V. Piotrovsky(1), G. Kopia(2), G.W. Vetrovec(3), D. Rizik(4), David Snead(2)
(1)J&J Pharmaceutical Research & Development, Beerse, Belgium; (2)Cordis Corporation, Warren, NJ; (3)MCV Hospitals at VCU Health Systems, Richmond, VA; (4)Scottsdale Heart Group at Scottsdale Health Care, Scottsdale, AZ
Objectives: The Bx Velocity, sirolimus-eluting balloon-expandable stent has shown remarkable results in terms of reducing the occurrence of in-stent restenosis following coronary intervention. The current work was aimed to elucidate the sirolimus (SL) pharmacokinetics in patients with de novo coronary artery lesions.
Methods: Two PK trials were conducted in the United States (19 patients) and in Japan (20 patients). After implantation of one or two stents (149.4 – 177.7 mcg SRLM/stent), blood samples were collected serially and assayed for SL using a validated liquid chromatography method. NONMEM V software and the first-order conditional estimation method was used to fit mixed-effects models to concentration-time data.
Results: The structural model was based on animal data and mechanistic considerations. It assumed two-compartment (CMT) linear disposition of SL and included also the stent CMT and the artery tissue CMT. The fraction F of the total drug amount is released from the stent CMT to the blood stream. The rate is controlled by the rate constant Ksb (h-1). The rest of the drug (1-F) is released to the artery tissue with the rate constant Ksa (h-1). From the artery the drug is transferred to blood (Kab, h-1). Other parameters are listed below:
CL: Total blood clearance, L/h
Vc: Volume of the central CMT, L
Vp: Volume of the peripheral CMT, L
Q: Inter-CMT exchange flow, L/h
The model provided a good fit. Structural PK parameters were well defined. In a typical patient of 77 kg body weight, CL was 1.3 L/h (5.3) and Q 0.67 L/h (20), both increased with body weight. In parentheses standard errors of estimates expressed as % CV are given. Ksa differed between studies: it was 0.0039 h-1 (12) and 0.0064 h-1 (8) in the US and Japan studies, respectively. The remaining parameters did not depend on patient characteristics: Vc was 0.22 (20), Vp 59 L (27), F 0.091 (18), Ksb 0.051 h-1 (11), and Kab 1.8 h-1 (15), respectively. Random inter-individual variability could be estimated in CL (18% CV), Vc (49), Vp (86), and Q (34) only. SL terminal half-life (T1/2) was assessed via simulation using individual Bayesian parameter estimates. It was found to be substantially longer (210 and 150 h in the US and Japan studies, respectively) than after oral SL administration (62 to 82 h, literature data).
Conclusion: SL-eluting stent releases more than 90% of the drug directly to the artery tissue, and T1/2 is controlled by the release rate. As predicted by the model, at 168 h since implantation (the last sampling time), approx. 50% of SL still persists in the artery.
Reference: PAGE 13 (2004) Abstr 487 [www.page-meeting.org/?abstract=487]
Poster: poster