Population pharmacokinetic model of nevirapine maternal to infant transfer through breastfeeding
Polly Clayden, HIV i-Base
Edmund Capparelli from the University of California, San Diego, USA, presented a population pharamcokinetic (PK) model of nevirapine (NVP) concentrations in maternal plasma, breast milk and infant dried blood spots (DBS) to better characterise infant NVP exposure via breast milk.
This analysis used data collected in a previously published substudy of the Kisumu breastfeeding study in Kenya (in which pregnant women received NVP-containing HAART to prevent mother to child transmission via breastmilk), the substudy measured antiretroviral concentrations in maternal plasma, breastmilk and infant DBS in 67 mother and infant pairs. There were 153 paired plasma and breast milk samples and 191 DBS samples.
The investigators performed PK modelling using the NONMEM programme. They developed a semi-physiologic population model to describe maternal plasma and breast milk concentrations simultaneously. These were linked with infant feeding times in order to estimate breast milk NVP concentrations at the time of feeding. In turn these breast milk concentrations were used to estimate NVP doses for the infant PK model of DBS concentrations.
Liquid chromatography mass spectrometry was used to measure NVP concentrations in the samples. The limits of quantification of the assay were 17ng/mL for plasma and breast milk, 40ng/mL for DBS and 43ng/mL for NVP. The analysis found maternal plasma NVP PK parameters were stable during the study period. Breast milk and plasma NVP concentrations reached equilibrium rapidly, relative to elimination, providing relatively stable breast milk: plasma ratio with breast milk concentrations above the IC50 throughout the dosing interval.
The investigators reported an overall population NVP breast milk: plasma of 0.74. The typical estimated PK parameters for infants were: CL/F 0.0265 (±0.003)L/h/kg and V/F 0.97 (±0.125) L/h/kg. CL/F among infants increased with age giving lower median DBS concentrations at 14 weeks (717ng/mL) compared to 2-6 weeks of age (1005ng/mL).
They concluded that infant NVP exposure via breastfeeding achieves prophylactic concentrations as seen in the first weeks of age with PMTCT dose (2mg/kg). They noted that, NVP breast milk concentrations rapidly equilibrate with maternal system concentrations and while slightly lower than plasma were well in excess of therapeutic NVP concentrations. Also that the variability in both maternal and infant NVP elimination contributes more to infant exposure than NVP the breast milk:plasma ratio variability.
Capparelli et al. Population pharmacokinetic model of nevirapine (NVP) maternal to infant transfer through breastfeeding. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Abstract 0_18.