Background: REFRESH is a 2-part Phase 2b, open-label clinical study assessing safety, efficacy, and pharmacokinetics (PK) of telaprevir (T) in combination with peginterferon alfa-2a (P) and ribavirin (R) in noncirrhotic liver transplant patients (pts) with recurrent genotype 1 hepatitis C virus (HCV). Tacrolimus (TAC) and cyclosporine (CsA) are metabolized by CYP3A; coadministration with T, a CYP3A inhibitor, increases TAC and CsA exposure in healthy volunteers. In this interim analysis, PK of T, R, TAC or CsA when coadministered are reported in initial cohort (n=23).

Methods: Pts were on stable doses of TAC or CsA prior to therapy and received T 1125 mg BID + P 180 ug/wk + R 600 mg/day (initial dose) for 12 wks plus 36 wks of PR (no lead-in). Initial post-T TAC or CsA dose was reduced ∼10- (min. dose 0.5 mg) and ∼4-fold from baseline, respectively. Further dosing guided by TAC or CsA levels Days 1-5, 7, 10 and Wks 2, 3, 4, 6, 8, 10, 12 (investigator discretion). Intensive PK analysis for T performed Wk 4 (n=13). Random blood samples collected at Wk 4 for R.

Results: Drug PK parameters are summarized in table. Three pts initiated R at 1200 mg/day, above protocol-specified dose; 2/3 had supratherapeutic R levels and developed Grade 3/4 anemia. R was reduced in 7 pts (including all 3 who started at 1200 mg) and increased in 3.

Conclusions: In initial subset of liver transplant pts, target levels of telaprevir were achieved (1125 mg BID). Target levels of R were achieved (initial dose 600 mg QD) with adjustments as necessary. When coadministered with telaprevir, TAC requires greater adjustment in dose and dosing interval than CsA.

Vargas, H.: Grant/Research Support, Vertex Pharmaceuticals Incorporated, Janssen/Tibotec, BMS, Novartis, Merck, Gilead. Dai, Y.: Employee, Vertex Pharmaceuticals Incorporated, Stockholder, Vertex Pharmaceuticals Incorporated. Brown, K.: Grant/Research Support, Exenenz, Speaker’s Bureau, Vertex Pharmaceuticals, Merck, Gilead, Other, Salix, Consultant, BCBS Transplant Centers, Consultant. Russo, M.: Grant/Research Support, Vertex Pharmaceuticals Incorporated, Speaker’s Bureau, Vertex Pharmaceuticals Incorporated. Yoshida, E.: Other, Vertex Pharmaceuticals Incorporated, CME Honouraria, Vertex Pharmaceuticals Incorporated, Clinical Trial Investigator, Janssen Inc. Clinical Trial Investigator, Vertex Pharmaceuticals Incorporated, Ad Board Honoraria. Fontana, R.: Grant/Research Support, Vertex Pharmaceuticals Incorporated, Gilead, Ocera, Other, Tibotec, Consultant, GSK, Consultant, Merck, Consultant. Levitsky, J.: Speaker’s Bureau, Vertex Pharmaceuticals Incorporated, Genentech. Rubin, R.: Employee, Vertex Pharmaceuticals Incorporated, Stockholder, Vertex Pharmaceuticals Incorporated. Garg, V.: Employee, Vertex Pharmaceuticals Incorporated, Stockholder, Vertex Pharmaceuticals Incorporated. Brown, R.: Other, Vertex Pharmaceuticals Incorporated, Consultant.

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