SI20854A - Once-day pharmaceutical composition containig brivudine - Google Patents

Abstract

There is disclosed the activity of brivudine once-a-day in acute herpes zoster infections and post-herpetic neuralgia and the compositions thereof.

Description

Once daily dosing of Brivudine with the active substance

FIELD OF THE INVENTION

The present invention describes a pharmaceutical composition of the anti-viral active ingredient Brivudine once daily for the treatment of acute infection of herpes zoster - a rash and for the prevention of post-herpes neuralgia - nerve pain.

BACKGROUND OF THE INVENTION

Over the ten years of the session, there has been a marked increase in the number of clinically useful agents for viral chemotherapy. After 1982, acyclovir in oral form was widely used to treat acute herpes zoster infection in immunocompetent patients. Despite the efficacy of acyclovir, treatment with the active substance has drawbacks. The main disadvantage of acyclovir therapy is the frequency of administration and the high amount of active substance required for treatment, which results from limited bioavailability. The aforementioned disadvantage often leads to low consent to treatment.

The newly developed anti-viral agents (penciclvir) and so-called pro-drugs such as valaciclovir (acyclovir pro-active substance) and famciclovir (penciclvir-active ingredient) partially eliminate the deficiency described. To date, famciclovir is the preferred drug for the treatment of acute herpes zoster infection in elderly patients with a dose of three tablets or capsules per day. For comparison, the acyclovir treatment protocol recommends using five tablets a day, or the valaciclovir treatment recommending the use of six tablets daily. Famciclovir, similar to acyclovir, alleviates acute signs and symptoms of herpes zoster infection and provides protection against the onset of pain associated with herpes zoster infection or PHN. Due to lower dose levels, less frequent administration of the drug and no major adverse effects of famciclovir compared to acyclovir, famciclovir treatment is advantageous and appropriate, especially for elderly patients. The prescribed daily amount of the active substance is between 750 mg and 1500 mg (Degreef et al., 1994. Int J Antimicrob Agents 4,241-246; Tyring et al., 1995. Ann Intem Med 123, 89-96; Dworkin et al., 1995 Antiviral Res. 26, 334; Dworkin et al., 1996; Pain 67, 241-251; Dworkin et al., 1998. Antiviral Research 33, 73-85).

The active substance Brivudine, a nucleoside analogue, is a potential virostatic active substance with specific action on Varicella zoster (VZV) and Herpes simplex type 1 (HSV-1) virus (De Clercq et al., 1979. Natl Acad Sci USA 76, 2947-2951 ; De Clercq et al., 1980. J Infect Dis 141, 563-574). The active substance Brivudine inhibits viral DNA synthesis without altering cellular activity. Over the past few years, the development of the Brivudine drug has been focused on the treatment of VZV infections in immunocompetent patients.

Based on the results of numerous uncontrolled and controlled studies, the active substance Brivudine for the treatment of HSV-1 and VZV infections in immunocompetent patients at 125 mg was given three to four times daily in Germany in 1990 (De Clercq et al., 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 in Fachinformation: Helpin® Germany 1992)

SUMMARY OF THE INVENTION

International studies have shown that treatment for herpes zoster infections in immunocompetent patients with Brivudine 125 mg daily is more effective than acyclovir 800 mg five times daily if some dermatological signs (5-Ho-b / 0078BC). A study of the effect of Brivudine and acyclovir on the reduction of PHN syndrome in patients 50 years of age and older who participated in the aforementioned studies showed a reduced incidence of PHN syndrome after treatment with Brivudine compared with acyclovir (5-Ho [a + b + c] PHN / 0078BC).

Compared to the use of acyclovir, valaciclovir or famciclovir, which are required in a large number of doses and in large quantities for the treatment of herpes zoster infections, Brivudine enables the treatment of patients with a once daily 125 mg active substance infection of herpes zoster. Even more striking is the fact that once a daily dose of 125 mg of the active substance Brivudine is sufficient to treat herpes zoster infections, whereas, according to the German 1990 registration, four times a daily dose of 125 mg of the active substance is required to treat HSV-1 and VZV infections in immunocompetent patients. The results of reducing the incidence of post-herpes neuralgia in the treatment of herpes zoster infections with a single daily dose of Brivudine are also surprisingly good.

DETAILED DESCRIPTION

Three major pivotal studies (5-Ho, 5-Ho-b, and 5-Ho-c studies) performed according to GCP standards have analyzed the efficacy and safety of treating immunocompetent adult patients with Brivudine herpes zoster infection. The research was organized in a multi-central, double-blind and parallel fashion. Each study covered adult immunocompetent patients who observed development of skin changes and acute pain over 35 days.

The primary criterion for evaluating treatment efficacy considered by all three studies was the time from the start of treatment to the last onset of new herpes zoster vesicles. This criterion refers to viral replication in the skin and defines the virostatic effect of the active substance. The criterion accepted in the literature has been identified as the most reliable clinical sign compared to other skin conditions. The remaining seconds for determining the stoppage of skin inflammation are: time from start of treatment to onset of scabies, time from start of treatment to complete onset of scabies, and time from start of treatment to disappearance of scabies.

Criteria taken from the literature to evaluate the effectiveness of anti-viral therapy in herpes zoster infections are: duration of itchy skin, onset and intensity of pain during the acute phase of infection. The occurrence of post-herpes neuralgia has also recently been considered to evaluate the effectiveness of anti-viral therapy. For this reason, the study also included an analysis of the active substance Brivudine to reduce the incidence of post-herpes neuralgia. The study was designed retrospectively, double-blindly and was performed on patients 50 years of age and older who were already enrolled in the studies described above.

Table 1 shows a list of studies performed on immunocompetent patients with herpes zoster infection. Previous uncontrolled studies performed on immunocompromised patients that provided evidence of successful action of Brivudine are not described here.

Table 1: Overview of clinical experiments

Study groups description treatment and daily doses (7-day treatment unless otherwise noted) 5-Ho's Dose volume study (Phase II) Brivudine 125 mg χ 1 Brivudine 62.5 mg χ 1 Brivudine 31.25 mg χ 1 Acyclovir 800 mg χ 5 5-Ho-b Performance confirmation study (Phase III) Brivudine 125 mg χ 1 Acyclovir 800 mg χ 5 5-Ho-c Performance confirmation study (Phase III) Brivudine 125 mg χ 1 3 days Acyclovir 800 mg χ 5 5-Ho-a + b-PHN PHN surveillance study after treatment Brivudine 125 mg χ 1 Acyclovir 800 mg x 5 5-Ho-c-PHN post-treatment PHN surveillance study Brivudine 125 mg χ 1 for three days Acyclovir 800 mg χ 5

These clinical studies are described in chronological order below.

5-Ho study

The plasma concentration of Brivudine in humans receiving 125 mg daily exceeds the IC50 value measured in clinical strains of Vericella zoster 10 to 50 times. In addition, pharmacokinetic data in humans show that, after a single administration, 125 mg of the active substance Brivudine is 24 hours higher than the IC50 for the viruses mentioned. It follows that 125 mg of Brivudine daily should be sufficient to treat herpes zoster infections.

The 5-Ho (Phase II) study study included a group of 625 patients treated with once daily administration of 125 mg of Brivudine for seven days. The analysis of the results evaluated the effect of the active substance in comparison with the results of the group of patients treated with 5 x 800 mg acyclovir for seven days. In parallel, two studies were conducted in which patients were treated for seven days with once daily doses of 62.5 mg and 32.25 mg of Brivudine to evaluate the efficacy of lower doses on treatment. The study showed that administering 1 x 125 mg of Brivudine over a seven-day treatment period to patients with herpes zoster infection was as effective as using acyclovir 5 x 800 mg for seven days. This is evident from the results of the primary parameter, the time from the start of treatment to the last appearance of new herpes zoster vesicles, as well as the secondary parameters, among others, the time of initiation of treatment until the cessation of pain (mild pain intensity or zero), which is clinically one of the major secondary parameters. The result of Brivudine 1 x 125 mg treatment is equivalent to acyclovir based on the results of the statistical analysis of the primary efficacy parameter as well as the secondary pain parameter. Studies have found that, according to the so-called secondary parameter, clinical signs are much better after treatment with Brivudine compared to acyclovir, given the start of treatment until full onset of scabies. Figure 1 is a graphical representation of the risk ratio calculated from Cox's proportional risk model between the group that consumed 1 x 125 mg of the active substance Brivudine and the group that consumed 5 x 800 mg of the active substance acyclovir.

The relationship between the efficacy of Brivudine treatment and the dose of active substance consumed during treatment is linear. Compared to placebo, Brivudine is statistically and clinically significantly more effective in treating immunocompetent patients with acute herpes zoster infection. Seven days treatment with Brivudine 1 x 125 mg is as effective as a seven day acyclovir 5 x 800 mg treatment if you take the time of vesicle onset and acute pain to evaluate the success of your treatment. The choice of Brivudine 1 x 125 mg for treatment is preferred given the results described and previous pharmacokinetic studies.

Figure 1: Risk ratio and one sided lower 95% confidence interval.

Comparison of Brivudine 1 x 125 mg with acyclovir 5 x 800 mg (protocol population)

Risk ratio calculated from Cox regression by co-variations. A risk ratio greater than 1 indicates a better effect of Brivudine treatment with acyclovir.

The lower limit of the unilateral 95% confidence interval above the 0.8 line (dashed line) represents equality and above the 1.0 line (straight line) represents the advantage of Brivudine 1 x 125 mg treatment over acyclovir 5 x 800 mg.

5-Ho Study b

1227 patients participated in the 5-Ho-b study (phase III). The study statistically confirmed the efficacy of a seven-day treatment of immunocompetent patients with Brivudine herpes zoster infection in 1 x 125 mg versus acyclovir in 5 χ 800 mg. Treatment outcomes for patients 50 years and older were also analyzed separately.

Figure 2 is a graphical representation of the risk ratio calculated from Cox's proportional hazard model between the group that consumed 1 χ 125 mg of the active substance Brivudine and the group that consumed 5 x 800 mg of the active substance acyclovir.

Figure 2: Risk blanks and one sided lower 95% confidence interval.

Comparison of Brivudine 1 x 125 mg with acyclovir 5 x 800 mg (protocol population)

Risk ratio calculated from Cox regression by co-variations. A risk ratio greater than 1 indicates a better effect of Brivudine treatment with acyclovir.

The lower limit of the unilateral 95% confidence interval above the 0.8 line (dashed line) represents equality and above the 1.0 line (straight line) represents the advantage of Brivudine 1 x 125 mg treatment over acyclovir 5 x 800 mg.

5-Ho-c Study: Reducing treatment time

The 5-Ho-c study should investigate the effectiveness of 3-day treatment of patients with herpes zoster infection with the active substance Brivudine 1 xl25 mg and was performed in the same way as the 5-Ho-b study. Patients in this study were treated with Brivudine 1 χ 125 mg for three days (followed by four days of placebo treatment). In parallel, a parallel study was conducted in which patients were treated with acyclovir 5 χ 800 mg for seven days.

A total of 1336 patients were enrolled in the study. The results of the primary efficacy parameters showed that treatment with Brivudine in the amounts described above is equivalent to treatment with acyclovir in the prescribed amounts of the active substance. Treatment with the active substance Brivudine in these amounts was not superior to treatment with the active substance acyclovir.

The results of the short treatment studies support the idea of the efficacy of Brivudine once daily for the treatment of herpes zoster infections in immunocompetent adult patients and support the validity of the results obtained in previous studies.

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Primary performance parameters

The efficacy of treated patients with the active substance Brivudine can be compared with the efficacy of treating patients with the active substance acyclovir by evaluating the primary parameters of the treatment effect. The confirmatory test is statistically significant at the 5% level. The predicted risk ratio is 1.14 (per protocol population), indicating a 14% better effect (endpoint achieved faster) for patients treated with 1 x 125 mg Brivudine compared to patients treated with acyclovir. The corresponding descriptive average over the period from the start of treatment to the last outbreak of herpes zoster vesicles was 25% lower in favor of Brivudine (mean 13.5 hours) compared to acyclovir (mean: 18 hours).

Based on the results of the primary parameters, treatment with Brivudine was statistically superior to acyclovir.

Secondary performance parameters

The results of the statistical analysis of secondary treatment efficacy parameters, including the pain onset parameter, indicate the same effects of Brivudine treatment in quantities of 1 χ 125 mg and acyclovir treatment in quantities of 5 χ 800 mg.

The incidence of skin sores (Brivudine 1; acyclovir 2) and other complications (Brivudine 0; acyclovir 6) was less than 1% of patients in both groups.

Analysis of treatment outcomes in a subset of patients 50 years of age or older showed similar treatment effects to the overall population. Patients treated with Brivudine were 18% better compared to acyclovir when evaluating treatment efficacy against primary parameters.

Statistical analysis of primary efficacy parameters can confirm better treatment with Brivudine compared to acyclovir. Non-subordination can be shown with a level of 5% significance for secondary efficacy parameters, including the pain parameter.

In a subset of patients 50 years of age and older, treatment with Brivudine compared to acyclovir was more effective with respect to primary efficacy parameters.

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A study of post-herpes neuraieiia surveillance.

Two reverse studies have also been conducted to evaluate the occurrence of post-herpes neuralgia (PHN) in patients 50 years of age and older who have previously been included in the studies mentioned. The survey was conducted according to GCP standards and performed double-blindly. The study included patients:

1) Selected from the 5-Ho and 5-Ho-b study (7-day Brivudine treatment versus 7-day acyclovir treatment)

2) selected from the 5-Ho-c study (3 days of Brivudine versus 7 days of acyclovir)

Patients who participated in the above-described studies on the treatment of herpes zoster infection and who reported by telephone contact that they had pain associated with the herpes zoster infection were invited to a center to confirm the occurrence of PHN and to obtain responses to questions related to pain characteristics. Pain that occurs after completion of treatment and is located in areas affected by a herpes zoster infection is defined as PHN (patients completed the 5-Ho, 5-Ho-b, and 5-Ho-c study when disappearing completely or after 35 days from the start of treatment).

These studies were performed in blinded circumstances (both: patients and investigators were unaware of the treatment modality at the time of 5-Ho, 5-Ho-b, and 5-Ho-c studies), which strongly supports the results.

1. Study of PHN surveillance after seven days of Brivudine treatment

The study involved 608 men and women patients 50 years of age or older from the 5-Ho and 5-Ho-b studies who were invited to be re-examined (between eight and seventeen months after treatment). The study confirmed the effectiveness of preventing post-herpes neuralgia with the active substance Brivudine. In the group of patients treated with 125 mg of Brivudine for the previous seven days, post-herpes neuralgia occurred in 32.7% after the study was completed. On acyclovir treatment, PHN occurred in 43.5%. The relative risk of post-herpes neuralgia is 25% lower when treated with Brivudine 125 mg compared to acyclovir. The reduction of PHN is statistically significant and speaks for the use of Brivudine for treatment.

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2. Study of PHN surveillance after three days of Brivudine treatment

The study included patients 50 years of age and older who were exposed to three daily treatment with Brivudine 125 mg or standard seven-day acyclovir treatment in the 5-Ho-c study. Patients were re-examined between three and eight months after treatment.

The results indicate that the incidence of post-herpes neuralgia in patients treated for three days with Brivudine once daily is comparable to the occurrence of PHN in patients treated for seven days with acyclovir in the prescribed amounts (41.6% vs 39.7%).

The results support the evidence that a three-day treatment of 125 mg mg herpes zoster infections with Brivudine is equivalent to acyclovir treatment.

Examples

The following are examples of the present invention which are not intended to limit the present invention.

Example 1: A 125 mg immediate-release tablet of the active substance Brivudine

St. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 lactose monohydrate 37 4 povidone K-value 25 6.5 5 magnesium stearate 2.5 6 pure water 245

Example 2:

St. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 corn starch 37 4 povidone K-value 25 6.5 5 magnesium stearate 2.5 6 pure water 245

Example 3:

No. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 lactose 37 4 povidone K-value 25 6.5 5 magnesium stearate 2.5 6 pure water 245

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Example 4:

No. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 corn starch 37 4 copovidone VA64 6.5 5 magnesium stearate 2.5 6 pure water 245

Example 5:

No. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 lactose 37 4 copovidone VA64 6.5 5 collidone CL 5 6 magnesium stearate 2.5 7 pure water 250

Example 6:

St. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose / aerosil 98/2 122.5 3 magnesium stearate 2.5 4 pure water 250

Example 7:

“No ^- raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose / aerosil 98/2 100.5 3 collidone CL 22 4 magnesium stearate 2.5 5 pure water 250

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Example 8: immediate release capsule

St. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose / aerosil 122.5 3 magnesium stearate 2.5 4 pure water 250

Example 9: a coated immediate-release tablet

St. raw material mg / tablet 1 Brivudine 125 2 microcrystalline cellulose 74 3 lactose monohydrate 32 4 aerosil 5 5 copovidone VA64 6.5 6 magnesium stearate 2.5 7 hydroxypropyl methyl cellulose 5 8 macrogol 6000 1.5 9 titanium dioxide 4.5 256

Claims (13)

PATENT APPLICATIONS A pharmaceutical composition with a single daily oral dosage comprising the active ingredient Brivudine, together with pharmaceutically acceptable carriers and excipients, for the treatment of herpes zoster infections or post-herpes neuralgia. Pharmaceutical composition according to claim 1, characterized in that the composition contains from 50 to 300 mg of active substance. Pharmaceutical composition according to claim 2, characterized in that the composition contains from 100 to 200 mg of active substance. Pharmaceutical composition according to claim 3, characterized in that the composition contains 125 mg of active ingredient. Pharmaceutical composition according to claim 4, characterized in that the composition is selected from the group consisting of: Brivudine 125 mg, microcrystalline cellulose 74 mg, lactose monohydrate 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg final weight, Brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg final weight, Brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, povidone Value 25 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg final weight, Brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, copovidone VA64 6.5 mg, magnesium stearate 2.5 mg, pure water up to 245 mg final weight, Brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, copovidone VA64 6.5 mg, collidone CL 5.0 mg, magnesium stearate 2.5 mg, pure water up to 250 mg final weight, Brivudine 125 mg, microcrystalline cellulose / aerosil 122.5 mg, magnesium stearate 2.5 mg, pure water up to 250 mg final weight, Brivudine 125 mg, microcrystalline cellulose / aerosil 100.5 mg, collidone CL 22.0 mg, magnesium stearate 2.5 mg, pure water up to 250 mg final weight, -13-4 ^ Brivudine 125 mg, microcrystalline cellulose 122.5 mg, magnesium stearate 2.5 mg, pure water up to 250 mg final weight (direct release), Brivudine 125 mg, microcrystalline cellulose 74.0 mg, lactose monohydrate 32.0 mg, aerosil 5.0 mg, copovidone VA64 6.5 mg, magnesium stearate 2.5 mg, macrogol 6000 1.5 mg, titanium dioxide 4.5 mg (coated immediate-release tablets). 6. A once-daily dosage formulation containing 50 to 300 mg of Brivudine as a medicine for the treatment of herpes zoster infections or post-herpes neuralgia. The composition of claim 6, wherein the content of Brivudine is 125 mg. 8. Use of a once daily dosage formulation containing 50 to 300 mg of Brivudine for the manufacture of a medicament for the treatment of herpes zoster or post-herpes neuralgia. The use according to claim 8, wherein the content of Brivudine is 125 mg. A pharmaceutical composition containing 50 to 300 mg of Brivudine as a medicine for the treatment of herpes zoster infections or post-herpes neuralgia, the said mixture being dosed once daily. The pharmaceutical composition of claim 10, wherein the content of Brivudine is 125 mg. Use of a pharmaceutical composition containing 50 to 300 mg of Brivudine for the manufacture of a medicament for the treatment of herpes zoster infections or post-herpes neuralgia, wherein said mixture is dosed once daily. Use according to claim 12, wherein the content of Brivudine is 125 mg.