ITMI20010009A1 - PHARMACEUTICAL COMPOSITIONS CONTAINING BRIVUDINA FOR SINGLE DAILY ADMINISTRATION - Google Patents

Description

Description of the industrial invention entitled:

"PHARMACEUTICAL COMPOSITION CONTAINING BRIVUDINE FOR SINGLE DAILY ADMINISTRATION"

Field of the invention

The present invention relates to pharmaceutical compositions containing the antiviral brivudine for single daily administration for the treatment of acute herpes zoster infections and their use in the prevention of post-herpetic neuralgia.

State of the art

Over the past decade, the number of clinically effective drugs proposed for the chemotherapy of viral diseases has significantly increased. Since its introduction in 1982, oral acyclovir has been used extensively in the treatment of acute herpes zoster in immunocompetent patients. A major disadvantage of aciclovir therapy is due to its limited bioavailability which requires frequent and high dosages, with consequent reduced patient compliance.

This has led to the development of a new antiviral (penciclovir) and prodrugs such as valaciclovir (prodrug of aciclovir) and famciclovir (prodrug of penciclovir). Famciclovir has been the most effective treatment of acute herpes zoster in elderly patients to date, with a dosage of three tablets or capsules per day, compared to the five tablets per day required for aciclovir and six for valaciclovir.

Famciclovir or aciclovir relieves the acute signs and symptoms of herpes zoster and provides protection against prolonged pain associated with herpes zoster (PHN). This treatment, carried out less frequently, in lower dosages, without a high risk of side effects compared to aciclovir, is particularly advantageous in elderly patients. The recommended daily dosage ranges from 750 mg to 1,500 mg (Degreef et al., 1994, Int. J. Antimicrob. Agents 4, 241 - 246; Tyring et al., 1995, Full Ann. 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 analogue, is a potent virostatic agent with selective activity against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) (De Clercq et al., 1979, Proc. Nati. Acad. Sci. USA, 76, 2947 - 2951; De Clercq et al., 1980, J. Infect. Dis. 141, 563 - 574). The product inhibits the synthesis of viral DNA, while the other cellular functions are not minimally modified. The continued development of brivudine over the past few years has been directed towards the treatment of VZV infections in immunocompetent patients.

Based on the results of a series of controlled and uncontrolled studies, brivudine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infection in immunocompromised patients at a dose of 125 mg for three or four daily doses. day (DeClercq et al., 1989, 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 the Fachinformation combined with the pharmaceutical product Helpin (R) marketed in Germany in 1992).

Description of the invention

In large recent international studies conducted in immunocompetent patients with herpes zoster, the single daily dose regimen of brivudine 125 mg for 7 days was surprisingly statistically superior to the classic five daily doses of 800 mg of aciclovir in dermatological effects. (5-I-b / 0078DC). Post-study surveillance of patients aged 50 or over who had suffered PHN at the end of the study indicated a significantly lower incidence of PHN after treatment with brivudine compared to aciclovir

Therefore it has surprisingly been found that it is possible to treat patients with herpes zoster with a single 125 mg brivudine tablet per day, instead of the high and frequent dosing protocols of aciclovir, valaciclovir or famciclovir. The efficacy of a single 125 mg tablet per day is even more surprising when considered in relation to the previous regimen of 125 mg four times a day, registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immune patients. compromises. With this single daily dose regimen, the further surprising result was obtained of reducing the incidence of post-herpetic neuralgia.

Experimental part

To evaluate the efficacy and safety of brivudine in immunocompetent adult patients with herpes zoster, three large-scale studies (studies 5-Ho-a, 5-Ho-b and 5-Ho-c) were recently conducted according to the GPC standard. The four studies were prospective and followed a randomized, double-blind, multicenter parallel program.

Patients were observed for up to 35 days to evaluate resolution of skin rash and acute pain. All patients were immunocompetent. Only adult patients aged 18 years or older were recruited.

In all three studies, the main measure of effectiveness was the "time from start of treatment to the last eruption of new blisters". This parameter reflects viral replication in the skin and therefore indicates the virostatic potency of the drug. The same is accepted in the literature as a more indicative clinical sign than other skin manifestations. Other parameters for assessing the resolution of the skin rash were the "time from start of treatment to the start of crusting", the "time from start of treatment to completion of crusting" and "time from start of crusting" treatment for the detachment of crusts ". The spread of skin lesions and the occurrence of other complications were also evaluated.

In the literature, the most frequently used criteria to evaluate the efficacy of antiviral therapies against herpes zoster are the duration of the skin rash and the onset and intensity of pain during the acute phase of the infection. Subsequently, however, post-herpetic neuralgia has become of greater importance in evaluating the benefits of antiviral therapies. Therefore, for a preliminary evaluation of the possible effect of brivudine in reducing the incidence of post-herpetic neuralgia, post-study, retrospective and double-blind surveillance studies were also conducted on patients aged 50 years or more previously recruited for study. Table 1 lists the tests conducted in immunocompetent patients with herpes zoster. Previous uncontrolled studies in immunocompromised patients, which provided initial evidence of the potential efficacy of brivudine, will not be discussed.

Table 1: Outline of clinical trials

Clinical trials are described below in chronological order.

Study 5-I-a

Since the piasmatic concentrations of brivudine in the patient treated with 125 mg once daily are 10 to 50 times the clinical strains of varicella-zoster virus, and because the pharmacokinetic data showed that the piasmatic concentrations of brivudine are maintained above the H'IC50 for 24 hours after a single administration of 125 mg brivudine, it was reasonably assumed that a single daily administration of 125 mg of brivudine would be sufficient for the treatment of herpes zoster.

The Phase II 5-Ho-a study, conducted in 642 patients, therefore had to preliminarily evaluate the effect of a single daily administration of brivudine 125 mg for seven days compared to aciclovir 5 x 800 mg for seven days. days. Two study protocols were also added with single daily brivudine doses of 62.5 mg and 32.25 mg for seven days to evaluate the efficacy of lower doses.

This study showed that brivudine 1 x 125 mg for 7 days in patients with acute herpes zoster has the same efficacy as treatment with aciclovir 5 x 800 mg for 7 days, compared to the primary parameter "time from start of treatment until last eruption of new vesicles ", as well as with respect to all secondary parameters, including" time from start of treatment to pain disappearance (no or light intensity) "as the most relevant secondary clinical parameter. Statistical analysis of the primary efficacy parameter and the pain parameter demonstrated the non-inferiority of brivudine 1 x 125 mg compared to aciclovir. For the parameter "time from start of treatment to completion of crusting", a certain superiority could be demonstrated at the outset. The graph of the risk ratios calculated with the “Cox proportional hazards” model for the 1 x 125 mg brivudine group compared to the 5 x 800 mg aciclovir group is shown in Figure 1.

Brivudine exhibits a linear dose-effect relationship. Superiority over placebo has been demonstrated to a statistically and clinically significant extent in immunocompetent patients with acute herpes zoster infection. Treatment with brivudine dose of 1 x 125 mg for seven days is at least as effective as treatment with aciclovir 5 x 800 mg for seven days with respect to the duration of blistering and acute pain. These results, together with previous pharmacokinetic evidence, led to the choice of brivudine 125 mg once daily as the treatment of choice.

Study 5-I-b

The Phase III 5-Ho-b study was conducted in 1,227 patients to statistically confirm the comparison between brivudine 1 x 125 mg for seven days and aciclovir 5 x 800 mg for seven days in immunocompetent patients with herpes zoster. A subgroup of patients aged 50 years or older was also assessed separately.

The graphic presentation of the risk ratios calculated with the "Cox proportional hazards" model for the 1 x 125 mg brivudine group compared to the 5 x 800 mg acyclovir group is shown in Figure 2.

Study 5-Ho-c: Reduction of the duration of treatment

To evaluate the efficacy of three-day treatment with brivudine 125 mg single daily dose in patients with herpes zoster, another large study was conducted using exactly the same schedule as 5-Ho-b. Brivudine 125 mg once daily for three days (followed by four days of placebo) was compared with aciclovir 800 mg 5 times daily for 7 days.

A total of 1,336 patients were recruited. The results show that this brivudine dosing regimen is not inferior to standard-dose aciclovir treatment, relative to the primary efficacy variable. In any case, it was not possible to establish greater effectiveness.

These data obtained with shortened treatment duration demonstrate that brivudine is effectively effective against herpes zoster when administered once daily in immunocompetent adults, and confirm the validity of the results obtained in previous studies.

Primary efficacy variable

For the primary parameter, the superiority of the brivudine group over aciclovir could be established. The confirmatory test procedure was statistically significant at the 5% level. The estimated hazard ratio was 1.14 (for the "Per Protocol population"), indicating an improved effect of 14% (the "endpoint" was reached faster) for patients treated with brivudine 1 x 125 mg compared to patients treated with acyclovir. The corresponding mean indicative value of "time from start of treatment to last herpes zoster vesicle eruption" was reduced by 25% for brivudine (mean: 13.5 hours) compared to aciclovir (mean: 18.0 hours).

Therefore, for the primary efficacy variable, treatment with brivudine was statistically significantly superior to treatment with aciclovir.

Secondary efficacy variables

Statistical tests for all secondary efficacy variables, including clinically relevant pain parameters, showed the equivalence between 1 x 125 mg brivudine and aciclovir 5 x 800 mg.

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

The subgroup analysis in patients aged 50 and over gave results similar to those obtained in the overall population, with an 18% improvement in the effect for the primary efficacy variable in patients treated with brivudine compared to those treated with aciclovir.

The superiority of brivudine over aciclovir could be statistically confirmed for the primary efficacy variable. Non-inferiority could be demonstrated at a significance level of 5% for all secondary variables, including pain parameters.

For the subpopulation of patients aged 50 or older, an even more favorable effect could be seen in relation to the primary efficacy parameter for brivudine compared to aciclovir.

Post-study surveillance in post-herpetic neyralgia

Two retrospective post-study surveillance was conducted under double-blind conditions according to the GCP standard to verify the appearance of post-herpetic neuralgia (PHN) in patients aged 50 years or older:

1) selected from studies 5-Ho-a and 5-Ho-b (7 days of brivudine versus 7 days of aciclovir treatment)

2) selected from 5-Ho-c studies (3 days of brivudine versus 7 days of aciclovir treatment)

Patients interviewed who reported pain related to zoster were invited to the center at the end of the study and examined by the researchers to confirm incidence of PHN and to answer questionnaires relating to the characteristics of the pain. PHN was defined as pain in herpes zoster dermatomes after the conclusion of the individual study (patients terminated studies 5-Ho-a, 5-Ho-b, and 5-Ho-c when all scabs had fallen off, or at 35th day after treatment, whichever came first).

The studies were conducted blinded (both patients and researchers were unaware of the treatment during studies 5-Ho-a, 5-Ho-b and 5-Ho-c), validating the results obtained.

1. Post-study surveillance of PHN following brivudine treatment for seven days

A large sample of 608 male and female patients aged 50 or over from studies 5-Ho-a and 5-Ho-b were retrospectively reviewed (between 8 and 17 months after treatment) to evaluate the effect of brivudine in the prevention of post-herpetic neuralgia. In the group of patients initially treated with 125 mg brivudine for seven days, 32.7% reported pain from post-herpetic neuralgia at the end of the study, while in the aciclovir group the proportion was 43.5%. Therefore, the risk relating to the incidence of post-herpetic neuralgia was 25% lower in the brivudine 125 mg group than in the aciclovir group. This is a statistically significant reduction that can be considered a clinically relevant benefit of brivudine.

2. Post-study surveillance of PHN following brivudine treatment for 3 days

This study included patients aged 50 years or older who received a three-day regimen of 125 mg brivudine or the standard seven-day aciclovir treatment from study 5-Ho-c. Patients were interviewed between 3 and 8 months after treatment.

The results show that the incidence of post-herpetic neuralgia in patients who received a regimen of brivudine 125 mg once daily for three days is comparable to that of patients who received standard-dose aciclovir for seven days (41,6 % versus 39.7%, respectively).

These additional data support the evidence that brivudine 125 mg, given once daily for three days, is not inferior to acyclovir in the treatment of herpes zoster.

Brief description of the figures

Figures 1 and 2: Risk ratios and "one-sided lower 95%" confidence interval

Comparison of 1 x 125 mg brivudine versus 5 x 800 mg aciclovir (Per Protocol Population).

Hazard ratios are calculated from Cox regression with covariants. A hazard ratio greater than 1 indicates a greater treatment efficacy of brivudine than aciclovir.

^ 11 lower limit of the one-sided 95% confidence interval "above the line at 0.8 (dashed) demonstrates non-inferiority and above 1.0 (solid line) demonstrates the superiority of brivudine 1 x 125 mg over 5 x 800 mg acyclovir.

♦ risk ratio

1 lower 95% CI

Examples

The invention will be illustrated by the following non-limiting examples:

Example 1: Immediate-release brivudine 125 mg tablet

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8 - Immediate-release capsules

Example 9 - Immediate release coated tablet

Claims (7)

CLAIMS 1. Use of brivudine for the preparation of a pharmaceutical composition for single daily administration. Use according to claim 1, wherein the amount of brivudine is between 50 and 300 mg. Use according to claim 2, wherein said amount varies from 100 to 200 mg. Use according to claim 3, wherein said amount is 125 mg. Use according to any one of the preceding claims, in which the pharmaceutical composition is selected from capsule and tablet, optionally with modified release. 6. Use according to claim 5, wherein said composition is selected from the following: brivudine 125 mg, microcrystalline cellulose 74 mg, lactose monohydrate 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water up to 245 mg total; brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water up to 245 mg total; brivudine 125 mg, microcrystalline cellulose 74 mg, lactose 37 mg, povidone K-value 25 6.5 mg, magnesium stearate 2.5 mg, purified water up to 245 mg total; brivudine 125 mg, microcrystalline cellulose 74 mg, corn starch 37 mg, VA64 25 copovidone 6.5 mg, magnesium stearate 2.5 mg, purified water up to 245 mg total; 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, purified water up to 250 mg total; brivudine 125 mg, microcrystalline cellulose / aerosil 122.5 mg, magnesium stearate 2.5 mg, purified water up to 250 mg total; brivudine 125 mg, microcrystalline cellulose / aerosil 100.5 mg, collidone CL 22.0 mg, magnesium stearate 2.5 mg, purified water up to 250 mg total; brivudine 125 mg, microcrystalline cellulose 122.5 mg, magnesium stearate 2.5 mg, purified water up to 250 mg total; 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; 7. Use of brivudine according to any one of the preceding claims in the treatment and prevention of post-herpetic neuralgia.