2007 - København - Denmark

PAGE 2007: Applications- Biologicals/vaccines
Armel Stockis

Population pharmacokinetics of certolizumab pegol

Etienne Pigeolet(1), PhilippeJacqmin(2), Maria Laura Sargentini-Maier(1), G. Parker(1) and Armel Stockis(1).

(1) UCB Pharma, Braine l'Alleud (Belgium) and Slough (UK); (2) Exprimo, Lummen (Belgium).

Objectives: Certolizumab pegol (CZP) is a pegylated Fab´ fragment of a humanized anti-TNF antibody.  The aim of the analysis was to identify demographic and physiologic determinants of the disposition of CZP, in Crohn's Disease (CD) patients.

Methods: We evaluated 10275 plasma concentration-time records from 1580 subjects of whom 80% were patients with Crohn's disease, 15% rheumatoid arthritis and 5% healthy subjects. The structural model was a two compartment model with mixed order (between 0 and 1) absorption and first order elimination rates, and inter-occasion variability on clearance. Modeling was performed using NONMEM V.

Results: Typical clearance was 0.428 L/day and distribution volume 4.0 L in a 70 kg subject. Age, gender, creatinine clearance, white blood cells count and concomitant drug treatment such as steroids, amino-salicylic acid and analogs or anti-infectives did not influence the pharmacokinetics of CZP. Anti-CZP antibodies, repeated administration, weight, monocyte count, immunosuppressant intake and ethnicity had a statistically significant effect on the pharmacokinetic model.  Simulations from the final model showed that, at steady state, only the presence of anti-CZP antibodies had a more than 30% effect on Cmax and AUCtau.  However, these were detected in only 8% of the patients and did not appear to influence the efficacy endpoint (CDAI score). Doubling body weight, the second most influential covariate, was associated with a 25 % and a 20% decrease in Cmax and AUCtau , respectively.

Conclusions: Amongst the numerous covariates tested for their contribution to the pharmacokinetic variability of CZP, none of them seemed to have a clinically relevant impact.

Reference: PAGE 16 (2007) Abstr 1094 [www.page-meeting.org/?abstract=1094]
Poster: Applications- Biologicals/vaccines