Liverpool HEP Interactions

Potential Interaction

Ombitasvir/Paritaprevir/r + Dasabuvir

Ciclosporin (Cyclosporine)

Summary:

Ciclosporin is a substrate of CYP3A4. Ciclosporin AUC and Ctrough increases by 5.8-fold and 15.8-fold respectively when coadministered with ombitasvir/paritaprevir/ritonavir + dasabuvir. Give one-fifth of the total daily dose of ciclosporin once daily when coadministered. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.

Description:

Coadministration increased ciclosporin Cmax by 1%, but increased AUC and Cmin by 5.82- and 15.8-fold (ciclosporin 100 mg dosed alone, 30 mg coadministered; dose normalized ciclosporin ratios are shown). Ombitasvir Cmax decreased by 1% but AUC and Cmin increased 8% and 15%. Paritaprevir Cmax, AUC and Cmin increased by 44%, 72% and 85%. Dasabuvir Cmax, AUC and Cmin decreased by 34%, 30% and 24%, respectively. The effect on ciclosporin is due to CYP3A4 inhibition by ritonavir and the increase in paritaprevir exposures may be due to OATP/BCRP/P-gp inhibition by ciclosporin. When starting co-administration, give one fifth of the total daily dose of ciclosporin once daily. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.
Viekirax Summary of Product Characteristics, AbbVie Ltd, January 2015.
Exviera Summary of Product Characteristics, AbbVie Ltd, January 2015.

Coadministration with cyclosporine (30 mg single dose) was studied in 10 subjects and compared to values obtained with cyclosporine (100 mg) alone. Ombitasvir Cmax decreased by 1% but AUC and Cmin increased 8% and 15%. Paritaprevir Cmax, AUC and Cmin increased by 44%, 72% and 85%. Ritonavir Cmax decreased by 10%, but AUC and Cmin increased by 11% and 49%. Dasabuvir Cmax, AUC and Cmin decreased by 34%, 30% and 24%, respectively. When compared to 100 mg alone, cyclosporine Cmax increased by 1%, but AUC and Cmin increased by 5.82- and 15.80-fold. When initiating therapy with 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-therapy dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.

Viekira Pak US Prescribing Information, AbbVie, December 2014.

Coadministration of ombitasvir/paritaprevir/ritonavir + dasabuvir (3D) (25/150/100 mg + 400 mg) with ciclosporin (individualized dose) was studied in 7 HCV+ Asian solid organ transplant patients with severe liver fibrosis or cirrhosis, in a retrospective single-centre trial. On day 1 of 3D administration, ciclosporin Cmax and AUC increased by 2.48-fold and 4.53-fold, respectively. By day 15, AUC had increased by 5.52-fold. PK simulations suggested that a 7-fold dose reduction of ciclosporin administered once-daily could result in ciclosporin Ctrough levels equivalent to ciclosporin alone. All patients were undetectable by week 8 and achieved SVR12. The correlation between the severity of the DDI and liver function was not studied, but the authors hypothesize that the difference seen between their suggested dose change and that in the product label (5-fold decrease) may be due to the severity of liver disease in this cohort. The effect of possible CYP34/5 polymorphism that may be present in an Asian population is unknown.

Drug-Drug Interactions With Cyclosporine in the Anti-Hepatitis C Viral PrOD Combination Regimen of Paritaprevir/Ritonavir-Ombitasvir and Dasabuvir in Organ Transplant Recipients With Severe Hepatic Fibrosis or Cirrhosis. Huang Y-Y, Huang Y-H, Loong C-C et al. Ther Drug Monit. 2022; 44(3):377-383.

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