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.
|