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CLINICAL PHARMACOLOGY
Mechanism of Action
Didanosine is an antiviral agent.
Pharmacokinetics
The pharmacokinetic parameters of didanosine are summarized in Table 10. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. 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 10: Mean ± SD Pharmacokinetic Parameters for
Didanosine in Adult and Pediatric Patients
| Parameter | Pediatric Patientsb | |||||
| Adult Patientsa | n | 8 months to 19 years | n | 2 weeks to 4 months | n | |
| Oral bioavailability (%) | 42 ± 12 | 6 | 25 ± 20 | 46 | ND | |
| Apparent volume of distributionc (L/m²) | 43.70 ± 8.90 | 6 | 28 ± 15 | 49 | ND | |
| CSF-plasma ratiod | 21 ± 0.03% | 5 | 46% (range 12-85%) |
7 | ND | |
| Systemic clearancec (mL/min/m²) | 526 ± 64.7 | 6 | 516 ± 184 | 49 | ND | |
| Renal clearancef (mL/min/m²) | 223 ± 85.0 | 6 | 240 ± 90 | 15 | ND | |
| Apparent oral clearanceg (mL/min/m²) | 1252 ± 154 | 6 | 2064 ± 736 | 48 | 1353 ± 759 | 41 |
| Elimination half-lifef (h) | 1.5 ± 0.4 | 6 | 0.8 ± 0.3 | 60 | 1.2 ± 0.3 | 21 |
| Urinary recovery of didanosinef (%) | 18 ± 8 | 6 | 18 ± 10 | 15 | ND | |
| CSF = cerebrospinal fluid, ND = not determined.
a Parameter units for adults were converted to the same units in pediatric patients to facilitate comparisons among populations: mean adult body weight = 70 kg and mean adult body surface area = 1.73 m². b In 1-day old infants (n=10), the mean ± SD apparent oral clearance was 1523 ± 1176 mL/min/m² and half-life was 2.0 ± 0.7 h. c Following IV administration. d Following IV administration in adults and IV or oral administration in pediatric patients. e Mean ± SE. f Following oral administration. g Apparent oral clearance estimate was determined as the ratio of the mean systemic clearance and the mean oral bioavailability estimate. |
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Effect of Food
Didanosine peak plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability [see DOSAGE AND ADMINISTRATION]. VIDEX should be taken on an empty stomach.
Special Populations
Renal Insufficiency: Data from two studies in adults indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 11). 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 11: Mean ± SD Pharmacokinetic Parameters for
Didanosine Following a Single Oral Dose
| Parameter | Creatinine Clearance (mL/min) | ||||
| at least 90 n=12 |
60-90 n=6 |
30-59 n=6 |
10-29 n=3 |
Dialysis Patients n=11 |
|
| CLc r (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 |
| ND = not determined due to anuria. CLcr = creatinine clearance. CL/F = apparent oral clearance. CLR = renal clearance. |
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Hepatic Impairment: The pharmacokinetics of didanosine have been studied in 12 non-HIVinfected 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. Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m² in pediatric patients less than 5 months old and from 80 to 180 mg/m² in children above 8 months old. For information on controlled clinical studies in pediatric patients, see Clinical Studies and Use In Specific Populations.
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 12 and 13 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI) when available, following coadministration of VIDEX (didanosine) with a variety of drugs. Drug-drug interactions for VIDEX buffered tablets are applicable to the VIDEX pediatric powder formulation and are noted in Tables 12 and 13. For clinical recommendations based on drug interaction studies for drugs in bold font, see DOSAGE AND ADMINISTRATION (for Concomitant Therapy with Tenofovir Disoproxil Fumarate), CONTRAINDICATIONS, and DRUG INTERACTIONS.
Table 12: Results of Drug Interaction Studies with VIDEX:
Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Didanosine Pharmacokinetic Parametersa | |
| AUC of Didanosine (95% CI) | Cmax of Didanosine (95%CI) | |||
| 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% |
| ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine | 200 mg every 12 hours for 3 days | 8b | ↓ 16 % | ↓28 % |
| ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine | 200 mg every 12 hours | 12 | ↑111% | NA |
| indinavir, 800 mg single dose, simultaneous | 200 mg single dose | 16 | ↔ | ↔ |
| 1 hour before didanosine | 200 mg single dose | 16 | ↓ 17 % (-27, - 7%) | ↓ 13 % (-28, 5%) |
| ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine | 375 mg every 12 hours for 4 days | 12b | ↔ | ↓ 12% |
| methadone, chronic maintenance dosef | 200 mg single dose | 16d | ↓57 % | ↓66 % |
| 400 mg single dose | 15,16e | ↓29 % (-40, -16%)c | ↓41 % (-54, -26%)c | |
| tenofovirg,h, 300 mg once daily, 1 hour after didanosine | 250 mg or 400 mg once daily for 7 days | 14 | ↑44% (31, 59%)c | ↑28% (11, 48%)c |
| loperamide, 4 mg every 6 hours for 1 day | 300 mg single dose | 12b | ↔ | ↓23 % |
| metoclopramide, 10 mg single dose | 300 mg single dose | 12b | ↔ | ↑13% |
| ranitidine, 150 mg single dose, 2 hours before didanosine | 375 mg single dose | 12b | ↑14% | ↑13% |
| rifabutin, 300 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 | 8b | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8b | ↔ | ↑17% (-23, 77%) |
| zidovudine, 200 mg every 8 hours for 3 days | 200 mg every 12 hours for 3 days | 6b | ↔ | ↔ |
| ↑ 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. c 90% CI. d Comparisons are made to a parallel control group not receiving methadone (n=10). e Comparisons are made to historical controls (n=68, pooled from 3 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively. f For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and methadone, see the complete prescribing information for VIDEX EC. g Tenofovir disoproxil fumarate. h For results of drug interaction studies between the enteric-coated formulation of didanosine (VIDEX EC) and tenofovir disoproxil fumarate, see the complete prescribing information for VIDEX EC. i Patients less than 60 kg with creatinine clearance of at least 60 mL/min. NA = Not available. |
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Table 13: Results of Drug Interaction Studies with VIDEX:
Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Coadministered Drug Pharmacokinetic Parametersa | |
| AUC of Coadministered Drug (95% CI) | Cmax of Coadministered Drug (95% CI) | |||
| ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine | 200 mg every 12 hours for 3 days | 8b | ↓26% | ↓16% |
| 750 mg single dose | buffered placebo tablet | 12 | ↓98% | ↓93% |
| delavirdine, 400 mg single dose simultaneous 1 hour before didanosine | 125 mg or 200 mg every 12 hours | 12b | ↓32% | ↓53% |
| 125 mg or 200 mg every 12 hours | 12b | ↑20% | ↑18% | |
| ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine | 200 mg every 12 hours | 12b | ↓21% | NA |
| indinavir, 800 mg single dose simultaneous | 200 mg single dose | 16 | ↓84% | ↓82% |
| 1 hour before didanosine | 200 mg single dose | 16 | ↓11% | ↓4% |
| ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine | 375 mg every 12 hours for 4 days | 12b | ↓14% | ↓20% |
| nelfinavir, 750 mg single dose, 1 hour after didanosine | 200 mg single dose | 10b | ↑12% | ↔ |
| dapsone, 100 mg single dose | 200 mg every 12 hours for 14 days | 6b | ↔ | ↔ |
| 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%) |
| tenofovir,c 300 mg once daily 1 hour after didanosine | 250d mg or 400 mg once daily for 7 days | 14 | ↔ | ↔ |
| 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%) |
| ↑ 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. c Tenofovir disoproxil fumarate. d Patients less than 60 kg with creatinine clearance of at least 60 mL/min. NA = Not available. |
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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 didanosinetreated 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.
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 VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX and other nucleoside analogues.
Clinical Studies
Adult Patients
Combination Therapy
START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV-1 RNA levels and increases in CD4 cell counts through 48 weeks.
Study AI454-148 was a randomized, open-label, multicenter study comparing treatment
with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir
(750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine
(150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive
patients, with a median CD4 cell count of 340 cells/mm³ (range 80 to 1568
cells/mm³) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL
(range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count
increases at 48 weeks were 188 cells/mm³ in both treatment groups. Treatment
response and outcomes through 48 weeks are shown in Figure 1 and Table 14.
 |
Table 14: Outcomes of Randomized Treatment Through Week 48,
AI454-148
| Week 48 Status | Percent of Patients with HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) | |
| VIDEX/stavudine/ nelfinavir n=503 |
lamivudine/zidovudine /nelfinavir n=253 |
|
| Respondera | 50* (34*) | 59 (47) |
| Virologic failureb | 36 (57) | 32 (48) |
| Death or disease progression | less than 1 (less than 1) | 1 (less than 1) |
| Discontinued due to adverse events | 4 (2) | 2 (less than 1) |
| Discontinued due to other reasonsc | 6 (3) | 4 (2) |
| Never initiated treatment | 4 (4) | 2 (2) |
| * p less than 0.05 for the differences between
treatment groups, by Cochran-Mantel-Haenszel test. a Patients achieved virologic response [two consecutive viral loads less than 400 (less than 50) copies/mL] and maintained it to Week 48. b Includes viral rebound and failing to achieve confirmed less than 400 (less than 50) copies/mL by Week 48. c Includes lost to follow-up, noncompliance, withdrawal, and pregnancy. |
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Monotherapy
The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG 116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups.
Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited.
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), VIDEX (120 mg/m² every 12 hours), or zidovudine (120 mg/m² every 6 hours) plus VIDEX (90 mg/m² every 12 hours). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.
Last reviewed on RxList: 12/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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