Effect fixed-dose drug combinations

Obstacles to successful therapy with this drug combination include the need for frequent dosing (i.e., three times daily with the fixed-dose combination product), a high frequency of adverse effects (e.g., headache, dizziness, GI distress), and increased cost for the fixed-dose combination product. 

Lopinavir is available in the United States only as a fixed-dose combination with ritonavir (Kaletra). In this regimen, a low dose of ritonavir is used to inhibit the rapid inactivation of lopinavir by CYP3A4. Side effects, which are generally mild, include diarrhea, nausea, asthenia, and headache. Pancreatitis occurs rarely. Ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6. In addition to the drugs contraindicated for all protease inhibitors, fiecainide, propafenone, pimozide, and rifampin should not be given with lopinavir-ritonavir combination therapy. 

A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy (6). In the 126 patients who took artemether + benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (12) but toxicity studies are lacking. 

A variable-dose plasma concentration-controlled approach to combination antiretroviral therapy (zidovudine, lamivudine, and indinavir) has been compared with conventional fixed-dose therapy in 40 patients in a randomized, 52-week, open trial (8). Significantly more concentration-controlled recipients achieved the desired concentrations for all three drugs there was a good response in 15 of 16 concentration-controlled recipients compared with nine of 17 conventional regimen recipients. However, there was no difference in the occurrence of drug-related clinical events or laboratory abnormalities between the two regimens. Three patients withdrew because of gastrointestinal adverse effects, one because... 

Angiotensin-II-receptor antagonists (ARBs) are approved for the treatment of hypertension. In addition, irbesartan and losartan are approved for diabetic nephropathy, losar-tan is approved for stroke prophylaxis, and valsartan is approved for heart failure patients who are intolerant of angiotensin-converting enzyme (ACE) inhibitors. The efficacy of ARBs in lowering blood pressure (BP) is comparable with that of other established antihypertensive drugs, with an adverse-effect profile similar to that of placebo. ARBs also are available as fixed-dose combinations with hydrochlorothiazide. 

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