Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

Abstract

AIMSEvidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy. METHODSTwo paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in NONMEM® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin. RESULTSA one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Preterm birth is associated with high morbidity and mortality resulting in a high demand for drug therapy.• Clinical evidence suggests that the oral absorption process of a drug undergoes substantial changes after birth. The impact of these physiological changes on oral drug therapy is currently unclear. WHAT THIS STUDY ADDS• This study improves our understanding of changes in oral drug absorption in preterm neonates for two drugs from both BCS class I and BCS class II.• Our findings indicate that these changes in oral absorption within the first few days after birth are a system-specific property, which can be used to guide oral dosing of BCS class I and BCS class II compounds in preterm neonates.

Lyophilized Drug-Loaded Solid Lipid Nanoparticles Formulated with Beeswax and Theobroma Oil

“…Thus, lyophilization did not affect drug release from the 1:1 beeswaxtheobroma oil SLN composite matrix and drug release is likely to remain identical between the fresh and lyophilized formulations following administration. The lower release rate of AMB and SSZ from the SLNs is consistent with the fact that AMB [32] and SSZ [33] are class IV drugs (low aqueous solubility and low membrane permeability) according to the biopharmaceutics classification system, whereas PAR is assigned to class I [34] due to its high aqueous solubility and high membrane permeability. The drug release data show that most of the PAR is likely to be released from the SLNs in aqueous/biological media, whereas there is likely to be significant retention of AMB and SSZ within the SLNs prior to absorption after administration.…”

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

“…Based on clinical literature data of selected compounds after iv and oral dosing, Somani et al performed a population PK analysis to evaluate changes in oral drug absorption postnatally. They concluded that the maturational changes in oral drug absorption occur within the first week after birth and are drug-independent (Somani et al, 2016). Besides drug administration by oral route, also nonenteral routes might be used.…”

Making Medicines Baby Size: The Challenges in Bridging the Formulation Gap in Neonatal Medicine

“…This is further exacerbated in preterm neonates, where issues around swallowing and ADME (absorption, distribution, metabolism, and excretion) factors may be less well understood. Clinical evidence suggests, that the oral absorption process of a drug undergoes substantial changes after birth [35,36]. The impact of these physiological changes on oral drug therapy is currently unclear.…”

“…Clinical examples of differences in absorption in neonates compared to adults are scarce. Recent work suggested that the processes underlying changes in oral drug absorption rate typically reach adult levels within one week of birth [35].…”