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Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection

Badri, Prajakta S. PhD; Parikh, Apurvasena PhD; Coakley, Eoin P. MD; Ding, Bifeng MS; Awni, Walid M. PhD; Dutta, Sandeep PhD; Menon, Rajeev M. PhD

doi: 10.1097/FTD.0000000000000315
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Background: Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study.

Methods: A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration–time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized.

Results: A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9–6.5 ng/mL versus 5.2 ng/mL; 4.2–6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6–9 ng/mL, 4–6 ng/mL, and 6–10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94–140 ng/mL versus 104 ng/mL; 82–140 ng/mL).

Conclusions: Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.

Departments of *Clinical Pharmacokinetics and Pharmacodynamics;

Infectious Disease Development; and

Biometrics, AbbVie Inc, North Chicago, Illinois. E. P. Coakley is now with Alnylam Pharmaceuticals, Cambridge, Massachusetts.

Correspondence: Rajeev M. Menon, PhD, Clinical Pharmacokinetics and Pharmacodynamics, Bldg. AP31-3, 1 N Waukegan Rd, North Chicago, IL 60064 (e-mail: rajeev.menon@abbvie.com).

The study was sponsored by AbbVie Inc. AbbVie contributed to the study design, research, interpretation of data, and the writing, reviewing, and approving of the manuscript for publication. All authors are employees or former employees of AbbVie and may hold AbbVie stock or stock options.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.drug-monitoring.com).

Received January 12, 2016

Accepted April 28, 2016

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.