pioglitazone + roflumilast

The combination of pioglitazone and roflumilast appears to be an investigational treatment that has been studied specifically for nonalcoholic steatohepatitis (NASH). According to the search results, there was a Phase 2 clinical trial (ROF-NASH_205) conducted by AstraZeneca to evaluate this combination. ## Drug Information Pioglitazone is a thiazolidinedione that improves glycemic control in type 2 diabetes mellitus by reducing insulin resistance. It's marketed under the brand name Actos and can be administered in combination with other antidiabetic medications. Pioglitazone exhibits various pleiotropic effects including anti-inflammatory, antioxidant, vasoprotective, antihypertensive, and hypolipidemic actions. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor that works by decreasing immune and inflammatory cell activation. It's primarily indicated for reducing the risk of exacerbations in patients with severe chronic obstructive pulmonary disease (COPD). Roflumilast is marketed under brand names including Daliresp and Zoryve. ## Clinical Trial Information The Phase 2 trial (ROF-NASH_205/NCT01703260) was designed to evaluate the effect of roflumilast and pioglitazone on liver enzymes and liver fat content in subjects with nonalcoholic steatohepatitis. The study included three experimental arms: 1. Roflumilast + pioglitazone: Roflumilast 500 mcg and pioglitazone 30 mg, both taken orally once daily for up to 4 months 2. Roflumilast alone: Roflumilast 500 mcg and pioglitazone matching-placebo 3. Pioglitazone alone: Pioglitazone 30 mg and roflumilast matching-placebo This was a randomized, double-blind, controlled, multi-center study that targeted adults aged 18-80 years with nonalcoholic steatohepatitis. ## Drug Interactions Both medications have significant interaction profiles: - Pioglitazone has 347 known drug interactions (9 major, 324 moderate, 14 minor), 9 disease interactions, and 3 alcohol/food interactions - Roflumilast has 380 known drug interactions, 3 disease interactions, and 2 alcohol/food interactions When considering this combination, special attention should be paid to potential drug interactions, particularly with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and 1A2 (such as erythromycin, ketoconazole, fluvoxamine, enoxacin, and cimetidine) which could increase roflumilast systemic exposure. ## Development Status Based on the search results, this combination appears to have been investigated specifically for nonalcoholic steatohepatitis in a Phase 2 trial. The trial status is listed as "terminated" according to one of the search results, suggesting that development for this indication may have been discontinued.