Pharmacokinetics of tacrolimus and cyclosporine in liver transplant recipients receiving 3 direct-acting antivirals as treatment for hepatitis C infection.
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Study Design
The effect of paritaprevir/ritonavir/ombitasvir + dasabuvir (ABT-450/r/ABT-267 + ABT-333, also known as DAAs) on the pharmacokinetics (PK), safety and tolerability of tacrolimus was assessed in 72 healthy subjects.
In period 1, tacrolimus 2mg was administered on day 1 followed by a 14-day washout period. In period 2, agents were given as follows: days 1-14: DAAs alone; day 15: tacrolimus + DAAs; and days 16-28: DAAs alone.
Administration combinations in period 2 were varied between three different arms.
Arm 1: paritaprevir/ritonavir 150/100mg QD + dasabuvir 400mg BID with tacrolimus 0.5mg single dose;
Arm 2: paritaprevir/ritonavir 150/100mg QD + ombitasvir 25mg QD, with tacrolimus 0.5mg single dose;
Arm 3: paritaprevir/ritonavir 150/100mg QD + dasabuvir 400mg BID + ombitasvir 25mg QD, with tacrolimus 2mg single dose.
PK sampling of tacrolimus and/or DAAs was performed on day 1 in perdiod 1, and on days 1, and 14-21 in period 2.
Study Results
The magnitude of interaction between the DAAs and tacrolimus was found to be comparable across all 3 arms. On day 15, a 57-86 fold increase in dose-normalized AUC of tacrolimus was noted, as was a 3.7-4.3 fold increase in Cmax, compared to administration of tacrolimus alone.
Paritaprevir, ritonavir and dasabuvir exposures decreased by 11-51%, while those for ombitasvir were not affected.
The effect (LSM Ratio) of cyclosporine on the DAAs was as follows
(all of the 90% confidence intervals fell within the bounds of 0.5-2, except the upper limit of paritaprevir C24)*:1,2
Cmax AUC C24
Paritaprevir 1.44 (1.16, 1.78) 1.72 (1.49, 1.99) 1.85 (1.58, 2.18)
Ritonavir 0.90 (0.78, 1.04) 1.11 (1.04, 1.19) 1.49 (1.28, 1.74)
Ombitasvir 0.99 (0.92, 1.07) 1.08 (1.05, 1.11) 1.15 (1.08, 1.23)
Dasabuvir 0.66 (0.58, 0.75) 0.70 (0.65, 0.76) 0.76 (0.71, 0.82)
*Data from Phase 2 studies indicate that a 50% decrease in exposure or a 100% increase in exposures did not meaningfully affect safety or efficacy.1
Study Conclusions
Based on simulations of concentration-time profiles to predict dose frequencies that would provide optimal tacrolimus levels, the authors recommend total daily dose adjustment of tacrolimus to approximately 0.5mg per week or 0.2mg every 3 days when coadministered with the 3D regimen, to maintain trough levels similar to pre-DAA troughs. Close clinical monitoring of tacrolimus is warranted when this combination is utilized.
No dose adjustment for DAAs is recommended when dosed with cyclosporine.
The effect of co-adminstering the DAAs with cyclosporine resulted in a 3-fold increase in the half-life of cyclosporine.
When initiating therapy with these DAAs (VIEKIRA PAK), reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
References
Badri PS, Parikh A, Coakley EP, Bing B, Awni WM, Dutta S, Menon RM. Pharmacokinetics of tacrolimus and cyclosporine in liver transplant recipients receiving 3 direct-acting antivirals as treatment for hepatitis c infection. Therapeutic Drug Monitoring. 2016; 5: 640-645.
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