Track: Clinical Pharmacology - Chemical - Modeling and Simulation - Physiologically Based Pharmacokinetics (PBPK) Model
Category: Poster Abstract
Investigation of the Oral Absorption of Azithromycin in Adults and Paediatrics Based on PBPK Modeling
Purpose: Azithromycin is an antibiotic listed in the essential list of medicines for adults and paediatrics. Conflicting evidence has been found regarding azithromycin BCS classification. The purpose of this study, performed under PEARRL (Pharmaceutical Education And Research with Regulatory Links, www.pearrl.eu), was to identify the critical variables that influence the oral absorption of azithromycin in adults and paediatrics. Methods: Solubility studies for azithromycin (dehydrate) were conducted in biorelevant media (adult and paediatrics) and Pharmacopoeia buffers. Initial gastric volumes for paediatrics were calculated according to body weight (BW) and body surface area (BSA) extrapolation methods. Dose number values were calculated for adults and paediatrics to assess the risk of changes in solubility classification from adults to paediatrics. Biorelevant age-appropriate dissolution studies for the immediate-release formulation of azithromycin (dehydrate) (Zithromax®, Pfizer, UK) were performed using the USP 4 apparatus (Erweka®, UK) in open-mode with sequential media change from gastric to intestinal simulated conditions. A physiologically based pharmacokinetic (PBPK) model was built with the SimCYP® software (Certara®, US). A middle-out approach was followed. Simulations of the intravenous and oral administration of azithromycin were carried out using the SimCYP® healthy volunteer and paediatric populations in the fasted or fed state. For the simulation of the oral administration of azithromycin, the ADAM model was used. Two approaches were investigated: 1) the impact of biorelevant solubility with the Diffusion Layer Model (DLM), and 2) the impact of biorelevant in vitro dissolution. Passive permeability was predicted for all intestinal segments (Peff,man of 1.33 x10-4 cm/s) with the MechPeff model in SimCYP®. The influence of intestinal P-glycoprotein (P-gP) was assessed. After building and validating the PBPK model for healthy adults for intravenous and oral administration, the paediatric model was built and validated. Oral administration was simulated for two age-groups: young children and infants (0.5 to 5 years) and old children and adolescents (6 to 15 years). Model predictability was assessed by the absolute average fold error (AAFE) [AAFE ≤ 2: acceptable prediction]. Parameter sensitivity analysis (PSA) of gastric emptying time, dose, solubility, and permeability was performed to define the critical variables of azithromycin absorption. Results: Azithromycin solubility ranged from 2.5 mg/mL to 15 mg/mL in all media tested. Higher solubility in acidic media (pH 1.2 - 1.6) was observed in comparison to more basic media (pH 6.5 - 6.8) based on azithromycin ionization properties (weak base, pKa = 8.6). Differences in solubility between buffers and biorelevant media were observed due to the presence of bile salts in the latter. Buffer capacity and ionic strength impact azithromycin solubility as can be revealed by the low solubility in FaSSIF. A change in the solubility classification from adults to paediatrics was seen when the dose number was calculated with biorelevant solubility and initial paediatric gastric volume calculated with the BW extrapolation approach. In vitro dissolution of azithromycin from the suspension was complete and rapid ( > 85% dissolved in 60 minutes) in both fasted and fed states for all the age-groups. Azithromycin plasma concentrations of Zithromax® oral suspension in adults and paediatrics in the fasted and fed state were successfully predicted with the PBPK model (AAFE< 2). The solubility based- and the dissolution based- ADAM models led to similar predictions. Based on the sensitivity analysis azithromycin’s solubility in the gastrointestinal fluids is not the rate-limiting step for its absorption for the whole therapeutic dose range in both adults and paediatrics. This finding sheds light on the BCS classification of azithromycin in terms of solubility, suggesting that it is a highly soluble compound. Permeation through the intestinal membrane, both passive and active transport, controls the absorption of azithromycin in both adults and paediatrics. The absorption process is similar in the paediatric age-groups investigated in this study compared to adults as passive and transport mediated processes are similar in these populations. Conclusion: The PBPK modeling approach revealed that permeation through the gut wall is the key driver of azithromycin oral absorption in both adults and paediatrics. This physiologically based approach is useful to determine the factors controlling drug’s absorption and assess the risk of alterations of the rate-limiting steps of absorption in the paediatric population.