Ingrid Ottevaere (1), Massimiliano Germani (1), Eline Vanheule (1), Laura Sargentini (1)
(1) Ablynx, Zwijnaarde, Belgium
Objectives: The anti-RSV Nanobody ALX-0171 is developed as a nebulizer solution to enable direct treatment at the site of RSV infection. The aim of the study was to characterize the pharmacokinetics (PK) of ALX-0171 in a healthy adult population after oral inhalation or intravenous (i.v.) administration.
Methods: Population PK analyses were performed on data from 2 clinical studies, including a total of 85 healthy volunteers. Subjects were either treated i.v. or via oral inhalation with ALX-0171. Plasma concentration data obtained after i.v. administration and inhalation were modeled simultaneously. A standard bi-compartment model with first-order absorption was compared with a transit compartment model [1] or a model describing different absorption rate constants, representing the absorption process of the nebulized particles at different levels of the respiratory tract [2].
Results: PK of ALX-0171 in healthy volunteers was consistent with a bi-compartmental disposition, with first-order absorption and linear clearance from the central compartment. Implementation of transit compartments [1] or different absorption rate constants [2] did not result in a clear improvement of the goodness of fit of the inhalation data. Concentration-time profiles indicated different terminal half-lives after inhalation as compared to i.v. administration, consistent with flip-flop kinetics. The inter-individual variability in the population PK parameters was limited, and body weight and creatinine clearance were identified as covariates on absorption rate and clearance respectively.
Conclusions: The PK of the inhaled Nanobody ALX-0171, described using the standard bi-compartmental model, is consistent with prolonged lung exposure and limited systemic exposure and is in line with the expected PK properties, warranting further clinical development of inhaled ALX-0171 for treatment of RSV infection in infants.
References:
[1] Savic R, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. Journal of Pharmacokinetics and Pharmacodynamics Volume 34, Issue 5, pp 711-726.
[2] Borghartd J, Staab A, Kunz C, Schiewe J, Kloft C. Characterization of different absorption rate constants after inhalation of olodaterol. PAGE 22 (2013) Abstr 2895.
Reference: PAGE 23 (2014) Abstr 3114 [www.page-meeting.org/?abstract=3114]
Poster: Drug/Disease modeling - Infection