Ketoconazole Fexofenadine

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Tannergren C, Knutson T, Knutson L and Lennernas H (2003) The Effect of Ketoconazole on the In Vivo Intestinal Permeability of Fexofenadine Using a Regional Perfusion Technique. BrJ Clin Pharmacol 55 pp 182-190. 

Terfenadine is at least 70% absorbed after oral administration but is rapidly metabolized by first-pass metabolism to fexofenadine (terfenadine carboxylate) and an inactive dealkylated product. Metabolism appears to be mediated entirely by the CYP (CYP3A4). Fexofenadine is about 70% protein bound and exhibits biphasic elimination with an initial plasma half-life of 3.5 hours and a terminal plasma half-life of 6 to 12 hours. Fexofenadine is excreted mostly unchanged (80% in feces, 12% in urine), with <10% converted to inactive metabolites (7). Fexofenadine excretion can be affected by compounds (e.g., ketoconazole) that interact with the P-glycoprotein transporter because fexofenadine is a substrate for this transporter (8). 

The occurrence of cardiac toxicity was closely correlated with terfenadine use, and subsequent in vitro studies confirmed that terfenadine (but not fexofenadine) efficiently blocks cardiac potassium channels (14). A study in healthy volunteers treated concomitantly with terfenadine and ketoconazole found a linear relationship between trough terfenadine concentrations and QTC intervals. The QTC interval lengthened up to 110 millisecond at the highest plasma concentrations of 45 ng/mL (9). Thus, the direct inhibitory effect of terfenadine on cardiac potassium channels results in prolongation of cardiac repolarization, which is a well-known cause of ventricular arrhythmias. In one death in which terfenadine was implicated, plasma level of the drug was 55 ng/mL several hours after the last ingestion of the drug (when it normally should be undetectable). 

Adverse effects. Terfenadine can prolong the QTc interval on the surface ECG. This is especially likely to occur when the recommended dose is exceeded or the drug is administered with substances that block hepatic metabolism. Since this is dependent solely on the 3A4 isoform of cytochrome P450, offending drugs include erythromycin, ketoconazole and even grapefruit juice. Fexofenadine is the active metabolite of terfenadine and appears safe in this respect. 

Tannergreen, C., Knutson. T. Knutson, L., and Lennernas, H. (2003) The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique. British Journal of Clinical Pharmacology, 55, 182-190. 

The primary metabolite of terfanidine (/ =OH) was recently (1996) marketed as fexofenadine (Allegra). It may not exhibit the serious drug interactions with ketoconazole and erythromycins. 

Many Hj antihistamines are metabolized by CYPs. Thus, inhibitors of CYP activity such as macrolide antibiotics (e.g., erythromycin) or imidazole antifungals (e.g.,ketoconazole) can increase Hj antihistamine levels, leading to toxicity. Some newer antihistamines, such as cetirizine, fexofenadine, levocabastine, and acrivastine, are not subject to these drug interactions. 

Ketoconazole raises the levels of desloratadine, emedastine, fexofenadine but as no adverse cardiac effects were seen these combinations are considered safe. No interaction occurs between ketoconazole and azelastine, cetirizine, intranasal levocabastine, and none is expected with levocetirizine. 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

Fexofenadine 120 mg twice daily Ketoconazole 400 mg daily 7 24 healthy subjects 135% 164% No change 7... 

Etesloratadine, emedastine and fexofenadine levels are raised by ketoconazole but because this does not result in adverse cardiac effects concurrent use is considered safe. Azelastine, cetirizine (and therefore probably... 

An in vitro study showed that ritonavir markedly reduced the transport of fexofenadine, thought to be via inhibition of P-glycoprotein. This would be predicted to markedly increase the bioavailability of fexofenadine, as occurs with verapamil, see Calcium-channel blockers + Antihistamines , p.861. However, the similar marked increases in fexofenadine levels that occurred with erythromycin , (p.589) and ketoconazole , (p.584) did not increase adverse effects and were not associated with any prolongation of the QT interval. This suggests that a clinically relevant interaction between ritonavir and fexofenadine is not expected. 

---