Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: antivirals for systemic use, nucleosides and nucleotides excl. reverse transcriptase inhibitors, ATC code: J05A B14.

Mechanism of action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir. After oral administration, valganciclovir is rapidly and extensively metabolised to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2’-deoxyguanosine and inhibits replication of herpes viruses in vitro and in vivo.
Sensitive human viruses include human cytomegalovirus (HCMV), herpes simplex virus-1 and -2 (HSV-1 and HSV-2), human herpes virus -6, -7 and -8 (HHV-6, HHV-7, HHV8), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and hepatitis B virus (HBV).

In CMV-infected cells, ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolised intracellularly. Triphosphate metabolism has been shown to occur in HSV- and HCMV- infected cells with half-lives of 18 and between 6 and 24 hours respectively, after the removal of extracellular ganciclovir. As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells.

The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by: (a) competitive inhibition of incorporation of deoxyguanosine-triphosphate into DNA by viral DNA polymerase, and (b) incorporation of ganciclovir triphosphate into viral DNA causing termination of, or very limited, further viral DNA elongation.

Antiviral activity

The in-vitro anti-viral activity, measured as IC50 of ganciclovir against CMV, is in the range of 0.08 M (0.02 g/ml) to 14 M (3.5 g/ml).

The clinical antiviral effect of Valcyte has been demonstrated in the treatment of AIDS patients with newly diagnosed CMV retinitis. CMV shedding was decreased in urine from 46 % (32/69) of patients at study entry to 7 % (4/55) of patients following four weeks of Valcyte treatment.

Clinical efficacy and safety

Adult patients
Treatment of CMV retinitis:
VALCYTE®                                                                                        Valcyte PI version 3 Patients with newly diagnosed CMV retinitis were randomised in one study to induction therapy with either Valcyte 900 mg b.i.d or intravenous ganciclovir 5 mg/kg b.i.d. The proportion of patients with photographic progression of CMV retinitis at week 4 was comparable in both treatment groups, 7/70 and 7/71 patients progressing in the intravenous ganciclovir and valganciclovir arms respectively.

Following induction treatment dosing, all patients in this study received maintenance treatment with Valcyte given at the dose of 900 mg once daily. The mean (median) time from randomisation to progression of CMV retinitis in the group receiving induction and maintenance treatment with Valcyte was 226 (160) days and in the group receiving induction treatment with intravenous ganciclovir and maintenance treatment with Valcyte was 219 (125) days.


Prevention of CMV disease in transplantation:
A double-blind, double-dummy, clinical active comparator study has been conducted in heart, liver and kidney transplant patients (lung and gastro-intestinal transplant patients were not included in the study) at high-risk of CMV disease (D+/R-) who received either Valcyte (900 mg od) or oral ganciclovir (1000 mg t.i.d.) starting within 10 days of transplantation until Day 100 post-transplant.
The incidence of CMV disease (CMV syndrome + tissue invasive disease) during the first 6 months post-transplant was 12.1 % in the Valcyte arm (n=239) compared with 15.2 % in the oral ganciclovir arm (n=125). The large majority of cases occurred following cessation of prophylaxis (post-Day 100) with cases in the valganciclovir arm occurring on average later than those in the oral ganciclovir arm.
The incidence of acute rejection in the first 6 months was 29.7 % in patients randomised to valganciclovir compared with 36.0 % in the oral ganciclovir arm, with the incidence of graft loss being equivalent, occurring in 0.8 % of patients, in each arm.

A double-blind, placebo controlled study has been conducted in 326 kidney transplant patients at high risk of CMV disease (D+/R-) to assess the efficacy and safety of extending Valcyte CMV prophylaxis from 100 to 200 days post-transplant. Patients were randomized (1:1) to receive Valcyte tablets (900 mg od) within 10 days of transplantation either until Day 200 post-transplant or until Day 100 post-transplant followed by 100 days of placebo.

The proportion of patients who developed CMV disease during the first 12 months post-transplant is shown in the table below.

Percentage of Kidney Transplant Patients with CMV Disease1, 12 Month ITT Population A Valganciclovir    Valganciclovir      Between
Treatment
900 mg od         900 mg od           Group Difference
100 Days          200 Days
(N = 163)         (N = 155)
Patients with confirmed or     71 (43.6%)        36 (23.2%)          20.3% 2 assumed CMV disease            [35.8% ; 51.5%]   [16.8% ; 30.7%]     [9.9% ; 30.8%] Patients with confirmed CMV    60 (36.8%)        25 (16.1%)          20.7% disease                        [29.4% ; 44.7%]   [10.7% ; 22.9%]     [10.9% ; 30.4%] 1 CMV Disease is defined as either CMV syndrome or tissue invasive CMV. 2 Confirmed CMV is a clinically confirmed  case of CMV disease. Patients were assumed to have CMV disease if there was no week 52 assessment and no confirmation of CMV disease before this time point.
A The results found up to 24 months were in line with the up to 12 month results: Confirmed or assumed CMV disease was 
48.5% in the 100 days treatment arm versus 34.2% in the 200 days treatment arm; difference between the treatment groups was 14.3% [3.2 %; 25.3%].

Significantly less high risk kidney transplant patients developed CMV disease following CMV prophylaxis with Valcyte until Day 200 post-transplant compared to patients who received CMV prophylaxis with Valcyte until Day 100 post-transplant.


VALCYTE®                                                                            Valcyte PI version 3 The graft survival rate as well as the incidence of biopsy proven acute rejection was similar in both treatment groups. The graft survival rate at 12 months post-transplant was 98.2 % (160/163) for the 100 day dosing regimen and 98.1 % (152/155) for the 200 day dosing regimen. Up to 24 month post- transplant, four additional cases of graft loss were reported, all in the 100 days dosing group. The incidence of biopsy proven acute rejection at 12 months post-transplant was 17.2% (28/163) for the 100 day dosing regimen and 11.0% (17/155) for the 200 day dosing regimen. Up to 24 month post- transplant, one additional case has been reported in the 200 days dosing group.

Viral resistance

Virus resistant to ganciclovir can arise after chronic dosing with valganciclovir by selection of mutations in the viral kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or the viral polymerase gene (UL54). In clinical isolates, seven canonical UL97 substitutions, M460V/I, H520Q, C592G, A594V, L595S, C603W are the most frequently reported ganciclovir resistance- associated substitutions. Viruses containing mutations in the UL97 gene are resistant to ganciclovir alone, whereas viruses with mutations in the UL54 gene are resistant to ganciclovir but may show cross-resistance to other antivirals that also target the viral polymerase.

Treatment of CMV retinitis:
Genotypic analysis of CMV in polymorphonuclear leucocytes (PMNL) isolates from 148 patients with CMV retinitis enrolled in one clinical study has shown that 2.2 %, 6.5 %, 12.8 %, and 15.3 % contain UL97 mutations after 3, 6, 12 and 18 months, respectively, of valganciclovir treatment.

Prevention of CMV disease in transplantation:
Active comparator study
Resistance was studied by genotypic analysis of CMV in PMNL samples collected i) on Day 100 (end of study drug prophylaxis) and ii) in cases of suspected CMV disease up to 6 months after transplantation. From the 245 patients randomised to receive valganciclovir, 198 Day 100 samples were available for testing and no ganciclovir resistance mutations were observed. This compares with 2 ganciclovir resistance mutations detected in the 103 samples tested (1.9 %) for patients in the oral ganciclovir comparator arm.

Of the 245 patients randomised to receive valganciclovir, samples from 50 patients with suspected CMV disease were tested and no resistance mutations were observed. Of the 127 patients randomised on the ganciclovir comparator arm, samples from 29 patients with suspected CMV disease were tested, from which two resistance mutations were observed, giving an incidence of resistance of 6.9 %.

Extending prophylaxis study from 100 to 200 days post-transplant
Genotypic analysis was performed on the UL54 and UL97 genes derived from virus extracted from 72 patients who met the resistance analysis criteria: patients who experienced a positive viral load (> 600 copies/ml) at the end of prophylaxis and/or patients who had confirmed CMV disease up to 12 months (52 weeks) post-transplant. Three patients in each treatment group had a known ganciclovir resistance mutation.

Paediatric population

Treatment of CMV retinitis:
The European Medicines Agency has waived the obligation to perform studies with Valcyte in all subsets of the paediatric population in the treatment of infection due to CMV in immuno-compromised patients (see section 4.2 for information on paediatric use).

Prevention of CMV disease in transplantation
A phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) receiving valganciclovir once daily for up to 100 days according to the paediatric dosing algorithm (see section 4.2) produced exposures similar to that in adults (see section VALCYTE®                                                                            Valcyte PI version 3 5.2). Follow up after treatment was 12 weeks. CMV D/R serology status at baseline was D+/R- in 40%, D+/R+ in 38%, D-/R+ in 19% and D-/R- in 3% of the cases. Presence of CMV virus was reported in 7 patients. The observed adverse drug reactions were of similar nature as those in adults (see section 4.8).

A phase IV tolerability study in paediatric kidney transplant recipients (aged 1 to 16 years, n=57) receiving valganciclovir once daily for up to 200 days according to the dosing algorithm (see section 4.2) resulted in a low incidence of CMV. Follow up after treatment was 24 weeks. CMV D/R serology status at baseline was D+/R+ in 45%, D+/R- in 39%, D-/R+ in 7%, D-/R- in 7% and ND/R+ in 2% of the cases. CMV viremia was reported in 3 patients and a case of CMV syndrome was suspected in one patient but not confirmed by CMV PCR by the central laboratory. The observed adverse drug reactions were of similar nature to those in adults (see section 4.8).

These data support the extrapolation of efficacy data from adults to children and provide posology recommendations for paediatric patients.

A phase I pharmacokinetic and safety study in heart transplant patients (aged 3 weeks to 125 days, n=14) who received a single daily dose of valganciclovir according to the paediatric dosing algorithm (see section 4.2) on 2 consecutive days produced exposures similar to those in adults (see section 5.2).
Follow up after treatment was 7 days. The safety profile was consistent with other paediatric and adult studies, although patient numbers and valganciclovir exposure were limited in this study.

Congenital CMV
The efficacy and safety of ganciclovir and/or valganciclovir was studied in neonates and infants with congenital symptomatic CMV infection in two studies.

In the first study, the pharmacokinetics and safety of a single dose of valganciclovir (dose range 14- 16-20 mg/kg/dose) was studied in 24 neonates (aged 8 to 34 days) with symptomatic congenital CMV disease (see section 5.2). The neonates received 6 weeks of antiviral treatment, whereas 19 of the 24 patients received up to 4 weeks of treatment with oral valganciclovir, in the remaining 2 weeks they received i.v. ganciclovir. The 5 remaining patients received i.v. ganciclovir for the most time of the study period. In the second study the efficacy and safety of six weeks versus six months of valganciclovir treatment was studied in 109 infants aged 2 to 30 days with symptomatic congenital CMV disease. All infants received oral valganciclovir at a dose of 16 mg/kg b.i.d. for 6 weeks. After 6 weeks of treatment the infants were randomized 1:1 to continue treatment with valganciclovir at the same dose or receive a matched placebo to complete 6 months of treatment.

This treatment indication is not currently recommended for valganciclovir. The design of the studies and results obtained are too limited to allow appropriate efficacy and safety conclusions on valganciclovir.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetic properties of valganciclovir have been evaluated in HIV- and CMV-seropositive patients, patients with AIDS and CMV retinitis and in solid organ transplant patients.

Dose proportionality with respect to ganciclovir AUC following administration of valganciclovir in the dose range 450 to 2625 mg was demonstrated only under fed conditions.Absorption Valganciclovir is a prodrug of ganciclovir. It is well absorbed from the gastrointestinal tract and rapidly and extensively metabolised in the intestinal wall and liver to ganciclovir. Systemic exposure to valganciclovir is transient and low. The bioavailability of ganciclovir from oral dosing of valganciclovir is approximately 60 % across all the patient populations studied and the resultant exposure to ganciclovir is similar to that after its intravenous administration (please see below). For comparison, the bioavailability of ganciclovir after administration of 1000 mg oral ganciclovir (as capsules) is 6 - 8 %.
VALCYTE®                                                                                     Valcyte PI version 3 
Valganciclovir in HIV positive, CMV positive patients:
Systemic exposure of HIV positive , CMV positive patients after twice daily administration of ganciclovir and valganciclovir for one week is:

Parameter                         Ganciclovir                     Valganciclovir (900 mg, p.o.) (5 mg/kg, i.v.)                             n = 25 n = 18
Ganciclovir                Valganciclovir

AUC(0 - 12 h) (g.h/ml)            28.6 ± 9.0                   32.8 ± 10.1                 0.37 ± 0.22 Cmax (g/ml)                       10.4 ± 4.9                    6.7 ± 2.1                  0.18 ± 0.06 
The efficacy of ganciclovir in increasing the time-to-progression of CMV retinitis has been shown to correlate with systemic exposure (AUC).

Valganciclovir in solid organ transplant patients:
Steady state systemic exposure of solid organ transplant patients to ganciclovir after daily oral administration of ganciclovir and valganciclovir is:

Parameter                         Ganciclovir                      Valganciclovir (900 mg, od) (1000 mg t.i.d.)                            n = 161 n = 82
Ganciclovir
AUC(0 - 24 h) (g.h/ml)           28.0 ± 10.9                                 46.3 ± 15.2 Cmax (g/ml)                       1.4 ± 0.5                                   5.3 ± 1.5 
The systemic exposure of ganciclovir to heart, kidney and liver transplant recipients was similar after oral administration of valganciclovir according to the renal function dosing algorithm.

Food effect:
When valganciclovir was given with food at the recommended dose of 900 mg, higher values were seen in both mean ganciclovir AUC (approximately 30 %) and mean ganciclovir Cmax values (approximately 14 %) than in the fasting state. Also, the inter-individual variation in exposure of ganciclovir decreases when taking Valcyte with food. Valcyte has only been administered with food in clinical studies. Therefore, it is recommended that Valcyte be administered with food (see section 4.2).

Distribution:
Because of rapid conversion of valganciclovir to ganciclovir, protein binding of valganciclovir was not determined. The steady state volume of distribution (Vd) of ganciclovir after intravenous administration was 0.680 ± 0.161 l/kg (n=114). For IV ganciclovir, the volume of distribution is correlated with body weight with values for the steady state volume of distribution ranging from 0.540.87 L/kg. Ganciclovir penetrates the cerebrospinal fluid. Binding to plasma proteins was 1%- 2% over ganciclovir concentrations of 0.5 and 51 µg/mL.

Biotransformation
Valganciclovir is rapidly and extensively metabolised to ganciclovir; no other metabolites have been detected. Ganciclovir itself is not metabolised to a significant extent.

Elimination
Following dosing with oral valganciclovir, the drug is rapidly hydrolysed to ganciclovir. Ganciclovir is eliminated from the systemic circulation by glomerular filtration and active tubular secretion. In VALCYTE®                                                                                           Valcyte PI version 3 patients with normal renal function greater than 90% of IV administered ganciclovir was recovered un-metabolized in the urine within 24 hours. In patients with normal renal function the post-peak plasma concentrations of ganciclovir after administration of valganciclovir decline with a half-life ranging from 0.4 h to 2.0 h.

Pharmacokinetics in special clinical situations

Paediatric population
In a phase II pharmacokinetic and safety study in paediatric solid organ transplant recipients (aged 4 months to 16 years, n = 63) valganciclovir was given once daily for up to 100 days. Pharmacokinetic parameters were similar across organ type and age range and comparable with adults. Population pharmacokinetic modeling suggested that bioavailability was approximately 60%. Clearance was positively influenced by both body surface area and renal function.
In a phase I pharmacokinetic and safety study in paediatric heart transplant recipients (aged 3 weeks to 125 days, n = 14), valganciclovir was given once daily for two study days. Population pharmacokinetics estimated that mean bioavailability was 64%.

A comparison of the results from these two studies and the pharmacokinetic results from the adult population shows that ranges of AUC 0-24h were very similar across all age groups, including adults.
Mean values for AUC0-24h and Cmax were also similar across the paediatric age groups < 12 years old, although there was a trend of decreasing mean values for AUC0-24h and Cmax across the entire pediatric age range, which appeared to correlate with increasing age. This trend was more apparent for mean values of clearance and half-life (t1/2); however this is to be expected as clearance is influenced by changes in weight, height and renal function associated with patient growth, as indicated by population pharmacokinetic modelling.

The following table summarizes the model-estimated AUC0-24h ranges for ganciclovir from these two studies, as well as mean and standard deviation values for AUC0-24h, Cmax, CL and t ½ for the relevant paediatric age groups compared to adult data:

PK Parameter            Adults*                                             Paediatrics 
≥ 18 years        < 4 months      4 months - ≤ 2 years   > 2 - < 12 years    ≥ 12 years – 16 years 
(n=160)            (n = 14)             (n=17)               (n=21)                (n=25) 
AUC0-24h (g.h/ml)    46.3 ± 15.2        68.1 ± 19.8          64.3 ± 29.2          59.2 ± 15.1           50.3 ± 15.0 
Range of AUC0-24h     15.4 – 116.1         34 - 124            34 - 152              36 - 108              22 - 93 
Cmax (g/ml)            5.3 ± 1.5        10.5 ± 3.36          10.3 ± 3.3            9.4 ± 2.7             8.0 ± 2.4 
Clearance (l/h)        12.7 ± 4.5        1.25 ± 0.473          2.5 ± 2.4            4.5 ± 2.9             6.4 ± 2.9  t1/2 (h)                6.5 ± 1.4        1.97 ± 0.185          3.1 ±1.4             4.1 ± 1.3             5.5 ± 1.1 
* Extracted from study report PV 16000

The once daily dose of Valcyte in both of the studies described above was based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and was calculated using the dosing algorithm presented below:

Paediatric Dose (mg) = 7 x BSA x CrCl (calculated using Mosteller BSA formula and the modified Schwartz formula) where
Height (cm) x Weight (kg )
Mosteller BSA (m 2 ) 
3600

VALCYTE®                                                                                    Valcyte PI version 3 k x Height (cm)
Schwartz Creatinine Clearance (ml / min / 1.73m 2 ) 
Serum Creatinine (mg / dl )
 where k = 0.45* for patients aged < 2 years, 0.55 for boys aged 2 to < 13 years and girls aged 2 to 16 years, and 0.7 for boys aged 13 to 16 years. Refer to adult dosing for patients older than 16 years of age.
The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used.
* For appropriate sub-populations a lowering of k value may also be necessary (e.g. in paediatric patients with low birth weight).
The dose should not exceed the adult 900 mg dose. In addition, if the calculated Schwartz creatinine clearance exceeds 150 ml/min/1.73m2, then a maximum value of 150 ml/min/1.73m2 should be used in the equation.

Ganciclovir pharmacokinetics following valganciclovir administration were also evaluated in two studies in neonates and infants with symptomatic congenital CMV disease. In the first study 24 neonates aged 8 to 34 days received 6 mg/kg intravenous ganciclovir twice daily. Patients were then treated with oral valganciclovir, where the dose of valganciclovir powder for oral solution ranged from 14 mg/kg to 20 mg/kg twice daily; total treatment duration was 6 weeks. A dose of 16 mg/kg twice daily of valganciclovir powder for oral solution provided comparable ganciclovir exposure as 6 mg/kg intravenous ganciclovir twice daily in neonates, and also achieved ganciclovir exposure similar to the effective adult 5 mg/kg intravenous dose.

In the second study, 109 neonates aged 2 to 30 days received 16 mg/kg valganciclovir powder for oral solution twice daily for 6 weeks and subsequently 96 out of 109 enrolled patients were randomized to continue receiving valganciclovir or placebo for 6 months. However, the mean AUC0-12h was lower compared to the mean AUC0-12h values from the first study. The following table shows the mean values of AUC, Cmax, and t½ including standard deviations compared with adult data: 
PK Parameter                    Adults                           Paediatrics (neonates and infants) 
5 mg/kg GAN              6 mg/kg GAN         16 mg/kg VAL          16 mg/kg VAL Single dose             Twice daily           Twice daily          Twice daily (n=8)                  (n=19)                (n=19)              (n = 100) AUC0-∞ (g.h/mL)             25.4 ± 4.32                    -                    -                    - 
AUC0-12h (g.h/mL)                  -                 38.2 ± 42.7           30.1 ± 15.1         20.85 ± 5.40 
Cmax (g/ml)                 9.03 ± 1.26              12.9 ± 21.5          5.44 ± 4. 04               -  t1/2 (h)                     3.32 ± 0.47              2.52 ± 0. 55         2.98 ± 1. 26          2.98 ± 1.12 
GAN = Ganciclovir, i.v. VAL = Valganciclovir, oral

These data are too limited to allow conclusions regarding efficacy or posology recommendations for paediatric patients with congenital CMV infection.

Elderly
No investigations on valganciclovir or ganciclovir pharmacokinetics in adults older than 65 years of age have been undertaken (see section 4.2).

Patients with renal impairment

VALCYTE®                                                                             Valcyte PI version 3 The pharmacokinetics of ganciclovir from a single oral dose of 900 mg valganciclovir was evaluated in 24 otherwise healthy individuals with renal impairment.

Pharmacokinetic parameters of ganciclovir from a single oral dose of 900 mg Valcyte tablets in patients with various degrees of renal impairment:

Estimated        N        Apparent Clearance        AUClast (μg∙h/mL)        Half-life (hours) Mean Creatinine                (mL/min) Mean ±SD        Mean ±SD                ±SD Clearance
(mL/min)
51-70            6        249 ±99                  49.5 ±22.4              4.85 ±1.4 21-50            6        136 ±64                  91.9 ±43.9              10.2 ±4.4
11-20            6        45 ±11                   223 ±46                 21.8 ±5.2 10              6        12.8 ±8                  366 ±66                 67.5 ±34 
Decreasing renal function resulted in decreased clearance of ganciclovir from valganciclovir with a corresponding increase in terminal half-life. Therefore, dosage adjustment is required for renally impaired patients (see sections 4.2 and 4.4).

Patients undergoing haemodialysis
For patients receiving haemodialysis dose recommendations for Valcyte 450 mg film-coated tablets cannot be given. This is because an individual dose of Valcyte required for these patients is less than the 450 mg tablet strength. Thus, Valcyte film-coated tablets should not be used in these patients (see sections 4.2 and 4.4).

Stable liver transplant patients
The pharmacokinetics of ganciclovir from valganciclovir in stable liver transplant patients were investigated in one open label 4-part crossover study (N=28). The bioavailability of ganciclovir from valganciclovir, following a single dose of 900 mg valganciclovir under fed conditions, was approximately 60%. Ganciclovir AUC0-24h was comparable to that achieved by 5 mg/kg intravenous ganciclovir in liver transplant patients.

Patients with hepatic impairment
The safety and efficacy of Valcyte film-coated tablets have not been studied in patients with hepatic impairment. Hepatic impairment should not affect the pharmacokinetics of ganciclovir since it is excreted renally and, therefore, no specific dose recommendation is made.

Patients with cystic fibrosis
In a phase I pharmacokinetic study in lung transplant recipients with or without cystic fibrosis (CF), 31 patients (16 CF/15 non-CF) received post-transplant prophylaxis with 900 mg/day Valcyte. The study indicated that cystic fibrosis had no statistically significant influence on the overall average systemic exposure to ganciclovir in lung transplant recipients. Ganciclovir exposure in lung transplant recipients was comparable to that shown to be efficacious in the prevention of CMV disease in other solid organ transplant recipients.