A PB-PK model to explore ALX-0171 PK in infants following inhalation

Transcription

1 A PB-PK to explore ALX-0171 PK in infants following inhalation Massimiliano Germani 27 th Nov Nanobodies - Inspired by nature

2 Background Respiratory syncytial virus (RSV): respiratory tract infections leading to pneumonia and bronchiolitis, especially in very young children ALX-0171 is a Nanobody (Nb) composed of 3 heavy chain variable region (VHH) domains providing avid binding to RSV and potently inhibits viral replication ALX kD ALX-0171 is delivered directly to the lungs through a mesh nebulizer, allowing to achieve a fast onset of action and high concentration at the site of infection 2

3 Objective The primary goal was to estimate a dose resulting in a target concentration, derived from in vitro assays and supported by pre-clinical studies, that potently inhibits viral replication in the alveolar space of RSV infected infants. 3

4 PB-PK inhalation for paediatric patients Different route of administration IV bolus or infusion Oral dose IM dose Inhalation... Different species Specific condition Project specific target tissues

5 Targeting the deep lung The standard PK-Sim for biologics has been extended with the inclusion of the alveolar lining fluid (ALF compartment) Exchange between ALF and cells of the lung via active (carriermediated) or passive (diffusion) permeation Direct transport from ALF to interstitium 5

6 PB-PK approach for dosing estimation RESPIRATORY SYSTEM SYSTEMIC CIRCULATION+EXCRETION DEVICE MPPD, Multiple-Path Particle Dosimetry Model (Centers for Health Research, USA and National Institute of Public Health and the Environment, Netherlands). Regional deposition depends on: Lung morphology (age specific) Particle properties (size and density) Breathing pattern (frequency, volume, ) PB-PK (PK-Sim by Bayer Tec.). 6

7 PB-PK approach for dosing estimation inhaled dose nominal dose delivered dose deposited dose Fraction deposited nebulizer characteristics and performance (efficiency) 7

8 PB-PK: beyond simple allometry A gallery of (PK) s: same object, different views! Empirical Compartmental Physiological

9 PB-PK: beyond simple allometry A gallery of (PK) s: same object, different views! Empirical Compartmental Physiological Learn and confirm process from in silico/in vitro to diseased children

10 Learn and confirm process: a multi-step approach to determine ALX-0171 paediatric dose rat dog Target concentration rats and dogs healthy adult humans pediatric diseased pediatric 10

11 Learn and confirm process: a multi-step approach to determine ALX-0171 paediatric dose ALFconcentration after inhalation Plasma concentration after IV Plasma concentration after inhalation Cumulative fraction excreted in urine after IV Target concentration rats and dogs healthy adult humans pediatric diseased pediatric 11

12 Learn and confirm process: a multi-step approach to determine ALX-0171 paediatric dose Model simulations after inhalation including variability in healthy adults Target concentration rats and dogs healthy adult humans pediatric diseased pediatric 12

13 Learn and confirm process: a multi-step approach to determine ALX-0171 paediatric dose Lamb study Confirm the target concentration derived in vitro Bridge between uninfected and infected Target concentration rats and dogs healthy adult humans pediatric diseased pediatric Preclinical studies Phase I studies 13

14 Scaling the PB-PK to children No trend in total lung deposition in the age range under study (3 months to 2 years) reported in literature Based on current data, no impact expected of RSV infection on PK: Deposition might be lowered due to changed breathing pattern and airway diameters Alveolar absorption rate modified by edema/change in alveolar permeability: - increased alveolar permeability (Kilani 2004, Singh 2007) leading to an increased absorption rate - decreased alveolar drug concentration due to edema (Domachowske1999, Johnson 2007) leading to a decreased absorption rate No different PKs observed in preclinical RSV infection in lamb Absorption, distribution and clearance were scaled according to the different anatomo-physiologic parameters in paediatrics

15 Fraction Deposited Fraction deposition (as percentage of inhaled dose in alveolar space) was estimated using MPPD tool. Age specific lung : 3 months, 21 months, 23 months and 28 months. Fraction deposited in alveolar space depends on device, breathing maneuver, particle size distribution and age Normal/healthy breathing parameters default used in the MPPD Table from R. De Winter-Sorkina and F.R. Cassee, RVIM report /2002 Distressed breathing patterns for RSV patients based on literature data 15

16 Sensitivity analysis Sensitivity analysis for the key parameters: fraction deposited in the alveolar space clearance (rate constant of the additional plasma clearance process) alveolar permeability thickness of the alveolar space hydrodynamic drug radius. The sensitivity coefficients sc were calculated as follows (Y: PK index, e.g. Cmax, AUC; X i : parameter i. sc i Y X i X Y i 16

17 Sensitivity analysis 17

18 Dose estimation for First in Infant study Assumptions: PK-Sim population with standard variability of anthropometric and physiological parameters (e.g. organ volumes, blood flows, GFR) Lognormal distribution of alveolar permeability: Lognormal distribution of fraction of dose deposited in alveolar space (referring to inhaled dose) Trial simulations: Once daily inhalation for 3 days PB-PK population simulations for pediatric age groups to estimate a dose for reaching or exceeding the predefined alveolar target concentration in 95% of the individuals 18

19 Predicted concentration in plasma and ALF 19

20 Conclusions A PB-PK of ALX-0171 in adult humans for pulmonary administration was established based on pre-clinical as well as clinical data. The provides a good description of the plasma and lung data (both the typical behavior and the variability) in pre-clinical as well as in clinical in adult healthy volunteers. This was scaled to infants with RSV infection to simulate the systemic and local PK of ALX-0171 in patients aged from 5 months to 2 years. PB-PK population simulations for predefined paediatric age groups were performed to estimate a dose that would reach or exceed the predefined alveolar target concentration for 95% of the individuals: Lung concentrations can be derived via systemic concentrations Local and systemic safety margin has been defined based on predicted concentrations 20