GB2370771A

GB2370771A - Once-a-day pharmaceutical composition comprising brivudine

Info

Publication number: GB2370771A
Application number: GB0110682A
Authority: GB
Inventors: Alessandro Casini; Bettina Stubinski; Attilio Crea
Original assignee: Berlin Chemie AG; Menarini Ricerche SpA
Current assignee: Berlin Chemie AG; Menarini Ricerche SpA
Priority date: 2001-01-03
Filing date: 2001-05-01
Publication date: 2002-07-10
Also published as: ITMI20010009A0; FR2818907B1; ES2192456A1; PT102642A; PL348480A1; CZ20012464A3; DK177084B1; FI20011446A; HRPK20010345B3; AT6141U1; DK200101019A; CH695662A5; PT102642B; SE0102309L; IE20010413A1; UA76402C2; HUP0102816A2; FI20011446A0; GB0110682D0; HRP20010345A2

Abstract

Use of brivudine in the preparation of an oral pharmaceutical composition for the once-a-day treatment of herpes zoster infections or post-herpetic neuralgia. The amount of brivudine in each dose may be between 50 and 300 mg, preferably 125 mg. Use of a once daily dosage regimen improves patient compliance.

Description

ONCE-A-DAY PHARMACEUTICAL COMPOSITION CONTAINING

BRIVUDINE

Scope of the invention 5 The present invention refers to once-daily pharmaceutical compositions containing the antiviral Brivudine for the treatment of acute herpes zoster infections and their use in preventing the occurrence of post-herpetic neuralgia. State of the art lo During the last ten years, the number of clinically useful drugs introduced for the chemotherapy of viral diseases has increased considerably.

Since its introduction in 1982, oral acyclovir has been widely used in the

treatment of acute herpes poster in immunocompetent patients. However, a major disadvantage of acyclovir therapy is that, due to its limited is bioavailability, frequent and high doses are required, which often leads to poor compliance.

This has led to the development of a new antiviral (penciclovir) and to so-called prodrugs such as valaciclovir (the prodrug of acyclovir) and famciclovir (the prodrug of penciclovir). To date, famciclovir offers the most no convenient treatment of acute herpes zoster in elderly patients, with a dosage of three tablets or capsule daily, compared to five tablets daily for acyclovir and six tablets daily for valaciclovir. Famciclovir relieves the acute signs and symptoms of herpes zoster as acyclovir does, and provides protection against the prolonged herpes zoster-associated pain or PHN. Taken less frequently, in as lower dosages, and without an increased risk of adverse events compared to acyclovir, such treatment is advantageous and more convenient, particularly for elderly patients. The recommended daily dosage varies 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).

Brivudin, a nucleoside analogue, is a potent virostatic agent with selective activity against varicella zoster virus (VZV) and herpes simplex 5 virus type 1 (HSV-1) (De Clercq et al., 1979, Proc. Natl. Acad Sci. USA, 76, 2947-2951; De Clercq et al, 1980, J. Infect. Dis. 141, 563- 574). While the synthesis of viral DNA is inhibited, the cellular functions remain largely unaffected. The continued development of Brivudin during the last years has been directed at the treatment of VZV infections in immunocompetent to patients.

Based on the results of a number of non-controlled and controlled studies Brivudine was registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised patients at a dosage of 125 mg three or four times daily (DeClercq 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 the Fachinformation united to the pharmaceutical product Helping marketed in the German territory in 1992).

Disclosure of the invention

In recent, large, multi-national studies on immunocompetent patients to with herpes Foster, a once daily dosage regimen of 125 mg brivudin per day for 7 days was surprisingly shown to be statistically superior to the standard five times daily oral treatment with 800 mg acyclovir, with respect to dermatological endpoints (5-Ho-b/0078BC). A post-study surveillance of patients aged 50 years or older who had participated in these studies, and who :5 had experienced PHN after study termination, indicated a significantly lower incidence of PHN after treatment with Brivudin compared to acyclovir (5-

Ho[a+b+c]PHN/0078BC). Brivudin therefore surprisingly offers the possibility of treating herpes zoster patients with a single 125 mg tablet per day, instead of the high and

frequent dosage schedules of acyclovir, valaciclovir, or famciclovir. A single 125 mg tablet per day is even more surprising if considered in relation to the previously scheduled 125 mg four times daily as registered in Germany in 1990 for the treatment of HSV-1 and VZV infections in immunocompromised s patients With this once daily dosage schedule a further surprising result was achieved: that of reducing the incidence of Postherpetic Neuralgia.

Experimental To assess the efficacy and safety of brivudin in immunocompetent adult patients with herpes poster, three large pivotal studies (studies S-Ho-a, S-Ho-b lo and S-Ho-c) were recently performed according to GCP standard. All four studies were prospective and had a multicentre, double-blind, randomised parallel design.

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

The primary parameter to assess efficacy was 'time from start of treatment to last eruption of new vesicles' in all three studies. This parameter parallels viral replication in the skin and therefore describes the virostatic potency of a drug. It is accepted in the literature and considered as the most to reliable clinical sign with respect to other cutaneous manifestations. Further parameters to assess the resolution of skin rash were 'time from start of treatment to start of crusting', 'time from start of treatment to complete crusting' and 'time from start of treatment to loss of crusts'. Dissemination of skin lesions and the occurrence of other complications were also assessed.

as In the literature the most frequently used measures to judge the benefit of antiviral therapy in herpes zoster are the duration of skin rash and the occurrence and intensity of pain during the acute phase of the infection.

Lately, however, postherpetic neuralgia has become of increasing importance in the assessment of the benefit of antiviral therapies. Thus, to assess the

possible effect of Brivudin on reducing the incidence of post-herpetic neuralgia in a preliminary manner, retrospective double-blind post-study surveillance studies were additionally conducted on patients aged 50 or older that had been enrolled into studies.

s Table 1 lists the trials performed in immunocompetent patients with herpes zoster. Former uncontrolled studies performed in immunocompromised patients, which provided early evidence of the potential benefit of brivudin, will not be discussed.

TABLE 1: OVERVIEW OF CLINICAL TRIALS

Studv code Description Treatment arms and daily dosage

-: (7-daytreat nentunless otherwise - snecif led) i; . . 5-Ho-a Dosefinding study Brivudin 125 mg x 1 (Phase II) Brivudin 62.5 mg x 1 Brivudin 31.25 mg x 1 Acyclovir 800 mg x 5 5-Ho-b Confirmatory efficacy Brivudin 125 mg x 1 study Acyclovir 800 mg x 5 (Phase III) . 5-Ho-c Confirmatory efficacy Briwdin 125 mg x 1 for 3 days study Acyclovir 800 mg x 5 (Phase III) 5-Ho-a+b- Post-study surveillance on Brivudin 125 mg x 1 PHN PHN Acyclovir 800 mg x 5 5-Ho-c-PHN Post-study surveillance on Brivudin 125 mg x 1 for 3 days PHN Acyclovir 800 mg x 5 _ These clinical trials are presented below in a chronological order.

Study 5-Ho-a Since brivudin plasma concentrations in man receiving 125 mg once a day are 10 to 50-fold the IC50 of clinical strains of Varicella roster virus and, additionally, human pharmacokinetic data showed that brivudin plasma concentrations are maintained above the IC50 for 24 hours following a single administration of brivudin 125 ma, the reasonable assumption was made that a

once daily application of 125 mg briwdin would be sufficient for the treatment of herpes poster.

Study 5-Ho-a, a Phase II study performed in 642 patients, therefore evaluated a once daily administration of brivudin 125 mg for seven days in s comparison to 5 x 800 mg acyclovir for seven days in an exploratory manner.

Two study arms with once daily brivudin doses of 62.5 mg and 32.25 mg for seven days were added to also assess the efficacy of lower doses. This study demonstrated that 1 x 125 mg brivudin for 7 days in patients lo with acute herpes zoster is as effective as the treatment with 5 x 800 mg acyclovir for 7 days with respect to the primary parameter "time from start of treatment to last eruption of rzew vesicles" as well as with respect to all secondary parameters, including "time from start of treatment to cessation of pain (intensity none or mild)" as the clinically more relevant secondary parameter. Statistical analysis of the primary efficacy parameter and the pain parameter demonstrated non- inferiority of 1 x 125 mg brivodin compared to acyclovir. For the parameter "time from start of treatment to complete crusting" superiority could be achieved in an exploratory manner. A graphical presentation of the risk ratios calculated from the Cox proportional hazards 20 model for the 1 x 125 mg brivudin group compared to the 5 x 800 mg acyclovir group is presented in Figure 1.

Brivudin has a linear dose-effect relationship. Superiority to placebo was demonstrated to a statistically and clinically significant extent in immunocompetent patients with acute herpes zoster infection. Brivudin 2s treatment with a dose of 1 x 125 mg for seven days is at least as effective as the treatment with 5 x 800 mg acyclovir for seven days as regards the duration of vesicle appearance and acute pain. These results, together with the previous pharmacokinetic considerations, led to the selection of brivudin 125 mg once daily as the treatment of choice.

Study 5-Ho-b The Phase III study 5-Ho-b was performed in 1227 patients to provide confirmatory statistics for the comparison of 1 x 125 mg brivudin for seven days and 5 x 800 mg acyclovir for seven days in immunocompetent patients 5 with herpes Roster. A subgroup of patients aged 50 and older was also evaluated separately.

A graphical presentation of the risk ratios calculated from the Cox proportional hazards model for the 1 x 125 mg brivudin group compared to the 5 x 800 mg acyclovir group is presented in Figure 2.

lo Study 5-No-c: Reduction of treatment duration In order to assess the efficacy of a three day treatment with brivudin 125 mg once daily in patients with herpes zoster, another large study was performed using exactly the same study design as study 5-Ho-b. Brivudin 125 mg once daily for three days (followed by four days of placebo) was Is compared to acyclovir 800 mg 5 times daily for 7 days.

A total of 1336 patients were enrolled. The results show that this dosage regimen of brivudin is non-inferior to treatment with acyclovir at the standard dosage for the primary efficacy variable. Superiority could, however, not be established.

zo These data with a reduced treatment duration therefore support the notion that brivudin is indeed an effective treatment given once daily for herpes zoster in immunocompetent adults and support the validity of the results obtained in the previous studies.

Primary efficarv variable as For the primary parameter superiority of the brivudin group compared with acyclovir could be established. The confirmatory test procedure was statistically significant at the 5% level. The estimated risk ratio was 1.14 (for the Per Protocol population), indicating a 14% better effect (endpoint was reached faster) for patients treated with 1 x 125 mg brivudin as compared to

patients treated with acyclovir. The corresponding descriptive mean value for the 'time from start of treatment to last eruption of herpes poster vesicles' was 25% smaller for brivudin (mean: 13.5 hours) than for acyclovir (mean: 18.0 hours). s Thus, for the primary efficacy variable brivudin treatment was demonstrated confirmatorily to be statistically significantly superior to acyclovir treatment.

Secondary efficarv variables The statistical tests for all secondary efficacy variables, including the lo clinically relevant pain parameters, showed equivalence of 1 x 125 mg brivudin as compared to 5 x 800 mg acyclovir.

Dissemination of skin lesions (brivudin: 1; acyclovir: 2) and other complications (brivudin: O; acyclovir: 6) occurred in less than 1% of patients in both groups.

is The subgroup analysis in patients aged 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 brivudin as compared to those treated with acyclovir.

Superiority of brivudin over acyclovir could be demonstrated by to confirmatory statistics for the primary efficacy variable. Noninferiority could be demonstrated at the 5% significance level for all secondary variables, including pain parameters.

For the subpopulation of patients aged 50 or older an even greater benefit concerning the primary efficacy parameter was found for brivudin 25 compared to acyclovir.

Post-studv surveillance on Postherpetic Neuralgia Two retrospective poststudy surveillances were performed under double-blind conditions to GCP standard to investigate the occurrence of postherpetic neuralgia (PHN) in patients aged 50 or older:

1) selected from studies 5-Ho-a and 5-Ho-b (7-day brivudin vs. 7-day acyclovir treatment) 2) selected from study 5-Ho-c (3-day brivudin vs. 7day acyclovir treatment) s Patients who, following a telephone contact, reported zoster-related pain after the end of the study were invited to the centre and examined by the investigator to confirm the incidence of PHN and to answer questions relating to the characteristics of pain. PHN was defined as pain in herpes poster affected dermatomes after the individual study termination (patients had to lo terminate studies 5-Ho-a, 5-Ho-b and 5-Ho-c when all crusts had fallen off, or on day 35 after start of treatment, whichever occurred first).

The studies were performed under blinded conditions (both the patients and the investigators were still unaware of the treatment that had been administered during the studies 5-Ho-a, 5-Ho-b and 5-Ho-c), which strongly Is validates the results of these studies.

1. Post-studv surveillance or' PHN following a seven-day brivadin treatment A large sample of 608 male and female patients aged 50 or older from studies 5-Ho-a and 5-Ho-b were re-examined retrospectively (between 8 and 17 months following treatment) to assess the benefit of brivudin in preventing so the occurrence of postherpetic neuralgia. In the patient group formerly treated with 125 mg brivudin for seven days' 32.7% reported suffering from postherpetic neuralgia after study termination, whereas in the acyclovir treatment group the proportion was 43.5%. Thus, the relative risk for the incidence of postherpetic neuralgia was 25% lower in the 125 mg briwdin 25 group compared to the acyclovir group. This was a statistically significant reduction and can be regarded as a clinically relevant benefit of briwdin.

2. Post-studv surveillance on PHN following a three-day brivadin treatment This study included patients aged 50 years or older who had received the three-day course of brivudin 125 mg or the standard seven- day dosage

schedule of acyclovir in study 5-Ho-c. Patients were questioned between 3 and 8 months following treatment.

The results show that the incidence of postherpetic neuralgia in patients who received a three-day course of brivudin 125 mg once daily is comparable 5 to that of patients who received acyclovir at the standard dosage for seven days (41.6% vs. 39.7 /O, respectively).

These additional data support the evidence that brivudin 125 ma, given once daily for only three days, is non-inferior to acyclovir in the treatment of herpes poster.

lo Examples

The following can be considered non-limitative example of the present invention: Examplel: 1 Brivudin 125 mg tablet-immediate release tablets No. raw material ma/ tablet 1 brivudin 125.0 2 microcrystalline 74.0 cellulose 3 lactose-monohydrat 37.0 4 povidon. K-value 25 6.5 5 magnesium stearate 2.5 6 purified water 245.0

Exemple 2 No. Raw material Mg / tablet 1 Brivudin 125.0 2 microcrystalline 74.0 cellulose 3 cornstarch 37.0 4 povidon. K-value 25 6. 5 5 magnesium stearate 2.5 6 purified water 245.0 _

Exemple 3 No. Raw material ma/ tablet 1 brivudin 125.0 2 cellulose powder 74.0 3 Lactose 37.0 4 povidon, K-value 25 6.5 S magnesium stearate 2.5 6 purified water 245.0 5 Example 4

No. raw material ma/ tablet 1 brivudin 125.0 2 microcrystalline 74.0 cellulose 3 cornstarch 37.0 4 copovidon VA 64 6.5 5 magnesium stearate 2. 5 6 purified water 245.0

Example 5

No. raw material mg/tablet 1 brivudin 125.0 2 microcrystalline 74.0 cellulose 3 lactose 37.0 4 copovidon. VA 64 6.5 5 collidone CL 5.0 6 magnesium stearate 2.5 7 purif ed water 250.0 Example 6

No. raw material ma/ tablet 1 brivudin 125.0 2 microcrystalline cellulose/aerosil 98/2 122.5 3 magnesium stearate 2.5 4 purified water 250.0 5 Example 7

No. raw material ma/ tablet 1 briwdin 125.0 2 microcrystalline cellulose/aerosil 98/2 100.5 3 collidone CL 22.0 4 magnesium stearate 2.5 5 purified water 250.0 Example 8- immediate release capsule No. Raw material mg powder/ capsule 1 brivudin 125.0 2 microcrystalline cellulose 122.5 3 magnesium stearate 2.5 4 purified water 250.0

Example 9- immediate release coated tablet No. raw material ma/ tablet | 1 brivudin 125.0 2 microcrystalline 74.0 cellulose 3 lactose-Monohydrat 32.0 4 Aerosil S.O S copovidon. VA 64 6.5 6 magnesium stearate 2.5 7 Hydroxypropyl-methyl - S. O cellulose 8 Macrogol 6000 1.5 9 Titandioxid 4. 5 256.0

FIGURE 1: RISK RATIOS* AND ONE-SIDED LOWER 95% CONFIDENCE

INTER CAL

COMPARISON OF I X 125 MG BRIVUDIN VS. 5 X 800 MG ACYCLOVIR

(PER PROTOCOL POPULATION)

1.5 tires from start of treatment to last eruption start of full loss of cessation of pain 0.5 (prirrary parameter) crusting none or mild none s * Risk ratios calculated from Cox regression with covariates. A risk ratio greater than 1 indicates better risk ratio treatment effect of brivudin vs. acyclovir l Lower limit of the one-sided 95 % confidence I interval above the 0.8 line (dashed line) demonstrates I lower non-inferiority and above the 1.0 line (solid line) 95 % CI demonstrates superiority of 1 x 125 mg brivudin vs. 5 x 800 mg acyclovir.

t FIGURE 2: RISK RATIOS* AND ONE-SIDED LOWER 95% CONFIDENCE

INTER CAL

COMPARISON OF I X 125 MG BRIVUDIN VS. 5 X 800 MG ACYCLOVIR

(PER PROTOCOL POPULATION)

1.5 time from start of treatrrent to o I, I I I I last eruption start of full loss of cessation of pain (primary parameter) crusting none or nild none 0.5 _

* Risk ratios calculated from Cox regression with covariates. A risk ratio greater than 1 indicates better risk ratio treatment effect of brivudin vs. acyclovir I Lower limit of the one-sided 95 % confidence I interval above the 0.8 line (dashed line) demonstrates I lower non- inferiority and above the 1.0 line (solid line) 95 % CI demonstrates superiority of 1 x 125 mg brivudin vs. 5 x 800 mg acyclovir.

Claims

1. The use of brivudine in the preparation of a pharmaceutical oral composition for the once-a-day treatment of herpes zoster infections or post-herpetic neuralgia.

2. A use according to claim 1, in which the amount of active ingredient in the once-a-day treatment is from 50 to 300 ma.

3. use according to claim 2, in which the amount of active ingredient is from 100 to200mg.

4. A use according to claim 3, in which the amount of active ingredient is about 125 ma.

5. A use according to claim 4, in which the composition is selected from the group consisting of: (a) brivudine 125 ma, microcrystalline cellulose 74 ma, lactose monohydrate 37 ma, povidon K-value 25 6.5 ma, magnesium stearate 2.5 ma, purified water to 245 mg total; (b) brivudine 125 ma, microcrystalline cellulose 74 ma, cornstarch 37 ma, povidon K-value 25 6. 5 ma, magnesium stearate 2.5 ma, purified water to 245 mg total; (c) brivudine 125 ma, microcrystalline cellulose 74 ma, lactose 37 ma, povidon K value 25 6.5 ma, magnesium stearate 2.5 ma, purified water to 245 mg total; (d) brivudine 125 ma, microcrystalline cellulose 74 ma, cornstarch 37 ma, copovidon VA64 6.5 ma, magnesium stearate 2.5 ma, purified water to 245 mg total; (e) brivudine 125 ma, microcrystalline cellulose 74 ma, lactose 37 ma, copovidon VA64 6.5 ma, collidone CL 5.0 ma, magnesium stearate 2.5 ma, purified water to 250 mg total; (f) brivudine 125 ma, microcrystalline cellulose/aerosil 122.5 ma, magnesium stearate 2.5 ma, purified water to 250 mg total,

(g) brivudine 125 ma, microcrystalline cellulose/aerosil 100.5 ma, collidone CL 22.0 ma, magnesium stearate 2.5 ma, purified water to 250 mg total; (h) brivudine 125 ma, microcrystalline cellulose 122.5 ma, magnesium stearate 2.5 ma, purified water to 250 mg total (immediate release); and (i) brivudine 125 ma, microcrystalline cellulose 74.0 ma, lactose-monohydrate 32.0 ma, aerosil 5.0 ma, copovidon VA64 6.5 ma, magnesium stearate 2.5 ma, macrogol 6000 1.5 ma, titaniumdioxide 4.5 mg (immediate release coated tablets).

6. A pack of brivudine tablets, each tablet containing from 50 to 300 mg brivudine together with pharmaceutical carriers and excipients for oral administration, the pack designed and disposed for the administration of single daily doses of one tablet.

7. A pack according to claim 6, in which each tablet contains 100 to 200 mg brivudine.

8. A pack according to claim 7, in which each tablet contains about 125 mg brivudine.