Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver transplant recipients

Norah A. Terrault, Tram T. Tran, Eugene R Schiff, Brendan M. McGuire, Robert S. Brown, Rebecca Tupper, Srini Ramanathan, Jeffrey Enejosa, Lijie Zhong, Jian Zong

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Adefovir dipivoxil has activity against wild-type and lamivudineresistant 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 openlabel, 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.

Original languageEnglish
Pages (from-to)1178-1183
Number of pages6
JournalLiver International
Volume29
Issue number8
DOIs
StatePublished - Dec 1 2009

Fingerprint

Tacrolimus
Pharmacokinetics
Liver
Drug Interactions
Hepatitis B virus
Confidence Intervals
Cercopithecine Herpesvirus 1
Transplant Recipients
adefovir dipivoxil
Virus Diseases
Immunosuppressive Agents
Hispanic Americans
Half-Life
adefovir
Creatinine
Kidney
Serum

Keywords

  • Calcineurin inhibitors
  • Hepatitis B
  • Nucleotide analogues

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver transplant recipients. / Terrault, Norah A.; Tran, Tram T.; Schiff, Eugene R; McGuire, Brendan M.; Brown, Robert S.; Tupper, Rebecca; Ramanathan, Srini; Enejosa, Jeffrey; Zhong, Lijie; Zong, Jian.

In: Liver International, Vol. 29, No. 8, 01.12.2009, p. 1178-1183.

Research output: Contribution to journalArticle

Terrault, NA, Tran, TT, Schiff, ER, McGuire, BM, Brown, RS, Tupper, R, Ramanathan, S, Enejosa, J, Zhong, L & Zong, J 2009, 'Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver transplant recipients', Liver International, vol. 29, no. 8, pp. 1178-1183. https://doi.org/10.1111/j.1478-3231.2009.01998.x
Terrault, Norah A. ; Tran, Tram T. ; Schiff, Eugene R ; McGuire, Brendan M. ; Brown, Robert S. ; Tupper, Rebecca ; Ramanathan, Srini ; Enejosa, Jeffrey ; Zhong, Lijie ; Zong, Jian. / Pharmacokinetics of tacrolimus co-administered with adefovir dipivoxil to liver transplant recipients. In: Liver International. 2009 ; Vol. 29, No. 8. pp. 1178-1183.
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abstract = "Background: Adefovir dipivoxil has activity against wild-type and lamivudineresistant 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 openlabel, 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.",
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AU - Terrault, Norah A.

AU - Tran, Tram T.

AU - Schiff, Eugene R

AU - McGuire, Brendan M.

AU - Brown, Robert S.

AU - Tupper, Rebecca

AU - Ramanathan, Srini

AU - Enejosa, Jeffrey

AU - Zhong, Lijie

AU - Zong, Jian

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N2 - Background: Adefovir dipivoxil has activity against wild-type and lamivudineresistant 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 openlabel, 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.

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KW - Hepatitis B

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