2019 - Stockholm - Sweden

PAGE 2019: Drug/Disease modelling - Infection
Jinju Guk

Modelling the dose-effect relationship between DAV132, an activated charcoal based product, and fecal concentration of moxifloxacin in healthy volunteers

Guk JJ, Guedj J, Burdet C, Andremont A, de Gunzburg J, Ducher A, Mentré F

1. INSERM, IAME, UMR 1137, F-75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, 8 Paris, France 2. Da Volterra, Paris, France

Objectives: The administration of antibiotics leads to disruption of the intestinal microbiota, which plays an important role in various host processes, including resistance to colonization and infection by potentially pathogenic bacteria in the intestines [1,2]. We previously modeled the co-evolution of plasma and fecal concentration of free moxifloxacin, a fluoroquinolone antibiotic, and of microbiota disruption in humans [3]. DAV132 is an oral product which delivers a powerful charcoal-based adsorbent to the late intestine, which reduces free fecal moxifloxacin concentrations in a dose-dependent manner [4,5]. We wished to develop a model of DAV132 effect on free fecal Moxifloxacin concentration using data of a randomized clinical trial where healthy volunteers received orally moxifloxacin alone or with 10 different doses of DAV132.

Methods: A total of 131 healthy volunteers (HVs) were recruited in the randomized clinical trial (Sponsored by Da Volterra) and received oral moxifloxacin (400 mg OAD) for 5 days alone or associated with various DAV132 doses for 7 days: 0 (no DAV132) 2g/d, 3g/d, 6g/d, 10g/d, 15g/d and 22.5g/d (2g/d was given BID, 22.5g/d TID, the other doses BID and TID). Plasma moxifloxacin concentrations were measured at Day 1 and Day 5 and fecal samples were taken daily from Day 1 to Day 9, at Day 12, Day 16 and Day 37 to measure free moxifloxacin concentrations by LC/MS/MS. The previously developed model of plasma and fecal moxifloxacin pharmacokinetics was used to characterize the pharmacokinetic properties of moxifloxacin and its fecal excretion [3]. Several models accounting for DAV132 kinetics in the gastrointestinal tract were studied. The effect of the amount of charcoal in the distal ileum of the large intestine (called the fecal compartment) in reducing the free fecal moxifloxacin was modeled. The analyses were performed using nonlinear mixed effect models and the Stochastic Approximation Expectation-Maximization in Monolix 2018R2 (Lixoft, France).

Results: Plasma concentrations of moxifloxacin were well described by a two-compartment model with two-transit compartment and free fecal moxifloxacin concentrations were successfully explained by a connection to plasma concentrations through two-transit compartments. The elimination of moxifloxacin in feces was modeled as in  [3], but adding a diffusion of moxifloxacin between the last transit elimination compartment and the fecal compartment. DAV132 was modeled with a transit compartment model and charcoal is assumed to be delivered in the fecal compartment. A specific model of the adsorption of charcoal and moxifloxacin in the fecal compartment was derived. This model allowed to describe the huge reduction of free fecal moxifloxacin concentrations when given 7.5 g of DAV132 TID and the low effect of small doses of DAV132.

Conclusions: The developed model was able to capture the delayed effect of moxifloxacin adsorption by charcoal following DAV132 administration and the relationship between DAV132 dose and the reduction in free fecal moxifloxacin concentrations.

[1] Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut  microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A 2011; 108(Suppl 1):4554–61.
[2] Perez-Cobas AE, Gosalbes MJ, Friedrichs A, et al. Gut microbiota disturbance during antibiotic therapy: a multiomic approach. Gut 2013; 62:1591–601.
[3] Burdet C, Nguyen TT, de Gunzburg J, Ferreira S, Ducher A, Duval X, Varastet M, Andremont A, Mentré F. Joint modeling of moxifloxacin pharmacokinetics and fecal microbiota disruption in healthy volunteers. PAGE, 6-9/06/2017, Budapest, Hungary
[4] Ducher A,  Mentré F, Donazzolo Y, Latreille M, Burdet C, Nguyen TT, Varastet M, Sablier F, Augustin V, Hugon P, Ferreira F, Andremont A, de Gunzburg J. Dose-effect and safety of DAV132, an activated charcoal based product, when given with oral moxifloxacin on free moxifloxacin fecal concentrations and intestinal microbiota diversity: A randomized controlled trial in 144 healthy volunteers. ECCMID, 21-24/04/2018, Madrid, Spain
[5] de Gunzburg J, Ghozlane A, Ducher A, et al. Protection of the human gut microbiome from
antibiotics. The Journal of Infectious Diseases. Jan 30 2018;217(4):628-636.

Reference: PAGE 28 (2019) Abstr 8945 [www.page-meeting.org/?abstract=8945]
Poster: Drug/Disease modelling - Infection