PB0789 - Impact of age on in vitro metabolism of clopidogrel: a potential explanation for high on-treatment platelet reactivity in elderly?

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

AP

Adeline PONTIS

Clinical pathologist
Department of Biological Hematology, Pontchaillou, University Hospital of Rennes, Institut de recherche en santé, environnement et travail - IRSET, Inserm UMR_S 1085, Univ Rennes, CHU Rennes, France
Rennes, Bretagne, France

Co-Author(s)

XD

Xavier Delavenne

PharmD, PhD
Department of Pharmacology, Saint-Etienne University Hospital, INSERM, UMR_S1059, University of Lyon, Saint-Etienne, France
Saint-Etienne, Centre, France
MV

Marie-Clémence VERDIER

Clinical pathologist
Laboratory of Clinical Pharmacology, University Hospital of Rennes, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, University of Rennes, France
Rennes, Bretagne, France
SH

Sophie HODIN

Engineer
INSERM U1059, Jean Monnet University of Saint-Etienne, France
Saint Etienne, Bretagne, France
AA

Annie ANDRIAMAHARO

Master student
University of Rennes, France
Rennes, Bretagne, France
PG

Pierre Gueret

MD, PhD
Department of Hematology/Hemostasis, Pontchaillou University Hospital of Rennes, Rennes, France
Rennes, Bretagne, France
FN

Fabienne Nedelec-Gac

PharmD
Department of Hematology/Hemostasis, Pontchaillou University Hospital of Rennes, Rennes, France
Rennes, Bretagne, France
PG

Pascale Gaussem

Professor
Université Paris Cité, INSERM U1140, Innovative Therapies in Haemostasis, France
Paris, Ile-de-France, France
CB

Christilla Bachelot-Loza

Researcher INSERM
Université Paris Cité, INSERM U1140, Innovative Therapies in Haemostasis, France
Paris, Ile-de-France, France
Isabelle Gouin-Thibault, Sr., PhD

Head of hemostasis department
Department of Hematology/Hemostasis, Pontchaillou University Hospital of Rennes, Univ Rennes, Irset - Inserm UMR_S 1085, Rennes, France.
Rennes, Bretagne, France

Background: High on-treatment platelet reactivity (HTPR) exits in about 30% of patients on clopidogrel and has been associated with an increased risk of cardiovascular events. Interestingly, this HTPR reaches 50% in elderly patients (≥70), but little is known on the mechanism of this resistance. One hypothesis is an age-related impaired hepatic metabolism of the prodrug clopidogrel, leading to a lower formation of its active metabolite (clopidogrel-AM).

Aims: To compare levels of clopidogrel-AM formed in vitro using “old” and “young” human liver microsomes (HLMs) and their consequences on platelet functions.

Methods: An in vitro model was developed using “young” (mean age=51.28.5y) and “old” (mean age=73.62.3y) HLMs. “Young” or “old” HLMs, in an incubation/reaction mixture, were added to a citrated platelet-rich plasma from healthy donors (1:1) in the presence or not of clopidogrel (50µM) and incubated at 37°C for 30 (T30) and 45min (T45).
Clopidogrel-AM was quantified by a validated LC MS/MS method (lower limit of quantification: 0.8 ng/mL).
Platelet aggregation was performed by light transmission aggregometry (LTA) at each incubation time.

Results: The generation of clopidogrel-AM was time-dependant and concentrations were comparable to those observed in treated patients. At T30, the mean concentration of clopidogrel-AM was significantly higher with “young” HLMs 8.56µg/L, 95%CI[5.87-11.24] than with “old” HLMs 7.64µg/L, 95%CI[5.14-10.14] (p=0.002) (n=21). Similar differences were found at T45: 11.40µg/L, 95%CI[7.57-15.22] and 10.63µg/L, 95%CI[7.10-14.15] with “young” and “old” HLMs (p=0.016), respectively(figure 1).
Despite a significant inhibition of platelet aggregation, no significant difference was found in LTA (ADP 10µM) after clopidogrel metabolism by “old” or “young” HLMs, probably due to a low sensitivity of the method to detect significant but small variations of clopidogrel-AM.

Conclusion(s): In this original model combining metabolic and functional approaches, less clopidogrel-AM was systematically produced with older HLMs. This provides support for a decreased in CYP450 activity that may contribute to HTPR in elderly patients.