VIDEX EC (Page 5 of 8)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Didanosine is an antiretroviral drug [see Microbiology (12.4) ].

12.3 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 kgn=10

25 kg to less than 60 kgn=17

At least 60 kgn=7

At least 60 kgn=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 (2.2) ].

Table 8: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation
Parameter Creatinine Clearance (mL/min) Dialysis Patients n=11
at least 90 n=12 60-90 n=6 30-59 n=6 10-29 n=3
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 (2.3) ].

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 (8.5) ].

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

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