Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Bristol-Myers Squibb Pharmaceuticals Limited Uxbridge Business Park Sanderson Road Uxbridge Middlesex UB8 1DH
Pharmacotherapeutic group: Nucleoside reverse transcriptase inhibitor
ATC Code: J05AF02
Didanosine (2', 3'-dideoxyinosine) is an inhibitor of the in vitro replication of HIV in cultured human cells and cell lines. After didanosine enters the cell, it is enzymatically converted to dideoxyadenosine-triphosphate (ddATP), its active metabolite. In viral nucleic acid replication, incorporation of this 2', 3'-dideoxynucleoside prevents chain extension, and thereby inhibits viral replication.
In addition, ddATP inhibits HIV-reverse transcriptase by competing with dATP for binding to the enzyme’s active site, preventing proviral DNA synthesis.
The relationship between in vitro susceptibility of HIV to didanosine and clinical response to therapy has not been established. Likewise, in vitro sensitivity results vary greatly and methods to establish virologic responses have not been proven.
Using the Videx tablet formulation, the effect of Videx BID administration, alone or in combination with zidovudine, was evaluated in several major randomised, controlled clinical trials (ACTG 175, ACTG 152, DELTA, CPCRA 007). These trials confirmed the reduced risk of HIV disease progression or death with Videx tablets therapy, alone or in combination with zidovudine, as compared with zidovudine monotherapy in HIV infected individuals, including symptomatic and asymptomatic adults with CD4 counts < 500 cells/mm3 and children with evidence of immunosuppression. The primary demonstration of clinical benefits of didanosine has been made through the ACTG 175 trial with the buffered tablet formulation of Videx administered twice daily (BID). This study showed that eight weeks of treatment with zidovudine, Videx tablets BID, or Videx tablets BID plus zidovudine decreased mean plasma HIV RNA by 0.26, 0.65 and 0.93 log10 copies/ml, respectively. In the tritherapy setting, the combination of Videx (200 mg) BID plus stavudine and indinavir has been compared to zidovudine plus lamivudine and indinavir in a randomised open label study (START II, n = 205): through 48 weeks of treatment, results were in favour of the Videx arm. However, no formal conclusion can be drawn on the equivalence of the two regimens.
Since didanosine exhibits a very long intracellular half-life (> 24 hours), permitting the accumulation of its pharmacologically active ddATP-moiety for extended time periods, administration of the total daily dose of Videx in a QD dosing regimen has been explored through clinical studies.
Several clinical studies have been performed with Videx (tablet) administered once daily (QD), including the following:
In the tritherapy setting, the randomised open label study –147 indicates that, in mostly asymptomatic patients (n= 123) that were stable on their first combination therapy containing Videx BID, the shift to a similar combination therapy with Videx QD did not impact at short term (24 weeks) on the existing antiviral efficacy.
The randomised open label study –148 (n= 756) compared Videx QD plus stavudine and nelfinavir to zidovudine plus lamivudine and nelfinavir. After 48 weeks of treatment, results were in favour of the zidovudine (BID), lamivudine and nelfinavir arm compared to Videx QD, stavudine and nelfinavir arm in terms of proportion of patients with undetectable viral load (the proportion of patients with HIV RNA copies < 400 copies/ml was 53% for the Videx-containing arm and 62% for the comparator). However, no formal conclusions can be drawn on this study due to methodological issues.
The efficacy of Videx gastro-resistant capsules was evaluated in treatment-naive HIV infected adults as part of a triple regimen in two (48-week) randomised open label clinical trials. Study –152 (n= 466) compared Videx gastro-resistant capsules (QD) plus stavudine and nelfinavir to zidovudine plus lamivudine and nelfinavir. The protocol-defined analysis showed the proportion of patients with HIV RNA levels < 400 copies/ml at week 48 to be similar for the Videx gastro-resistant arm and for the comparator. Similar log10 plasma HIV RNA decreases from baseline (Time Averaged Difference) were observed between treatment arms.
In study -158 (n= 138) the antiviral activity and tolerability of Videx gastro-resistant capsules were compared to tablets, each given QD in combination with stavudine and nelfinavir. At 24 weeks of follow-up, there were similar log10 plasma HIV RNA decreases from baseline (Time Averaged Difference) between treatment arms. The percentages of patients with undetectable viral load (limit of detection < 400 copies/ml) were of the same magnitude between the two Videx arms. Due to the high drop-out rate (> 50%) in this study, no definitive conclusion could be drawn on the long-term data. The efficacy of Videx gastro-resistant capsules has not been established in advanced disease or in highly antiretroviral experienced patients.
Current evidence indicates that the incidence of resistance to didanosine is an infrequent event and the resistance generated is modest in degree. Didanosine-resistant isolates have been selected in vivo and are associated with specific genotype changes in the reverse transcriptase codon region (codons L74V (most prevalent), K65R, M184V and T69S/G/D/N). Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. Mutant viruses containing the L74V substitution show a decline in viral fitness and these mutants quickly revert to wild type in the absence of didanosine. Cross-resistance between didanosine and protease inhibitors or non nucleoside reverse transcriptase inhibitor is unlikely. Cross-resistance between didanosine and nucleoside reverse transcriptase inhibitor is observed in isolates containing multi-resistant mutations such as Q151M and T69S-XX (an amino acid substitution with a 2-amino acid insertion) and multiple nucleoside analogue associated mutations (NAMs).
Absorption: Didanosine is rapidly degraded at an acidic pH. Therefore, the granules in the Videx gastro-resistant capsules release didanosine into the higher pH of the small intestine.
Compared to the fasting condition, the administration of Videx gastro-resistant capsules with a high fat meal significantly decreases the didanosine AUC (19%) and Cmax(46%). Co-administering Videx gastro-resistant capsules with a light meal, 1 hour before or 2 hours after a light meal, results in a significant decrease in both AUC (27%, 24% and 10% respectively) and Cmax of didanosine (22%, 15% and 15% respectively) compared to the fasting condition.
In another study, administration of Videx gastro-resistant capsules 1.5, 2 and 3 hours prior to a light meal results in equivalent Cmax and AUC values compared to those obtained under fasting conditions.
To minimise the impact of food on the didanosine pharmacokinetics, Videx gastro-resistant capsules should be administered on an empty stomach at least 2 hours before or 2 hours after a meal (see section 4.2).
Relative to administration of intact Videx gastro-resistant capsule on empty stomach, co-administration of didanosine enteric coated beadlets sprinkled on yoghurt and applesauce resulted in a significant decrease in the AUC (20% and 18%, respectively) and Cmax (30% and 24%, respectively).
Equivalent values for AUC are observed for the tablet and capsule formulations of Videx in healthy volunteers and subjects infected with HIV. The rate of absorption from Videx capsules is slower compared to the tablet; the value for Cmax for the gastro-resistant capsule is 60% of the value for the tablet. The time to reach Cmax is approximately 2 hours for the Videx gastro-resistant capsule and 0.67 hour for the Videx tablet.
In 30 patients receiving didanosine 400 mg once daily in the fasted state as Videx gastro-resistant capsules, single dose AUC was 2432 ± 919 ng/h/ml (38%) (mean ± SD [CV]) and Cmax was 933 ± 434 ng/ml (47).
Distribution: The volume of distribution at steady state averages 54 l, suggesting that there is some uptake of didanosine by body tissues. The level of didanosine in the cerebrospinal fluid, one hour after infusion, averages 21% of that of the simultaneous plasma level.
Biotransformation: The metabolism of didanosine in man has not been evaluated. However, based on animal studies, it is presumed that it follows the same pathways responsible for the elimination of endogenous purines.
Elimination: The average elimination half-life after IV administration of didanosine is approximately 1.4 hours. Renal clearance represents 50% of total body clearance (800 ml/min), indicating that active tubular secretion, in addition to glomerular filtration, is responsible for the renal elimination of didanosine. Urinary recovery of didanosine is approximately 20% of the dose after oral treatment. There is no evidence of didanosine accumulation after the administration of oral doses for 4 weeks.
Hepatic impairment: No significant changes in the pharmacokinetics of didanosine were observed among haemophiliac patients with chronic, persistent elevations in liver function enzymes (n= 5), which may be indicative of impaired hepatic function; haemophiliac patients with normal or less severe increases in liver function enzymes (n= 8); and non-haemophiliac patients with normal enzyme levels (n= 8) following a single IV or oral dose. The pharmacokinetics of didanosine has also been studied in 12 non-HIV infected patients with moderate (n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUC and Cmax values following a single 400 mg didanosine dose were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. AUC and Cmax values in these patients with hepatic impairment were similar to those observed in healthy subjects from other studies and are within the pharmacokinetic variability of didanosine (see section 4.2).
Renal impairment: The half-life of didanosine after oral administration increased from an average of 1.4 hours in subjects with normal renal function to 4.1 hours in subjects with severe renal impairment requiring dialysis. After an oral dose, didanosine was not detectable in peritoneal dialysis fluid; recovery in haemodialysate ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. Patients with a creatinine clearance < 60 ml/min may be at greater risk of didanosine toxicity due to decreased drug clearance. A dose reduction is recommended for these patients (see section 4.2).
There are no specific pharmacokinetic data from children treated with Videx gastro-resistant capsules.
The lowest dose to cause death in acute toxicity studies in the mouse, rat and dog was greater than 2000 mg/kg which is equivalent to approximately 300 times the maximum recommended human dose (tablet).
Repeated dose toxicity: Repeat-dose oral toxicity studies revealed evidence of a dose-limiting skeletal muscle toxicity in rodents (but not in dogs) following long-term (> 90 days) dosing with didanosine at doses that were approximately 1.2 – 12 times the estimated human dose. Additionally, in repeat dose studies, leukopenia was observed in dogs and rats, and gastrointestinal disturbances (soft stool, diarrhoea) were seen in dogs at doses approximately 5 – 14 times the maximum human dose.
Carcinogenicity: In the carcinogenicity studies, non-neoplastic alterations have been observed including skeletal muscle myopathy, hepatic alterations and an exacerbation of spontaneous age-related cardiomyopathy.
Lifetime dietary carcinogenicity studies were conducted in mice and rats for 22 or 24 months, respectively. No drug-related neoplasms were observed in any didanosine-treated groups of mice during, or at the end of, the dosing period. In rats, statistically significant increased incidences of granulosa cell tumours in females receiving the high dose, of subcutaneous fibrosarcomas and histiocytic sarcomas in males receiving the high dose and of haemangiomas in males receiving the high and intermediate dose of didanosine were noted. The drug-relationship and clinical relevance of these statistical findings were not clear.
Genotoxicity: Results from the genotoxicity studies suggest that didanosine is not mutagenic at biologically and pharmacologically relevant doses. At significantly elevated concentrations in vitro, the genotoxic effects of didanosine are similar in magnitude to those seen with natural DNA nucleosides.
Reproduction: In rats, didanosine did not impair the reproduction ability of male or female parents following treatment prior to and during mating, gestation and lactation at daily didanosine doses up to 1000 mg/kg/day. In a perinatal and postnatal reproduction study in rats, didanosine did not induce toxic effects.
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