Higher clearance of micafungin in neonates compared with adults: role of age‐dependent micafungin serum binding

Abstract

Micafungin, a new echinocandin antifungal agent, has been widely used for the treatment of various fungal infections in human populations. Micafungin is predominantly cleared by biliary excretion and it binds extensively to plasma proteins (>99.5%). Micafungin body weight-adjusted clearance is higher in neonates than in adults, but the mechanisms underlying this difference are not understood. Previous work had revealed the roles of sinusoidal uptake (Na+-taurocholate co-transporting peptide, NTCP; organic anion transporting polypeptide, OATP) as well as canalicular efflux (bile salt export pump, BSEP; breast cancer resistance protein, BCRP) transporters in micafungin hepatobiliary elimination. In the present study, the relative protein expression of hepatic transporters was compared between liver homogenates from neonates and adults. Also, the extent of micafungin binding to serum from neonates and adults was measured in vitro. The results indicate that relative expression levels of NTCP, OATP1B1/3, BSEP, BCRP, and MRP3 were similar in neonates and in adults. However, micafungin fraction unbound (fu) in neonatal serum was about 8-fold higher than in adult serum (0.033 ± 0.012 versus 0.004 ± 0.001, respectively). While there was no evidence for different intrinsic hepatobiliary clearance of micafungin between neonates and adults, our data suggest that age-dependent serum protein binding of micafungin is responsible for its higher clearance in neonates compared to adults.

Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life

“…Stable: In neonates and adults (n = 10, Western blotting), expression was similar (Yanni et al, 2011). In 7-70 yr of age, OATP1B1 (n = 64, LC-MS/MS) protein expression was stable (Prasad et al, 2014 (Burgess et al, 2015).…”

“…From 7 yr of age onward, stable expression (n = 51, LC-MS/MS) (Deo et al, 2012 (Sharma et al, 2013) and in perinatal/neonatal (prenatal to postnatal day 30, n = 6; and 0-4 yr, n = 8) compared with older than 7-yr liver samples (Klaassen and Aleksunes, 2010). Stable: In liver samples of neonates and adults (n = 10, Western blotting), ABCC3 protein expression was stable (Yanni et al, 2011).…”

“…Stable: ABCG2 protein expression was stable in neonates and adult livers (n = 10, Western blotting) (Yanni et al, 2011). And in 7-70 yr of age, ABCG2 (n = 56, LC-MS/MS), protein expression was stable (Prasad et al, 2013).…”

Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People

“…However, expression of NTCP and OATP has been shown to be reduced in animal models of obesity and diabetes (4,24), which would not explain the increased clearance seen in the present study. Another possible mechanism may be the consequence of differences between lean and obese patients with respect to protein binding, analogous to the differences between neonates and adult patients in protein binding (31). It has been demonstrated that there is an 8-fold difference between neonates and adults in micafungin protein binding levels that accounts for differences between these 2 age groups in micafungin clearance.…”

Population Pharmacokinetics of Oral Topotecan in Infants and Very Young Children with Brain Tumors Demonstrates a Role of ABCG2 rs4148157 on the Absorption Rate Constant

“…While the majority of the research has focused on central nervous system and hepatic ABCG2 expression, no difference between adults and term neonates was observed (Daood et al, 2008;Yanni et al, 2011). Therefore, it is unlikely that ontogeny of ABCG2 is playing a role.…”