HRP20010345A2 - Pharmaceutical preparation containing brivudin to be administered once a day - Google Patents

Description

Field of invention

This invention relates to new pharmaceutical preparations that are applied once a day and contain the antiviral Brivudin for the treatment of acute herpes zoster infection and for the prevention of neuralgia after herpes.

Previous knowledge

During the last ten years, the number of drugs that are clinically useful in the chemotherapy of viral diseases has increased significantly. Since its introduction in 1982, oral aciclovir has been widely used in the treatment of acute herpes zoster in immunocompetent patients. However, the frequent major drawback of acyclovir therapy is the need for large doses due to low bioavailability, which often leads to poor results.

This led to the development of new antiviral (penciclovir) so-called prodrugs such as valciclovir (cyclovir prodrug) and famciclovir (penciclovir prodrug). To date, famciclovir offers the most convenient treatment of acute herpes zoster in elderly patients, with a dose of three tablets or capsules per day, compared to the required five tablets of acyclovir per day, and six tablets per day of valacyclovir. Famciclovir relieves the acute signs and symptoms of herpes zoster as well as aciclovir and provides protection against the pain associated with herpes zoster or PHN. If it is used less often, in smaller doses and without an increased risk of undesirable side effects, such treatment is better compared to aciclovir treatment and has more advantages, especially in elderly patients. The recommended daily dose ranges between 750 mg and 1500 mg (Degreef et al. 1994, Int. J. Antimicrob. Agents 4, 241-246; Tyring et al., 1995, Ann. Intern. Med. 123, 89-96; Dworkin et al., 1995, Antiviral Res. 26, 344; Dworkin et al., 1996, Pain, 67, 241-251; Dworkin et al., 1998, Antiviral Research 33, 73-85).

Brivudine, a nucleoside analog, is a potent virostatic agent with selective activity against varicella zoster virus (VZV) and herpes simplex virus type I (HSV-1) (DeClercq et al., 1979, Proc. Natl. Acad. Sci. USA, 76, 2947 -2951; DeClercq et al., 1980 J. Infect. Dis. 141, 563-574). While viral DNA synthesis is inhibited, cellular function remains largely unchanged. The continued development of brivudine during the last years is aimed at the treatment of VZV infections in immunocompetent patients.

Based on the results of numerous uncontrolled or controlled studies, Brivuidine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in patients with compromised immune status at doses of 125 mg three to four times a day (DeClercqetal., 1980, Br. Med. J., 281, 1178; Tricot et al., 1986, J. Med. Virology, 18, 11-20; Wutzler et al., 1995, J. Med. Virology, 46, 252-257; see also Fachinformation united for the pharmaceutical product Helpin ® which was on the German market in 1992).

Presentation of the invention

Recently, large multinational studies on immunocompetent patients with herpes zoster who were treated once a day with 125 mg of brivudine per day for seven days surprisingly showed that this treatment was statistically superior to the standard oral treatment with 800 mg of acyclovir five times a day, and according to the dermatologically determined end point (5-Ho-b/0078BC). Monitoring of patients older than 50 years after the study, who participated in these studies, and who had PHN after the end of the study, showed a significantly reduced occurrence of PHN after treatment with brivudine than after treatment with acyclovir (5-Ho[a+b+ c]PHN/0078BC).

Brivudin therefore surprisingly offers the possibility of treating herpes zoster with one tabetomod 125 mg daily, instead of high and frequent doses of acyclovir, valacyclovir or famciclovir. One tablet of 125 mg per day is even more surprising when considering the ratio of the previously prescribed daily dose of four times 125 mg, as registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients. With that one dose a day, a further surprising result was achieved: reduction of neuralgia after herpes.

Experimental part

To determine the efficacy and safety of brivudine in immunocompetent adult patients with herpes zoster, three major studies (studies 5-Ho-a, 5-Ho-b, and 5-Ho-c) were recently conducted according to the CP standard. All four studies were multicenter, double-blind, randomized, parallel-planned.

Patients were observed for 35 days to assess the passage of rash on the bed in the acute phase of pain. All patients were immunocompetent. Only adult patients aged 18 and over were included in the research.

The primary parameter to examine efficacy is "time from start of treatment to the last appearance of a new blister" in all three studies. This parameter follows viral replication in the skin and therefore describes the virostatic potential of the drug. It is accepted in the literature and is considered the most reliable cliché sign compared to other manifestations on the skin. Further parameters for examining the passage of skin rashes are "time from the start of treatment to the start of scab formation", "time from the start of treatment to complete scab coverage", and "time from the start of treatment to the falling off of the scab". The spread of lesions to the skin and occurrence of other complications was also evaluated.

In the literature, the most commonly used measures for evaluating the benefit of antiviral therapy in herpes zoster are the duration of the skin rash and the occurrence and intensity of pain during the acute phase of the infection. Recently, however, post-herpes neuralgia has become of interest for assessing the benefit of antiviral therapy. Thus, in order to evaluate the possible effects of brivudine on reducing the occurrence of neuralgia after herpes in a preliminary way, retrospective studies were conducted with a double blind experiment on patients aged 50 years and older who were included in the research.

Table 1 shows studies performed on immunocompetent patients with herpes zoster. Previous uncontrolled studies in immunocompromised patients showing early evidence of potential benefit from brivudine will not be presented.

TABLE 1: OVERVIEW OF CLINICAL RESEARCH

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These clinical studies are presented chronologically below.

Exploring the 5-Ho

As the concentration of brivudine in plasma in a human who received 125 mg once daily is from 10 to 50 times the IC50 of the clinical type of Varicellazoster virus, and in addition, human pharmacokinetic data show that the concentration of brivudine in plasma was maintained above the IC50 for more than 24 hours after a single administration 125 mg of brivudine, it is a reasonable assumption that once daily administration of 125 mg of brivudine will be sufficient for the treatment of herpes zoster.

The 5-Ho, Phase II study was conducted on 642 patients, and therefore the administration of 125 mg brivudine once daily for seven days and 5 x 800 mg aciclovir for seven days was compared in an exploitative manner. Two arms of the study with a dose of 62.5 mg and 32.25 mg per day of brivudine for seven days were also conducted to examine the effectiveness of lower doses.

This study shows that treatment with 1 x 125 mg of brivudine over 7 days in a patient with acute herpes zoster is as effective as treatment with 5 x 800 mg of acyclovir over 7 days, and according to the primary parameter "time from the start of treatment to the last appearance of a new blister" as well as according to all secondary parameters including "time from start of treatment to cessation of pain (no pain or low intensity)" as a clinically more important secondary parameter. Statistical analysis of the primary efficacy parameter and the pain parameter showed that treatment with 1 x 125 mg brivudine was not less effective than treatment with acyclovir. For the parameter "time from the start of the treatment to complete scab coverage", and "time from the start of the treatment until the scab falls off", the advantage can be achieved in an exploitative way. A graphic presentation of the risk ratio calculated according to the Cox proportional hazard model for the group with 1 x 125 mg brivudine compared to 5 x 800 mg acyclovir is shown in Figure 1.

Brivudine has a linear dose-dependent effect. It has been shown to give a statistically and clinically significant advantage over placebo in immunocompetent patients with acute herpes zoster infection. Brivudine treatment with a dose of 1 x 125 mg for seven days is at least as effective as treatment with 5 x 800 mg of aciclovir for seven days, and according to the duration of blisters and acute pain. These results, together with previous pharmacokinetic considerations, lead to 125 mg of brivudine given once daily being chosen for treatment.

Research 5-Ho-b

The Phase III SHo-b study was conducted in 1227 patients to obtain statistics differentiating the treatment of 1 x 125 mg brivudine for seven days and 5 x 800 mg acyclovir for seven days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 years and older was also evaluated separately.

A graphic representation of the risk ratio calculated according to the Cox proportional hazards model for the group treated with 1 x 125 mg brivudine compared to the group treated with 5 x 800 mg acyclovir is shown in Figure 2.

5-Ho-c research: reduction of treatment duration

To examine the efficacy of a three-day once-daily treatment with brivudine in patients with herpes zoster, another large study was conducted using exactly the same study design as 5-Ho-b. Tretamsa 125 mg brivudine administered once daily for three days (followed by placebo on the fourth day) was compared with treatment with acyclovir 800 mg 5 times daily for 7 days.

A total of 1336 patients were included. The results show that this treatment with that dose of brivudine is not more unfavorable than the treatment with acyclovir at the standard dosage, according to the primary efficacy variable. Better results, however, may remain undetermined.

These data on reduced treatment time therefore support the idea that bruvidin is really effective in the treatment of herpes zoster when given once daily to immunocompetent adults and support the results obtained in previous studies.

Primary efficiency variable

The advantage of brivudine over acyclovir can be determined according to the primary parameter. A difference of 5% is considered statistically significant and confirmation in the test. The resulting hazard ratio was 1.14 (for the Per Protocol half-dose), indicating a 14% better effect (the end point was reached faster) in patients treated with 1 x 125 mg brivudine than in those treated with acyclovir. The corresponding descriptive mean for "time from start of treatment to last new blister" was 25% less for brivudine (mean time 13.5 hours) than for acyclovir (mean time 18.0 hours).

Therefore, the primary efficacy variable proves that brivudine treatment is statistically significantly better than acyclovir treatment.

Secondary efficiency variables

Statistical tests for all secondary efficacy variables, including clinically important pain parameters, show equivalence of treatment with 1 x 125 mg brivudine and 5 x 800 mg acyclovir.

Spread of skin lesions (brivudine 1; aciclovir 2) and occurrence of other complications (brivudine 0; aciclovir 6) occurred in less than 1% of patients in both groups.

Analysis of the subgroup of patients 50 years and older yielded similar results to those obtained in the overall population, with an 18% better treatment effect for the primary efficacy variable in patients treated with brivudine compared to those treated with acyclovir.

The superiority of brivudine over acyclovir can be shown statistically according to the primary efficacy variable. Non-inferiority can be demonstrated at a significance level of 5% for all secondary variables, including pain parameters.

In the subpopulation of patients aged 50 years and older, a better effect of brivudine was found in relation to acyclovir, according to the primary efficacy parameter.

Postherpetic neuralgia surveillance after research

Two retrospective follow-up studies were performed under GCP standard double-blind conditions to investigate the occurrence of postherpetic neuralgia (PHN) in patients aged 50 and over:

1) selected from the research group 5-Ho-a and 5-Ho-b (treatment for 7 days with brivudine vs. 7 days with acyclorite)

2) selected from the 5-Ho-c research group (treatment for 3 days with brivudine vs. 7 days with acyclorite)

Patients who reported pain associated with zoster in a telephone contact after the end of the study were called to the center and were questioned by an investigator to confirm the occurrence of PHN and to answer the question related to the nature of the pain. PHN was defined as herpes zoster pain affecting the dermatomes after the end of the individual study (patients were supposed to stop study 5-Ho-a, 5-Ho-b and 5-Ho-c when all scabs fell off or 35 days after the start of treatment, but what happened before).

The research was conducted under conditions of a blind test (both the patients and the researcher do not yet know which treatment was given during the research of 5-Ho-a, 5-Ho-b and 5-Ho-c), which significantly confirms the results of these studies.

1. Monitoring of PHN after seven days of brivudine treatment

A large sample of men and women aged 50 years and older from the 5-Ho-a and 5-Ho-b studies were re-examined retrospectively (between 8 and 17 months post-treatment) to examine the efficacy of brivudine in preventing the onset of postherpetic neuralgia. In the group of patients previously treated with 125 mg of brivudine for seven days, 32.7% suffered from postherpetic neuralgia after the end of the study, while in the group treated with acyclovir, this proportion was 43.5%. Therefore, the relative risk of postherpetic neuralgia was 25% lower in the group treated with 125 mg brivudine than the group treated with acyclovir. This is a statistically significant reduction and can be attributed to the clinically significant utility of brivudine.

2. Monitoring of PHN after a three-day brivudine treatment

This study included patients 50 years of age and older who received a three-day course of 125 mg brivudine or a standard seven-day course of acyclovir in the 5-Ho-c study. Patients were examined outside between 3 and 8 months after treatment. The results show that the occurrence of postherpetic neuralgia in patients who received a three-day treatment of 125 mg brivudine once a day is comparable to the occurrence in patients who received acyclovir at the standard dosage and for seven days (41.6% vs. 39.7%).

These additional data support the evidence that treatment of herpes zoster with brivudine given once daily for three days is non-inferior to treatment with acilavir.

Examples

The following are non-limiting examples of this invention:

Example 1: One immediate-release 125m brivudine tablet

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Example 2

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Example 3

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Example 4

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Example 5

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Example 6

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Example 7

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Example 8 - quick release capsule

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Example 9 - coated tablet with rapid release

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Claims (7)

1. Pharmaceutical oral preparation for once-a-day use, characterized by the fact that it contains brivudine as an active ingredient, together with pharmaceutically acceptable carriers and excipients, and for the treatment of herpes zoster infection or neuralgia after herpes. 2. Pharmaceutical preparation according to patent claim 1, characterized in that the amount of active ingredient is from 50 to 300 mg. 3. Pharmaceutical preparation according to patent claim 2, characterized in that the amount of active ingredient is from 100 to 200 mg. 4. Pharmaceutical preparation according to patent claim 3, characterized in that the amount of active ingredient is 125 mg. 5. Pharmaceutical preparation according to patent claim 4, characterized in that it is also selected from the following group: - brivudine 125 mg, microcrystalline cellulose 74 mg, lactose monohydrate 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 245 mg, - brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 245 mg, - brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 245 mg, - brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, coprovidone VA 64 6.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 245 mg, - brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, coprovidone VA 64 6.5 mg, collidon CL 5.0 mg, magnesium stearate 2.5 mg, and purified water up to a total of 250 mg, - brivudine 125 mg, microcrystalline cellulose/aerosil 98/2 122.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 250 mg, - brivudine 125 mg, microcrystalline cellulose/aerosil 98/2 100.5 mg, collidon CL 22.0 mg, magnesium stearate 2.5 mg, and purified water up to a total of 250 mg, - brivudine 125 mg, microcrystalline cellulose 122.5 mg, magnesium stearate 2.5 mg, and purified water up to a total of 250 mg (quick release), - brivudine 125 mg, microcrystalline cellulose 74.0 mg, lactose monohydrate 32.0 mg, aerosil 5.0 mg, coprovidone VA 64 6.5 mg, magnesium stearate 2.5 mg, mactrogol 6000 1.5 mg, titanium oxide 4.5 mg (coated tablets with quick release). 6. Use of a pharmaceutical preparation for once-a-day administration, indicated that the content is 50 to 300 brivudine for the treatment of herpes zoster infection or post-herpes neuralgia. 7. Use according to patent claim 6, characterized in that the brivudine content is 125 mg.