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Videx EC (Didanosine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

VIDEX® EC is the brand name for an enteric-coated formulation of didanosine, USP, a synthetic purine nucleoside analogue active against HIV-1. VIDEX EC Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain gelatin and titanium dioxide. The capsules are imprinted with edible inks.

Didanosine is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.

The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is:

Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid.

CLINICAL PHARMACOLOGY

Mechanism of Action

Didanosine is an antiviral agent [see Clinical Pharmacology ].

Pharmacokinetics

The pharmacokinetic parameters of didanosine in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (± standard deviation) oral bioavailability following single oral dosing with a buffered formulation is 42 (±12)%. After oral administration, the urinary recovery of didanosine is approximately 18 (±8)% of the dose. The CSF-plasma ratio following IV administration is 21 (±0.03)%. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.

Table 7: Pharmacokinetic Parameters for Didanosine in HIV-infected Patients
a The pharmacokinetic parameters (mean ± standard deviation) of didanosine were determined by a population pharmacokinetic model based on combined clinical studies.
Parametera Pediatrics Adults
20 kg to less than 25 kg
n=10
25 kg to less than 60 kg
n=17
At least 60 kg
n=7
At least 60 kg
n=44
Apparent clearance (L/h) 89.5 ± 21.6 116.2 ± 38.6 196.0 ± 55.8 174.5 ± 69.7
Apparent volume of distribution (L) 98.1 ± 30.2 154.7 ± 55.0 363 ± 137.7 308.3 ± 164.3
Elimination half-life (h) 0.75 ± 0.13 0.92 ± 0.09 1.26 ± 0.19 1.19 ± 0.21
Steady-state AUC (mg•h/L) 2.38 ± 0.66 2.36 ± 0.70 2.25 ± 0.89 2.65 ± 1.07

Comparison of Didanosine Formulations

In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid.

In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC.

Effect of Food

In the presence of food, the Cmax and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state [see Dosage and Administration (2) ]. VIDEX EC should be taken on an empty stomach.

Special Populations

Renal Insufficiency: Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 8). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis. [See Dosage and Administration .]

Table 8: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation
  Creatinine Clearance (mL/min)
Parameter at least 90
n=12
60-90
n=6
30-59
n=6
10-29
n=3
Dialysis Patients
n=11
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F = apparent oral clearance.
CLR = renal clearance.
CLcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND
CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174
CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 less than 10
T½ (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2.0 ± 0.3 4.1 ± 1.2

Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIV-infected subjects 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 dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [See Dosage and Administration .]

Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from 9 clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [see Dosage and Administration (2) ].

Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age [see Use in Specific Populations ].

Gender: The effects of gender on didanosine pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 summarize the effects on AUC and Cmax, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. For clinical recommendations based on drug interaction studies for drugs in bold font, see Dosage and Administration and Drug Interactions .

Table 9: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
Drug Didanosine Dosage n AUC of
Didanosine
(90% CI)
Cmax of
Didanosine
(90% CI)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.
c Tenofovir disoproxil fumarate.
d 373 kcalories, 8.2 grams fat.
e Compared with VIDEX EC 250 mg administered alone under fasting conditions.
f Compared with VIDEX EC 400 mg administered alone under fasting conditions.
g Comparisons are made to historical controls (n=148, pooled from 5 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.
tenofovir,b,c 300 mg
  once daily with a light meald
400 mg single dose fasting
2 hours before tenofovir
26 ↑ 48%
(31, 67%)
↑ 48%
(25, 76%)
tenofovir,b,c 300 mg
  once daily with a light meald
400 mg single dose
with tenofovir and a light meal
25 ↑ 60%
(44, 79%)
↑ 64%
(41, 89%)
tenofovir,b,c 300 mg
  once daily with a light meald
200 mg single dose
with tenofovir and a light meal
33 ↑ 16%
(6, 27%)e
↓ 12%
(-25, 3%)e
  250 mg single dose
with tenofovir and a light meal
33
(-13, 5%)f
↓ 20%
(-32, -7%)f
  325 mg single dose
with tenofovir and a light meal
33 ↑ 13%
(3, 24%)f
↓ 11%
(-24, 4%)f
methadone, chronic maintenance dose 400 mg single dose 15, 16g ↓ 17%
(-29, -2%)
↓ 16%
(-33, 4%)
Table 10: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa,b
Drug Didanosine Dosage n AUC of Coadministered Drug
(90% CI)
Cmax of Coadministered Drug
(90% CI)
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.
c Tenofovir disoproxil fumarate.
d 373 kcalories, 8.2 grams fat.
ciprofloxacin, 750 mg
  single dose
400 mg single dose 16
indinavir, 800 mg
  single dose
400 mg single dose 23
ketoconazole, 200 mg
   single dose
400 mg single dose 21
tenofovir,c 300 mg
  once daily with a light meald
400 mg single dose
fasting 2 hours before tenofovir
25
tenofovir,c 300 mg
  once daily with a light meald
400 mg single dose
with tenofovir and a light meal
25

Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. The results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. For clinical recommendations based on drug interaction studies for drugs in bold font, see Dosage and Administration (2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications , and Drug Interactions .

Table 11: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values
% Change of Didanosine
Pharmacokinetic Parametersa
Drug Didanosine Dosage n AUC of Didanosine
(95% CI)
Cmax of Didanosine
(95% CI)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b 90% CI.
c HIV-infected patients.
NA = Not available.
allopurinol,
renally impaired, 300 mg/day
200 mg single dose 2 ↑ 312% ↑ 232%
healthy volunteer, 300 mg/day
for 7 days
400 mg single dose 14 ↑ 113% ↑ 69%
ganciclovir, 1000 mg every 8 hours,
2 hours after didanosine
200 mg every 12 hours 12 ↑ 111% NA
ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine 200 mg every 12 hours
for 3 days
8c ↓ 16% ↓ 28%
indinavir, 800 mg single dose        
    simultaneous 200 mg single dose 16
   1 hour before didanosine 200 mg single dose 16 ↓ 17%
(-27, -7%)b
↓ 13%
(-28, 5%)b
ketoconazole, 200 mg/day for 4 days,
   2 hours before didanosine
375 mg every 12 hours
for 4 days
12c ↓ 12%
loperamide, 4 mg every 6 hours for 1 day 300 mg single dose 12c ↓ 23%
metoclopramide, 10 mg single dose 300 mg single dose 12c ↑ 13%
ranitidine, 150 mg single dose,
   2 hours before didanosine
375 mg single dose 12c ↑ 14% ↑ 13%
rifabutin, 300 mg or 600 mg/day for 12 days 167 mg or 250 mg every 12 hours
for 12 days
11 ↑ 13%
(-1, 27%)
↑ 17%
(-4, 38%)
ritonavir, 600 mg every 12 hours for 4 days 200 mg every 12 hours
for 4 days
12 ↓ 13%
(0, 23%)
↓ 16%
(5, 26%)
stavudine, 40 mg every 12 hours for 4 days 100 mg every 12 hours
for 4 days
10
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8c
trimethoprim, 200 mg single dose 200 mg single dose 8c ↑ 17%
(-23, 77%)
zidovudine, 200 mg every 8 hours for 3 days 200 mg every 12 hours
for 3 days
6c
Table 12: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
% Change of Coadministered Drug
Pharmacokinetic Parametersa
Drug Didanosine Dosage n AUC of Coadministered Drug
(95% CI)
Cmax of Coadministered Drug
(95% CI)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change, or mean increase or decrease of less than 10%.
a The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.
b HIV-infected patients.
NA = Not available.
dapsone, 100 mg single dose 200 mg every 12 hours for 14 days 6b
ganciclovir, 1000 mg every 8 hours,
2 hours after didanosine
200 mg every 12 hours 12b ↓ 21% NA
nelfinavir, 750 mg single dose,
1 hour after didanosine
200 mg single dose 10b ↑ 12%
ranitidine, 150 mg single dose,
2 hours before didanosine
375 mg single dose 12b ↓ 16%
ritonavir, 600 mg every 12 hours for 4 days 200 mg every 12 hours
for 4 days
12
stavudine, 40 mg every 12 hours for 4 days 100 mg every 12 hours
for 4 days
10b ↑ 17%
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8b ↓ 11%
(-17, -4%)
↓ 12%
(-28, 8%)
trimethoprim, 200 mg single dose 200 mg single dose 8b ↑ 10%
(-9, 34%)
↓ 22%
(-59, 49%)
zidovudine, 200 mg every 8 hours for 3 days 200 mg every 12 hours
for 3 days
6b ↓ 10%
(-27, 11%)
↓ 16.5%
(-53, 47%)

Microbiology

Mechanism of Action

Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5′-triphosphate. Dideoxyadenosine 5′-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5′-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.

Antiviral Activity in Cell Culture

The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 μM (1 μM = 0.24 μg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.

Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, zalcitabine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.

Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.

Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.

Animal Toxicology and/or Pharmacology

Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues.

CLINICAL STUDIES

Adult Patients

Study Al454-152 was a 48-week, randomized, open-label study comparing VIDEX EC (400 mg once daily) plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily) to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 13, respectively.

Table 13: Outcomes of Randomized Treatment Through Week 48, AI454-152
Outcome Percent of Patients with HIV-1 RNA less than 400 copies/mL
(less than 50 copies/mL)
VIDEX EC + stavudine
+ nelfinavir
n=258
zidovudine/lamivudinea
+ nelfinavir
n=253
a Zidovudine/lamivudine combination tablet.
b Corresponds to rates at Week 48 in Figure 1.
c Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.
d Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.
e Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons.
Responderb,c 55% (33%) 56% (33%)
Virologic failured 22% (45%) 21% (43%)
Death or discontinued due to disease progression 1% (1%) 2% (2%)
Discontinued due to adverse event 6% (6%) 7% (7%)
Discontinued due to other reasonse 16% (16%) 15% (16%)

Pediatric Patients

Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), didanosine (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus didanosine (90 mg/m2 every 12 hours). Patients treated with didanosine or didanosine plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.

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