Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Direct acting antivirals, nucleosides and nucleotides (excl. reverse transcriptase inhibitors), ATC code: J05A B04.

Mechanism of action
Ribavirin (Rebetol) is a synthetic nucleoside analogue which has shown in vitro activity against some RNA and DNA viruses. The mechanism by which Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b exerts its effects against HCV is unknown. Oral formulations of Rebetol monotherapy have been investigated as therapy for chronic hepatitis C in several clinical trials.
Results of these investigations showed that Rebetol monotherapy had no effect on eliminating hepatitis virus (HCV-RNA) or improving hepatic histology after 6 to 12 months of therapy and 6 months of follow-up.

Clinical trials efficacy and safety in adult subjects
Tritherapy:
Refer to the SmPC for boceprevir.

Bitherapy:
The use of Rebetol in combination treatment with peginterferon alfa-2b or interferon alfa-2b was evaluated in a number of clinical trials. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

Naïve patients
Three trials examined the use of interferon in naïve patients, two with Rebetol + interferon alfa-2b (C95-132 and I95-143) and one with Rebetol + peginterferon alfa-2b (C/I98-580). In all cases the treatment was for one year with a follow-up of six months. The sustained response at the end of follow-up was significantly increased by the addition of Rebetol to interferon alfa-2b (41 % vs 16 %, p < 0.001).

In clinical trials C95-132 and I95-143, Rebetol + interferon alfa-2b combination therapy proved to be significantly more effective than interferon alfa-2b monotherapy (a doubling in sustained response). Combination therapy also decreased the relapse rate. This was true for all HCV genotypes, particularly Genotype 1, in which the relapse rate was reduced by 30 % compared with interferon alfa-2b monotherapy.

In clinical trial C/I98-580, 1,530 naïve patients were treated for one year with one of the following combination regimens:
•      Rebetol (800 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week) (n = 511).
•      Rebetol (1,000/1,200 mg/day) + peginterferon alfa-2b (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) (n = 514).
•      Rebetol (1,000/1,200 mg/day) + interferon alfa-2b (3 MIU three times a week) (n = 505).

In this trial, the combination of Rebetol and peginterferon alfa-2b (1.5 micrograms/kg/week) was significantly more effective than the combination of Rebetol and interferon alfa-2b, particularly in patients infected with Genotype 1. Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of Rebetol administered in combination with peginterferon alfa-2b or interferon alfa-2b. In those patients that received > 10.6 mg/kg Rebetol (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received  10.6 mg/kg Rebetol (Table 5), while response rates in patients that received > 13.2 mg/kg Rebetol were even higher.



Table 5   Sustained response rates with Rebetol + peginterferon alfa-2b (by Rebetol dose [mg/kg], genotype and viral load)
HCV Genotype              Rebetol dose P 1.5/R             P 0.5/R                     I/R (mg/kg)
All Genotypes             All             54 %             47 %                        47 %  10.6          50 %             41 %                        27 %
> 10.6          61 %             48 %                        47 %
Genotype 1                All             42 %             34 %                        33 %  10.6          38 %             25 %                        20 %
> 10.6          48 %             34 %                        34 %
Genotype 1               All             73 %             51 %                        45 %  600,000 IU/ml           10.6          74 %             25 %                        33 % > 10.6          71 %             52 %                        45 %
Genotype 1               All             30 %             27 %                        29 % > 600,000 IU/ml           10.6          27 %             25 %                        17 % > 10.6          37 %             27 %                        29 %
Genotype 2/3              All             82 %             80 %                        79 %  10.6          79 %             73 %                        50 %
> 10.6          88 %             80 %                        80 %
P1.5/R         Rebetol (800 mg) + peginterferon alfa-2b (1.5 micrograms/kg) P0.5/R         Rebetol (1,000/1,200 mg) + peginterferon alfa-2b (1.5 to 0.5 microgram/kg) I/R            Rebetol (1,000/1,200 mg) + interferon alfa-2b (3 MIU)

In a separate trial, 224 patients with genotype 2 or 3 received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with ribavirin 800 mg –1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 6). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).


Table 6   Virologic Response at End of Treatment, Sustained Virologic Response and Relapse by HCV Genotype and Viral Load*
Rebetol 800-1,400 mg/day plus peginterferon alfa-2b 1.5 g/kg once weekly
End of Treatment      Sustained Virologic            Relapse
Response              Response
All Subjects         94 % (211/224)        81 % (182/224)                 12 % (27/224) HCV 2               100 % (42/42)         93 % (39/42)                   7 % (3/42)  600,000        100 % (20/20)         95 % (19/20)                   5 % (1/20) IU/ml
> 600,000        100 % (22/22)         91 % (20/22)                   9 % (2/22) IU/mL
HCV 3               93 % (169/182)        79 % (143/182)                 14 % (24/166)  600,000        93 % (92/99)          86 % (85/99)                   8 % (7/91) IU/ml
> 600,000        93 % (77/83)          70 % (58/83)                   23 % (17/75) IU/ml
* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow- up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.



In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received peginterferon alfa-2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).
Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two peginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 μg/kg and 1 μg/kg subcutaneously once weekly both in combination with Rebetol 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 μg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 7).

Table 7 Virologic response at treatment week 12, end of treatment response, relapse rate* and Sustained Virologic Response (SVR)

Treatment group                                   % (number) of patients peginterferon alfa-2b     peginterferon alfa-2b      peginterferon alfa-2a 1.5 µg/kg                  1 µg/kg                     180 µg
+ Rebetol                 + Rebetol                  + ribavirin
Undetectable HCV-RNA
40 (407/1,019)             36 (366/1,016)             45 (466/1,035) at treatment week 12
End of treatment
53 (542/1,019)             49 (500/1,016)             64 (667/1,035) response*
Relapse*                  24 (123/523)               20 (95/475)                32 (193/612) SVR*                    40 (406/1,019)             38 (386/1,016)             41 (423/1,035) SVR in patients with undetectable HCV-RNA              81 (328/407)               83 (303/366)               74 (344/466) at treatment week 12
*HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml
Lack of early virologic response by treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with peginterferon alfa-2b (1.5 μg/kg)/Rebetol combination therapy resulted in a higher sustained virologic response rate compared to peginterferon alfa-2b 1 μg/kg dose. At the peginterferon alfa- 2b 1.5 μg/kg plus Rebetol dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response in naïve patients
Virological response by week 12, defined as at least 2-log viral load decrease or undetectable levels of HCV RNA. Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 8).

Table 8    Predictive Value of In-Treatment Virologic Response while on peginterferon alfa-2b 1.5 µg/kg/Rebetol 800-1,400 mg Combination Therapy
Negative                             Positive

No response                                 Response at           No                          at
Treatment     sustained     Predictive   Treatment     Sustained      Predictive Week        Response        Value        Week        Response         Value Genotype 1*
By Week 4***
(n= 950)
HCV-RNA negative            834           539          65%            116           107          92% (539/834)                                 (107/116)
HCV-RNA negative             220           210          95%            730           392          54% or                                            (210/220)                                 (392/730) ≥ 1 log decrease in viral load
By Week 12***
(n= 915)
HCV-RNA negative             508           433          85%            407           328          81% (433/508)                                 (328/407)
HCV-RNA negative             206           205          N/A†           709           402          57% or                                                                                       (402/709) ≥ 2 log decrease in viral load
Genotype 2, 3**
By Week 12
(n=215)
HCV-RNA negative             2             1           50%           213           177          83% or                                                (1/2)                                  (177/213) ≥ 2 log decrease in viral load
*Genotype 1 receive 48 weeks treatment
**Genotype 2, 3 receive 24 weeks treatment
***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12.
†
These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2 log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased ≥ 2 log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

HCV/HIV Co-infected patients
Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 9. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol (800 mg/day) plus peginterferon alfa-2b (1.5 µg/kg/week) or Rebetol (800 mg/day) plus interferon alfa-2b (3 MIU TIW) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV. Patients were randomized to receive either Rebetol (800-1,200 mg/day based on weight) plus peginterferon alfa-2b (100 or 150 µg/week based on weight) or Rebetol (800-1,200 mg/day based on weight) plus interferon alfa-2b (3 MIU TIW). The duration of therapy was 48 weeks with a follow-up period of 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/ml (Amplicor) who were treated for 24 weeks with a 6 month follow-up period.

Table 9 Sustained virological response based on genotype after Rebetol in combination with peginterferon alfa-2b in HCV/HIV co-infected patients
Study 11                                Study 22
Rebetol         Rebetol                 Rebetol (800-   Rebetol (800- (800 mg/day) (800 mg/day) p             1,200 mg/day)d 1,200 mg/day)d +               +               value +                 +                p a                                              b peginterferon Interferon                peginterferon   Interferon alfa- value 
alfa-2b          alfa-2b (3 MIU               alfa-2b (100 or    2b
(1.5 µg /kg/     TIW)                         150c µg/week)      (3 MIU TIW) week)
All           27 %             20 % (41/205)       0.047    44 % (23/52)       21 % (9/43)       0.017 (56/205)
Genotype      17 %             6 % (8/129)         0.006    38 % (12/32)       7 % (2/27)        0.007 1, 4     (21/125)
Genotype      44 % (35/80)     43 % (33/76)        0.88     53 % (10/19)       47 % (7/15)       0.730      2, 3
MIU = million international units; TIW = three times a week.
a: p value based on Cochran-Mantel Haenszel Chi square test.
b: p value based on chi-square test.
c: subjects < 75 kg received 100 µg/week peginterferon alfa-2b and subjects ≥ 75 kg received 150 µg/week peginterferon alfa-2b .
d: Rebetol dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.
1
Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
2
Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Histological response
Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Rebetol in combination with peginterferon alfa-2b. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

Previously treated patients
- Retreatment of prior treatment failures (relapse and nonresponder patients) with peginterferon alfa-2b in combination with Rebetol:
In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alfa interferon/ribavirin were retreated with peginterferon alfa 2b, 1.5 microgram/kg subcutaneously, once weekly, in combination with weight adjusted Rebetol.
Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at Treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Responseweek 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 10).

Table 10       Rates of Response to retreatment in prior treatment failures Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatement
Overall interferon alpha/ribavirin           peginterferon alpha/ribavirin    Population* Response          SVR % (n/N)           Response        SVR % (n/N)      SVR % (n/N) week 12 %         99% CI                week 12 %       99% CI           99 % CI (n/N)                                   (n/N)
Overall            38.6              59.4                  31.5            50.4             21.7 (549/1,423)       (326/549)             (272/863)       (137/272)        (497/2,293) 54.0,64.8                             42.6, 58.2       19.5, 23.9
Prior Response
Relapse           67.7 (203/300)     59.6                 58.1            52.5             37.7 (243/645) (121/203)            (200/344)       (105/200)        32.8, 42.6
50.7, 68.5                           43.4, 61.6


Table 10         Rates of Response to retreatment in prior treatment failures Patients with undetectable HCV–RNA at treatment week 12 and SVR upon retreatement
Overall interferon alpha/ribavirin        peginterferon alpha/ribavirin     Population* Response          SVR % (n/N)        Response        SVR % (n/N)       SVR % (n/N) week 12 %         99% CI             week 12 %       99% CI            99 % CI (n/N)                                (n/N)
Genotype      59.7 (129/216) 51.2 (66/129)         48.6            44.3 (54/122)     28.6 (134/468) 1/4                                   39.8, 62.5         (122/251)       32.7, 55.8        23.3, 34.0 
Genotype        88.9 (72/81)       73.6 (53/72)      83.7 (77/92)     64.9 (50/77)     61.3 (106/173) 2/3                                    (60.2, 87.0)                       50.9, 78.9       51.7, 70.8
NR                 28.6 (258/903)     57.0              12.4             44.1 (26/59)     13.6 (147/258)         (59/476)         27.4, 60.7       (188/1,385)
49.0, 64.9                                          11.2, 15.9
Genotype      23.0 (182/790)     51.6 (94/182)     9.9 (44/446)     38.6 (17/44)     9.9 1/4                                    42.1, 61.2                         19.7, 57.5       (123/1,242) 7.7, 12.1
Genotype        67.9 (74/109)      70.3 (52/74)      53.6 (15/28)     60.0 (9/15)      46.0 (63/137) 2/3                                    56.6, 84.0                         27.4, 92.6       35.0, 57.0
Genotype
1                30.2               51.3              23.0             42.6 (69/162) 14.6 (343/1,135)        (176/343)         (162/704)        32.6, 52.6    (270/1,846) 44.4, 58.3                                       12.5, 16.7
2/3            77.1 (185/240)     73.0              75.6             63.5 (61/96)  55.3 (203/367)
(135/185)         (96/127)         50.9, 76.2    48.6, 62.0
64.6, 81.4
4             42.5 (17/40)       70.6 (12/17)      44.4 (12/27)     50.0 (6/12)      28.4 (19/67)
42.1, 99.1                         12.8, 87.2       14.2, 42.5
METAVIR
Fibrosis score
F2               46.0 (193/420)     66.8              33.6             57.7 (45/78)     29.2 (191/653) (129/193)         (78/232)         43.3, 72.1       24.7, 33.8
58.1, 75.6
F3             38.0 (163/429)     62.6              32.4             51.3 (40/78)     21.9 (147/672) (102/163)         (78/241)         36.7, 65.9       17.8, 26.0
52.8, 72.3
F4             33.6 (192/572)     49.5 (95/192)     29.7             44.8 (52/116) 16.5 (159/966) 40.2, 58.8        (116/390)        32.9, 56.7    13.4, 19.5
Baseline Viral
Load
HVL (>600,000       32.4 (280/864)     56.1              26.5             41.4 (63/152) 16.6 IU/ml)                                 (157/280)         (152/573)        31.2, 51.7    (239/1,441) 48.4, 63.7                                       14.1, 19.1
LVL (≤600,000       48.3 (269/557)     62.8              41.0             61.0 (72/118) 30.2 (256/848) IU/ml)                                 (169/269)         (118/288)        49.5, 72.6    26.1, 34.2 55.2, 70.4
NR: Non-responder defined as serum/plasma HCV-RNA positive at the end of a minimum of 12 weeks of treatment.
Plasma HCV-RNA is measured with a research-based quantitative polymerase chain reaction assay by a central laboratory
*Intent to treat population includes 7 patients for whom at least 12 weeks of prior therapy could not be confirmed.

Overall, approximately 36 % (821/2,286) of patients had undetectable plasma HCV-RNA levels at week 12 of therapy measured using a research-based test (limit of detection 125 IU/ml). In this subgroup, there was a 56 % (463/823) sustained virological response rate. For patients with prior failure on therapy with non-pegylated interferon or pegylated interferon and negative at week 12, the sustained response rates were 59 % and 50 %, respectively. Among 480 patients with > 2 log 
viral reduction but detectable virus at week 12, altogether 188 patients continued therapy. In those patients the SVR was 12%.

Non-responders to prior therapy with pegylated interferon alfa/ribavirin were less likely to achieve a week 12 response to retreatment than non-responders to non-pegylated interferon alfa/ribavirin (12.4% vs. 28.6%). However, if a week 12 response was achieved, there was little difference in SVR regardless of prior treatment or prior response.

- Retreatment of relapse patients with Rebetol and interferon alfa-2b combination treatment: Two trials examined the use of Rebetol and interferon alfa-2b combination treatment in relapse patients (C95-144 and I95-145); 345 chronic hepatitis patients who had relapsed after previous interferon treatment were treated for six months with a six month follow-up. Combination therapy with Rebetol and interferon alfa-2b resulted in a sustained virological response that was ten-fold higher than that with interferon alfa-2b alone (49 % vs 5 %, p < 0.0001). This benefit was maintained irrespective of standard predictors of response to interferon alfa-2b such as virus level, HCV genotype and histological staging.

Long-term efficacy data- Adults
Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with non-pegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon alfa-2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. 12 out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.
The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95- 99 %) for patients receiving non-pegylated interferon alfa-2b (with or without Rebetol), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).
SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and non-pegylated, with or without Rebetol) results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Ribavirin is absorbed rapidly following oral administration of a single dose (mean Tmax= 1.5 hours), followed by rapid distribution and prolonged elimination phases (single dose half-lives of absorption, distribution and elimination are 0.05, 3.73 and 79 hours, respectively). Absorption is extensive with approximately 10 % of a radiolabelled dose excreted in the faeces. However, absolute bioavailability is approximately 45 %-65 %, which appears to be due to first pass metabolism. There is a linear relationship between dose and AUCtf following single doses of 200-1,200 mg ribavirin. Volume of distribution is approximately 5,000 l. Ribavirin does not bind to plasma proteins.

Distribution
Ribavirin transport in non-plasma compartments has been most extensively studied in red cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the high volume of distribution of ribavirin. The ratio of whole blood:plasma ribavirin concentrations is approximately 60:1; the excess of ribavirin in whole blood exists as ribavirin nucleotides sequestered in erythrocytes.

Biotransformation
Ribavirin has two pathways of metabolism: 1) a reversible phosphorylation pathway; 2) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxyacid metabolite. Both ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are also excreted renally.

Ribavirin has been shown to produce high inter- and intra-subject pharmacokinetic variability following single oral doses (intrasubject variability of approximately 30 % for both AUC and Cmax), which may be due to extensive first pass metabolism and transfer within and beyond the blood compartment.

Elimination
Upon multiple dosing, ribavirin accumulates extensively in plasma with a six-fold ratio of multiple-dose to single-dose AUC12hr. Following oral dosing with 600 mg BID, steady-state was reached by approximately four weeks, with mean steady state plasma concentrations approximately 2,200 ng/ml.
Upon discontinuation of dosing the half-life was approximately 298 hours, which probably reflects slow elimination from non-plasma compartments.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

Food effect: The bioavailability of a single oral dose of ribavirin was increased by co-administration of a high fat meal (AUCtf and Cmax both increased by 70 %). It is possible that the increased bioavailability in this study was due to delayed transit of ribavirin or modified pH. The clinical relevance of results from this single dose study is unknown. In the pivotal clinical efficacy trial, patients were instructed to take ribavirin with food to achieve the maximal plasma concentration of ribavirin.

Renal function: Single-dose ribavirin pharmacokinetics were altered (increased AUCtf and Cmax) in patients with renal dysfunction compared with control subjects (creatinine clearance > 90 ml/minute).
This appears to be due to reduction of apparent clearance in these patients. Ribavirin concentrations are essentially unchanged by haemodialysis.

Hepatic function: Single-dose pharmacokinetics of ribavirin in patients with mild, moderate or severe hepatic dysfunction (Child-Pugh Classification A, B or C) are similar to those of normal controls.

Elderly patients ( 65 years of age): Specific pharmacokinetic evaluations for elderly subjects have not been performed. However, in a population pharmacokinetic study, age was not a key factor in the kinetics of ribavirin; renal function is the determining factor.

Population pharmacokinetic analysis was performed using sparsely sampled serum concentration values from four controlled clinical trials. The clearance model developed showed that body weight, gender, age, and serum creatinine were the main covariates. For males, clearance was approximately 20 % higher than for females. Clearance increased as a function of body weight and was reduced at ages greater than 40 years. Effects of these covariates on ribavirin clearance appear to be of limited clinical significance due to the substantial residual variability not accounted for by the model.