Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers

Abstract

Background and aims: The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments.

Methods: Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC).

Results: Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP.

Conclusions: Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.

Fig. 1

Study designs. *12 subjects were enrolled; 1 subject withdrew from the study due to non-medical personal reasons and was not included in the pharmacokinetic analyses. 3D regimen ombitasvir/paritaprevir/ritonavir and dasabuvir, PK pharmacokinetic, SMZ/TMP sulfamethoxazole/trimethoprim

Fig. 2

Effect of commonly coadministered medications on ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures. Geometric mean ratios indicate C _max (open circles), AUC (open squares), and C _trough (open triangles) values for coadministration of the 3D regimen with the medication versus administration of the 3D regimen alone. C _trough samples were not obtained in the presence of SMZ/TMP. Geometric mean ratios were obtained by taking antilogarithm of the difference of the least squares means on the logarithmic scale within the framework of the repeated measures analysis model. 3D regimen ombitasvir/paritaprevir/ritonavir and dasabuvir, AUC area under the plasma concentration–time curve from time 0–24 h (AUC₂₄) for ombitasvir, paritaprevir, and ritonavir, time 0–12 h (AUC₁₂) for dasabuvir, and time 0 to infinity (AUC_∞) for ombitasvir, paritaprevir, dasabuvir, and ritonavir during coadministration with SMZ/TMP, CI confidence interval, C _max maximum plasma concentration, C _trough plasma trough concentration at 24 h (C ₂₄) for medications administered once daily and 12 h (C ₁₂) for medications administered twice daily, SMZ/TMP sulfamethoxazole/trimethoprim

Fig. 3

Effect of the 3D regimen on exposures of commonly coadministered medications and applicable metabolites. Geometric mean ratios indicate C _max (open circles), AUC (open squares), and C _trough (open triangles) values for coadministration of the medication with the 3D regimen versus administration of the medication alone. C _trough samples were obtained only for sulfamethoxazole and trimethoprim. Geometric mean ratios were obtained by taking the antilogarithm of the difference of the least squares means on the logarithmic scale within the framework of the repeated measures analysis model. 3D regimen ombitasvir/paritaprevir/ritonavir and dasabuvir, AUC area under the plasma concentration–time curve from time 0 to 12 h (AUC₁₂) for sulfamethoxazole and trimethoprim and time 0 to infinity (AUC_∞) for all other medications and metabolites, CI confidence interval, C _trough plasma trough concentration at 24 h (C ₂₄) for medications administered once daily and 12 h (C ₁₂) for medications administered twice daily