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Possible Dose Adjustments With Four Drugs and Abbvie 3D HCV Regimen
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
People taking the Abbvie 3D regimen for HCV (paritaprevir/ritonavir, ombitasvir, and dasabuvir) may need to halve the dose of concomitant hydrocodone, according to results of a pharmacokinetic study [1]. Doses of diazepam, carisoprodol, and cyclobenzaprine may have to be raised with the 3D combination if monitoring shows the need.
Licensed for treatment of HCV genotype 1 infection, 3D contains the once-daily NS3/4A protease inhibitor paritaprevir (boosted by 100 mg of ritonavir), the once-daily NS5A inhibitor ombitasvir, and the twice-daily NS5B polymerase inhibitor dasabuvir. Abbvie investigators tested these three direct-acting antivirals (DAAs) and ritonavir at standard doses for interactions with 2 mg of diazepam (the anxiolytic, antiseizure agent, and alcohol withdrawal drug Valium), 5/300 mg of hydrocodone bitartrate/acetaminophen (the pain reliever Vicodin), 800/160 mg of sulfamethoxazole/trimethoprim (an antimicrobial) twice daily, 500 mg of metformin (an antidiabetic agent), 250 mg of carisoprodol (a muscle relaxant and pain reliever), and 5 mg of cyclobenzaprine (a muscle relaxant and pain reliever) in study groups including 12 to 15 healthy volunteers.
Participants took the comedication alone, took no drug for several days, then took the comedication after 2 or more weeks of standard 3D dosing. The pattern differed with sulfamethoxazole/trimethoprim, which involved a single dose of the 3D drugs alone, 8 days with no drug, then the 3D agents with steady-state sulfamethoxazole/trimethoprim. The researchers evaluated drug exposure with central value ratios for maximum concentration (Cmax) and area under the concentration-time curve (AUC).
None of the comedications affected concentrations of paritaprevir, ritonavir, ombitasvir, or dasabuvir. The investigators saw no need to recommend dose changes for acetaminophen (17% AUC increase with DAAs), sulfamethoxazole (17% AUC increase, 21% Cmax increase), trimethoprim (22% AUC increase, 17% Cmax increase), or metformin (10% AUC decrease, 23% Cmax decrease).
Hydrocodone AUC jumped 90% when taken with the 3D drugs, while Cmax rose 27%, results leading the researchers to recommend cutting the hydrocodone dose in half and/or monitoring clinical response when prescribing it with the 3D medley.
Levels of three other drugs should be checked when they are taken with 3D because of potentially clinically significant interactions necessitating higher doses of the comedications:
Diazepam Cmax rose 18% while AUC fell 22% with 3D coadministration. Cmax of the diazepam metabolite nordiazepam climbed 10% while AUC fell 44% with 3D.
Carisoprodol AUC dropped 38% and Cmax 46% with the 3D drugs, but the 3D agents did not have a clinically significant impact on the carisoprodol metabolite meprobamate.
Cyclobenzaprine AUC fell 40% and Cmax 32% with 3D. AUC of the cyclobenzaprine metabolite norcyclobenzaprine waned 36% with the 3D drugs.
No serious adverse events or unexpected safety concerns arose with coadministration of 3D and any of the study drugs.
Reference
1. Polepally AR, King JR, Shuster DL, et al. Drug-drug interactions of commonly used medications with direct acting antiviral HCV combination therapy of paritaprevir/r, ombitasvir and dasabuvir. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 16.
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