Terfenadine pharmacokinetics

Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996 59(4) 383-388. 

Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 1993 33(12) 1201-6. 

Cantilena LR, Sorrels S, Wiley T, Wortham D. Fluconazole alters terfenadine pharmacokinetics and electrocardiographic pharmacodynamics. Clin Pharmacol Then (1995) 57, 185. 

Healthy subjects were given terfenadine 60 mg every 12 hours for 14 days, with montelukast 10 mg daily from day 8 to day 14. It was found that the terfenadine pharmacokinetics and the QTc interval were unaltered by concurrent use. No adverse interactions were seen in large numbers of patients given montelukast 10 or 20 mg and loratadine 10 mg, and the combination was found to be beneficial in the treatment of allergic rhinitis and conjunctivitis. No special precautions are therefore needed if these drugs are given concurrentiy. 

Several nonsedative Hj inhibitors have been marketed—for example, astemizole (4.149) and terfenadine (4.150). They are quite polar molecules and therefore cannot cross the blood-brain barrier to reach central histamine receptors. This is a good example of drug design exploiting knowledge of the pharmacokinetic processes to preclude undesirable CNS side effects. 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Stern RH, Smithers JA, Olson SC. Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine. J Clin Pharmacol 1998 38(8) 753-7. 

Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993 269 1513-1518. 

Honig PK, Woosley RL, Zamani K, et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992 52 231-238. 

Lamberg TS, Kivisto KT, Neuvonen PJ. Lack of effect of terfenadine on the pharmacokinetics of the CYP3A4 substrate buspirone. Pharmacol Toxicol 1999 84 165-169. 

Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTC interval. This can cause potentially dangerous interactions. In a double-blind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTC interval (27). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTC interval. This effect of nefazodone on... 

The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine plus placebo (52). Azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QT interval. 

Honig P, Wortham D, Zamani K, Cantilena L. Comparison of the effect of the macrolide antibiotics erythromycin, clarithromycin and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters. Drug Invest 1994 7 148. 

Terfenadine is normally metabolized by CYP3A4 to fexofenadine, which has negligible cardiac effects. Atorvastatin is also a CYP3A4 substrate, and its effects on the pharmacokinetics of terfenadine have been studied in healthy volunteers who took atorvastatin 80 mg/day from 7 days before to 2 days after terfenadine 120 mg (8). Concentrations of terfenadine and fexofenadine were measured for 72 hours. There were no alterations in the pharmacokinetics of the parent compound or of its metabolite and there were no alterations in QTc intervals after terfenadine alone or with atorvastatin. 

Ten healthy volunteers took oral terfenadine 120 mg/day for 3 days and then took buspirone 10 mg terfenadine had no significant effects on the pharmacokinetics of buspirone (9). 

Sertindole 30 mg/day had no effects on the pharmacokinetics of a single dose of terfenadine 120 mg or of its metabolite (11). The authors concluded that sertindole at this dose does not inhibit the metabolism of terfenadine. 

The effect of the concomitant administration of terfenadine and sparfloxacin on the QTc interval has been studied in healthy men aged 18 9 years (12). Sparfloxacin was given in a dose of 400 mg on the first day and 200 mg/day thereafter for 3 days with terfenadine 60 mg bd. Terfenadine had no effect on the pharmacokinetics of sparfloxacin and there were no apparent effects on the QTc interval. 

Drugs used in the treatment of depression and psychosis can alter the metabolism of terfenadine. When the antidepressant venlafaxine was given to steady state (37.5 mg bd for 3 days and then 75 mg bd for 5 days), the pharmacokinetics of a single dose of terfenadine 120 mg were not altered and there were no changes in the electrocardiogram (13). The authors concluded that cardiotoxicity is unlikely to arise with co-administration of terfenadine and venlafaxine. 

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