Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection. Issue 5 (October 2016)

• Record Type: Journal Article
• Authors: Badri, Prajakta S.; Parikh, Apurvasena; Coakley, Eoin P.; Ding, Bifeng; Awni, Walid M.; Dutta, Sandeep; Menon, Rajeev M.
• Is Part Of: Therapeutic drug monitoring. Volume 38:Issue 5(2016:Oct.)
• Publication Date: 2016-10
• Subjects: calcineurin inhibitors -- ombitasvir -- paritaprevir -- dasabuvir -- liver transplant; Pharmacokinetics -- Periodicals; Patient monitoring -- Periodicals; Drugs -- Analysis -- Periodicals; Body fluids -- Analysis -- Periodicals; Drug Therapy -- Periodicals; Monitoring, Physiologic -- Periodicals; Pharmacology -- Periodicals; 615.7
• DOI: 10.1097/FTD.0000000000000315
• Languages: English
• ISSNs: 0163-4356

Abstract

Abstract : 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 ( C trough ) 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 C trough 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 C trough 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 C trough 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 C trough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in C trough levels of 6–9 ng/mL, 4–6 ng/mL, and 6–10 ng/mL, respectively, during 3D treatment. For CSA, C trough 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. Abstract : Supplemental Digital Content is Available in the Text.