Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-21
2003-07-29
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06599913
ABSTRACT:
BACKGROUND OF THE INVENTION
Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a non-sedating antihistamine useful for treating allergic reactions in animals including humans. See also Claritin brand of Loratadine. Product Information Sheet, dated 1/99. Desloratadine is disclosed in U.S. Pat. No. 4,659,716 as a non-sedating antihistamine.
Histamine H
1
-receptor antagonists are effective first-line therapeutic agents in the management of allergic rhinitis, a condition affecting approximately 45 million Americans with a trend toward a larger afflicted population. Due to the high incidence of allergic rhinitis across the full range of the population, antihistamines are often administered concurrently with other drugs. Because drug disposition and exposure can drastically change when a co-administered drug inhibits an avenue of elimination or disposition, e.g., a drug/drug interaction, the elevated exposure to one or more drugs can lead to potentially grave consequences.
Mammalian cells possess a natural battery of defense mechanisms against xenobiotic assault. A particular class of proteins actively transports an extensive array of structurally unrelated large lipophilic compounds from the cell, providing what is often known as multiple drug resistance (MDR). Multidrug resistance is characterized by active efflux or pumping of xenobiotics and pharmaceuticals via transmembrane proteins acting as hydrophobic “vacuum cleaners.” The protein product of the MDR1 gene encodes a 170 kD integral plasma membrane phosphorylated glycoprotein, P-glycoprotein (P-gp), which is the best known and most extensively studied among these transporters and thus far appears to have the largest substrate list. The gross structural features of P-gp appear to be shared by a large family of membrane transporters known as ATP-binding cassette (ABC) transporters, which evidently act as ATP-driven pumps that remove xenobiotics from the interior of cells. Expression of P-gp in normal human tissues, particularly within the cellular membranes of the gastrointestinal tract, liver, blood-brain barrier, adrenals, and kidneys, suggests that the protein plays a role in cellular protection as well as in secretion. While the primary function of this protein is unknown, its ability to confer resistance to a wide variety of structurally and chemically unrelated compounds remains impressive. Indeed, the substrate list for this transporter reveals that P-gp shares a similar tolerance or acceptance as cytochrome P450 3A4 (CYP3A4), the predominant intestinal and hepatic cytochrome P450 oxygenase enzyme, and may even prove to be more extensive in its substrate recognition and as an avenue of drug elimination.
Among the more grave examples of clinical drug interactions are the H
1
-receptor antagonist terfenadine with ketoconazole, as well as simvastatin with itraconazole and mibefradil; all are reportedly substrates/inhibitors of P-gp. Another H
1
-receptor antagonist, fexofenadine, also reportedly interacts with erythromycin and ketoconazole. A report implicates active transporters as a major factor in the disposition of fexofenadine. Cvetkovic M., et al.,
Drug Metab Dispos
1999, Aug;27(8):866-71. Additionally, P-gp polymorphisms may cause wide-ranging reactions to treatment with P-gp substrates. If a polymorphic gene product of MDR1 has inferior selectivity toward a therapy, increased systemic exposure to that erstwhile P-gp substrate could be expected. Decleves X., et al.,
Hum Mutat
15:486.
At therapeutically effective doses, desloratadine was surprisingly found to not detectably bind to the P-gp protein. Also, in clinical studies, desloratadine pharmacokinetics were minimally affected by coadministration of grapefruit juice, which is known to alter drug transporter function.
The molecular mechanism underlying the hepatic uptake of organic anions has been significantly elucidated. Meier, et al.,
Hepatology
, 1997 26(6):1667-77. The organic anion transport polypeptide 1 (OATP1) is a Na
+
- and ATP-independent transporter localized to the basolateral membrane of hepatocytes (as well as cells in other tissues), where it plays a major role in uptake of a variety of structurally unrelated anionic, neutral, and even some cationic compounds from the blood into the cell. Ibid. OATP1 mediates uptake of a variety of amphipathic organic anions in exchange for HCO
3
−
and/or GSH and has been detected in the cells of kidney, liver, brain, lung, and muscle tissue. OATP1 has been demonstrated to transport bromosulfophthalein (BSP), bile acids, anionic steroid conjugates, neutral steroids, and other drugs. The inhibition of OATP1 function results in decreased exposure of substrates to cytosol and hence tissue.
The human OATP uptake antiport transporter has been shown to effect the disposition of fexofenadine. Cvetkovic M, et al.,
Drug Metab Dispos
1999, Aug;27(8):866-71. This report shows results from cells transfected with an OATP clone given by the University Hospital, Zurich, Switzerland. Using monolayers of the transfected cells and parent cells as controls, the rate of uptake was measured over a range of [
14
C]fexofenadine concentrations. By analyzing the hyperbolic saturation curve a K
m
of 6.4±2.2 &mgr;M and a V
max
of 58 pmol/mg protein·min was determined and this was an efficiency of transport ranking high among tested substrates. Ibid. Additionally, the researchers were able to show significant inhibition of fexofenadine uptake by the drugs ritonavir, saquinavir, and lovastatin, and some other drugs.
Many food constituents (polyphenols and flavonoids) can directly effect the function of this uptake transporter. It is known that grapefruit juice and a coumarin constituent of grapefruit juice can have an effect on human OATP1. Additionally, grapefruit juice at 5% inhibited about 90% of human OATP1 mediated fexofenadine uptake and a major coumarin constituent of grapefruit juice inhibited rat oatp1 with an IC
50
<1 &mgr;M. Dresser G. K.,
Drug Met Reviews
, 2000, 32 (s2):193. This impedance can be predicted to cause clinical effects on fexofenadine.
As a substrate of transporters that is not metabolized by CYP enzymes, fexofenadine is commonly used as a probe of drug transporter function. In vitro and in vivo studies have shown that fexofenadine pharmacokinetics are dependent upon drug transporters: fexofenadine AUC is increase. 5- to 9-fold in mdr1 null (-l-) mice, which are devoid of P-gp activity. Murray, 2001 SCI-1124-01/EAS Abstract 4/01. Consequently, substances that alter the function of these transporters by decreasing or increasing their activity have the potential to alter the clinical safety and efficacy profiles of other P-gp/OATP substrates. Ibid.
Clinical studies have shown that consumption of such common foods as grapefruit juice, apple juice, and orange juice decrease fexofenadine AUC by 30% to 77%; inhibition of OATP-mediated drug uptake and/or induction of active drug efflux appears to be responsible. Ibid. Agents that modify P-gp/OATP activity-including St. John's Wort, ketoconazole, and erythromycin, and terfenadine have also reportedly been shown in clinical trials to alter the bioavailability of fexofenadine. Ibid.
A recent clinical interaction study performed has produced a reduction in fexofenadine exposure when co-administered with grapefruit juice. In this four-way crossover study grapefruit juice reduced both C
max
and AUC of fexofenadine by 30%. Cohen A., et al., (Protocol No. P01380), SPRI Clinical Pharmacology Study, P01380. This result is consistent with the inhibition of OATP1 mediated uptake of fexofenadine since constituents in grapefruit are known to be potent inhibitors of this transporter. This result was corroborated and extended in a 5 way, cross-over study in which the reduction of fexofenadine bioavailability was also observed with orange, apple and grapefruit juice. Bailey D. G., et al.,
Clin Pharn Ther
2001 69(2):21 (Abs PI-82). Apples and oranges are known to contain various polyphenolics and flavonoids that inhibit some transporters.
Casciano Christopher
Clement Robert P.
Johnson William W.
Wang Er-Jia
Lipka Robert J.
Reamer James H
Schering Corporation
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