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http://www.ingentaconnect.com/content/mksg/liv/2009/00000029/00000008/art00008

Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver

transplant recipients

Authors: Terrault, Norah A.1; Tran, Tram T.2; Schiff, Eugene3; McGuire, n

M.4; Brown, S.5; Tupper, 6; Ramanathan, Srini6; Enejosa, 6;

Zhong, Lijie6; Zong, Jian6

Source: Liver International, Volume 29, Number 8, September 2009 , pp.

1178-1183(6)

Publisher: Blackwell Publishing

Abstract:

Background:

Adefovir dipivoxil has activity against wild-type and lamivudine-resistant

hepatitis B virus (HBV) and is frequently used to manage HBV infection in

transplant recipients. Calcineurin inhibitors are a central component of

immunosuppressive therapy.

Aims:

Study GS-02-531 was an open-label, multicentre drug interaction trial to examine

potential drug interactions between adefovir and tacrolimus in stable

post-transplant recipients.

Materials and Methods:

Sixteen non-HBV-infected post-transplant recipients with median age 45.5 years

(69% male, 44% Caucasian, 50% Hispanic and 6% Black) and stable hepatic and

renal function on a stable daily dose of tacrolimus (2-10 mg total daily dose)

were studied before (tacrolimus alone) and after co-administration of adefovir

10 mg daily for 14 days (Days 1-14). Pharmacokinetic (PK) analyses utilized

non-compartmental methods.

Results:

The median elimination half-life of tacrolimus was 14.47 and 12.59 h for Day 0

and Day 14 respectively. The geometric mean ratios for tacrolimus on Day 14 vs

Day 0 were 105.2% [90% confidence interval (90% CI): 89.8-123%] for Cmax and

106.4% (90% CI: 92.9-122%) for AUCtau. Both 90% CIs for the ratios were

contained within the predefined lack of interaction bounds of 80 and 125% (i.e.

within the bounds for the equivalence assessment), indicating that these PK

parameters of tacrolimus are not significantly altered by co-administration of

adefovir. Similarly, the observed adefovir PK parameters after 14 days of

co-administration with tacrolimus were comparable to historical data in

non-transplant patients receiving adefovir alone. Serum creatinine values were

stable during the study period.

Conclusion:

There is no significant PK interaction between tacrolimus and adefovir

co-administered to liver transplant recipients for 14 days.

Document Type: Research article

DOI: 10.1111/j.1478-3231.2009.01998.x

Affiliations: 1: Department of Medicine and Surgery, University of California

San Francisco, San Francisco, CA, USA 2: Division of Gastroenterology and

Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA,

USA 3: Department of Internal Medicine, University of Miami, Miami, FL, USA 4:

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

5: Department of Medicine, Columbia University College of Physicians & Surgeons,

New York, NY, USA 6: Gilead Sciences, City, CA, USA