Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-11-13
2001-01-30
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S255030, C514S473000
Reexamination Certificate
active
06180634
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides combination therapy for the treatment of HIV infection and AIDS. More particularly, the combination comprises an HIV protease inhibitor, Compound A, with one or more nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)].
The compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-benzo[b]furanylmethyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide disclosed in U.S. Pat. No. 5,646,148, issued Jul. 8, 1997, and referred to herein as “Compound A,” is a potent inhibitor of HIV protease and is useful in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of AIDS or ARC (AIDS related complex), without significant side effects or toxicity.
One substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents employed to treat the disease. Thus, a need remains for an efficacious and long lasting therapy for AIDS which lowers HIV viral levels of patients to undetectable levels and raises CD4 cell counts for prolonged periods of time without the development of resistance. Therefore, it is an object of the invention to provide a combination therapy which lowers HIV viral levels below the limit of detection. It is another object of the invention to increase the count of CD4 cells for prolonged periods of time. Furthermore, it is an object of the invention to achieve both of these favorable results for extended periods of time without the development of resistance to the therapies.
Applicants have discovered that the combinations of this invention are effective inhibitors of HIV protease. In the present invention, Applicants co-administer a potent HIV protease inhibitor, Compound A, or pharmaceutically acceptable salts or esters thereof, with one or more nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors. Optionally, Compound A, or pharmaceutically acceptable salts or esters thereof, is co-administered with Zidovudine and Lamivudine. This combination therapy is a method to enhance the effectiveness in treating AIDS and to preclude the development of resistance to the individual therapeutic agents.
SUMMARY OF THE INVENTION
The instant invention involves a composition comprising Compound A of the formula
and one or more antiretroviral agents selected from Zidovudine, Lamivudine, Stavudine, DMP-266, Ritonavir, Nelfinavir, Abacavir, Indinavir, 141-W94, Delavirdine, or Saquinavir; and pharmaceutically acceptable salts or esters thereof.
In one embodiment of the instant invention is the composition comprising Compound A and one, two, or three antiretroviral agents selected from Zidovudine, Lamivudine, Stavudine, DMP-266, Ritonavir, Nelfinavir, Abacavir, Indinavir, 141-W94, or Delavirdine; and pharmaceutically acceptable salts or esters thereof.
In a class of the instant invention is the composition comprising Compound A and one or two of the above mentioned antiretroviral agents; and pharmaceutically acceptable salts or esters thereof.
In a subclass of the instant invention is the composition comprising Compound A and one of the above mentioned antiretroviral agents.
Preferred embodiments of the instant invention include the compositions comprising: (1) Compound A, Zidovudine and Lamivudine; (2) Compound A, Stavudine and Lamivudine; (3) Compound A and DMP-266; (4) Compound A and Ritonavir; (5) Compound A and Nelfinavir; (6) Compound A and Abacavir; (7) Compound A and Indinavir; (8) Compound A and 141-W94; (9) Compound A and Delavirdine.
Another preferred embodiment of the invention is a composition comprising (a) Compound A or a pharmaceutically acceptable salt or ester thereof and (b) a compound selected from the group consisting of Indinavir, Ritonavir, Nelfinavir, Delavirdine, 141-W94, and pharmaceutically acceptable salts and esters thereof. Compound (b) is preferably selected from the group consisting of Indinavir, Ritonavir, and pharmaceutically acceptable salts thereof, and is most preferably Indinavir or a pharmaceutically acceptable salt or ester thereof. Particularly preferred is the composition in which (a) is the sulfate salt of Compound A and (b) is the sulfate salt of Indinavir. It has been discovered that the foregoing compounds of (b), when employed in combination with Compound A, can increase the plasma concentration of Compound A to a level having substantial antiviral activity. Compound A is a potent protease inhibitor, exhibiting approximately two-fold greater potency than Indinavir against wild type HIV-1 and a similar potency with respect to other HIV-1 variants in in vitro assays (e.g., CIC95 of Compound A=25 nM against wild-type HIV-1 versus 50 nM of Indinavir, as determined by the Cell Spread Assay described in U.S. Pat. No. 5,646,148). It was unexpectedly found, however, that the administration of Compound A to humans resulted in very low plasma concentrations of Compound A relative to concentrations achieved from administration of comparable doses of Indinavir. Furthermore, pharmacokinetic studies in human subjects have resulted in significant inter-individual variation in the plasma levels of Compound A, a variation much greater than that observed for Indinavir.
The problems of low plasma concentration and of high inter-individual plasma level variation encountered with the administration of Compound A have been solved by the co-administration of Compound A with Indinavir. This solution was arrived at as a result of the following findings:
(i) Compound A has a low affinity for CYPIIIA4, the enzyme which metabolizes it; i.e., the IC50 of Compound A for in vitro inhibition of CYPIIIA4=30 micromolar. In contrast, Indinavir has a comparatively very high affinity for CYPIIIA4 (IC50=0.2 micromolar).
(ii) In addition to the unexpectedly very low plasma concentrations noted above for Compound A relative to those achieved with comparable doses of Indinavir, it was also unexpectedly found that the administration of successively higher doses of Compound A to humans resulted in greater than proportional increases in plasma concentrations.
These findings led to the theory that the very low plasma concentrations and high intersubject variability of Compound A achieved following administration to humans was due to extensive metabolism by CYPIIIA4 prior to entry of drug into the systemic circulation. This in turn led to the hypothesis that the concomitant administration
Chodakewitz Jeffrey A.
Deutsch Paul J.
Ju William D.
Lin Jiunn H.
Vacca Joseph P.
Merck & Co. , Inc.
Travers Russell
Walton Kenneth R.
Winokur Melvin
LandOfFree
Combination therapy for the treatment of AIDS does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Combination therapy for the treatment of AIDS, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Combination therapy for the treatment of AIDS will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2494701