective on the current use of the phase distribution model for predicting milk‐to‐plasma drug concentration ratio

“…As another area for caution, in two recent papers, 3,5 the term was misrepresented as and , respectively, with slight differences in notations. Note that the latter mistake is identical with that in Equation , where or was mistakenly used in the place of or .…”

“…As another area for caution, in two recent papers, 3 , 5 the term was misrepresented as and , respectively, with slight differences in notations. Note that the latter mistake is identical with that in Equation 16 , where or was mistakenly used in the place of or .…”

“…The phase distribution model, developed upon the same theoretical basis as Fleishaker's model, was coupled with additional equations to allow M/P ratio predictions using unbound drug fraction in plasma, pKa, and Log P or Log D of the drug 2 . Although the phase distribution model has been widely cited, the derivation of the equations has not been explicitly presented, and misrepresentations of the equations have been noted in recent publications 3–5 . Considering the increasing public health concerns around drug safety in lactation and renewed interest in the phase distribution model, we provide the theoretical background linking these important previous works within the context of recent applications and areas for caution that we have observed.…”

“… 2 Although the phase distribution model has been widely cited, the derivation of the equations has not been explicitly presented, and misrepresentations of the equations have been noted in recent publications. 3 , 4 , 5 Considering the increasing public health concerns around drug safety in lactation and renewed interest in the phase distribution model, we provide the theoretical background linking these important previous works within the context of recent applications and areas for caution that we have observed.…”

Prediction of milk plasma ratio for amphoteric substances

“…If a molecule were neutral, which does not dissociate with ions, prediction of the M / P value uses the following equation (Equation 9 ), which was modified from a prior study 3 : …”