Adefovir Dipivoxil (Page 4 of 9)

11 DESCRIPTION

Adefovir dipivoxil is a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV).

The chemical name of adefovir dipivoxil is 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]-methoxy]ethyl]adenine. It has a molecular formula of C20 H32 N5 O8 P, a molecular weight of 501.47 g/mol and the following structural formula:

adefovir-dipivoxil

Adefovir dipivoxil is a white to off-white powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. It has an octanol/aqueous phosphate buffer (pH 7) partition coefficient (log p) of 1.91.

Adefovir dipivoxil tablets are for oral administration. Each tablet contains 10 mg of adefovir dipivoxil and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, starch and talc.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Adefovir is an antiviral drug [See Microbiology (12.4)].

12.3 Pharmacokinetics

Adult Subjects

The pharmacokinetics of adefovir have been evaluated in healthy volunteers and patients with chronic hepatitis B. Adefovir pharmacokinetics are similar between these populations.

Absorption

Adefovir dipivoxil is a diester prodrug of the active moiety adefovir. Based on a cross study comparison, the approximate oral bioavailability of adefovir from adefovir dipivoxil is 59%.

Following oral administration of a 10 mg single dose of adefovir dipivoxil to chronic hepatitis B patients (N=14), the peak adefovir plasma concentration (Cmax ) was 18.4 ± 6.26 ng/mL (mean ± SD) and occurred between 0.58 and 4.00 hours (median = 1.75 hours) post dose. The adefovir area under the plasma concentration-time curve (AUC0–∞ ) was 220 ± 70.0 ng•h/mL. Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.

The pharmacokinetics of adefovir in subjects with adequate renal function were not affected by once daily dosing of 10 mg adefovir dipivoxil over seven days. The impact of long-term once daily administration of 10 mg adefovir dipivoxil on adefovir pharmacokinetics has not been evaluated.

Effects of Food on Oral Absorption

Adefovir exposure was unaffected when a 10 mg single dose of adefovir dipivoxil was administered with food (an approximately 1000 kcal high-fat meal). Adefovir dipivoxil may be taken without regard to food.

Distribution

In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 microg/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 ± 75 and 352 ± 9 mL/kg, respectively.

Metabolism and Elimination

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. Forty-five percent of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses of adefovir dipivoxil. Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion [See Drug Interactions (7) and Clinical Pharmacology (12.3)].

Assessment of Drug Interactions

Adefovir dipivoxil is rapidly converted to adefovir in vivo. At concentrations substantially higher (greater than 4000-fold) than those observed in vivo , adefovir did not inhibit any of the common human CYP450 enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Adefovir is not a substrate for these enzymes. However, the potential for adefovir to induce CYP450 enzymes is unknown. Based on the results of these in vitro experiments and the renal elimination pathway of adefovir, the potential for CYP450 mediated interactions involving adefovir as an inhibitor or substrate with other medicinal products is low.

The pharmacokinetics of adefovir have been evaluated in healthy adult volunteers following multiple dose administration of adefovir dipivoxil (10 mg once daily) in combination with lamivudine (100 mg once daily) (N=18), trimethoprim/sulfamethoxazole (160/800 mg twice daily) (N=18), acetaminophen (1000 mg four times daily) (N=20), ibuprofen (800 mg three times daily) (N=18), and enteric coated didanosine (400 mg) (N=21). The pharmacokinetics of adefovir have also been evaluated in post-liver transplantation patients following multiple dose administration of adefovir dipivoxil (10 mg once daily) in combination with tacrolimus (N=16). The pharmacokinetics of adefovir have been evaluated in healthy volunteers following single dose pegylated interferon α-2a (PEG-IFN) (180 microg) (N=15).

Adefovir did not alter the pharmacokinetics of lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, ibuprofen, enteric coated didanosine (didanosine EC), or tacrolimus. The evaluation of the effect of adefovir on the pharmacokinetics of pegylated interferon α-2a was inconclusive due to the high variability of pegylated interferon alpha-2a.

The pharmacokinetics of adefovir were unchanged when adefovir dipivoxil was coadministered with lamivudine, trimethoprim/sulfamethoxazole, acetaminophen, didanosine EC, tacrolimus (based on cross study comparison), and pegylated interferon α-2a. When adefovir dipivoxil was coadministered with ibuprofen (800 mg three times daily) increases in adefovir Cmax (33%), AUC (23%) and urinary recovery were observed. This increase appears to be due to higher oral bioavailability, not a reduction in renal clearance of adefovir.

Apart from lamivudine, trimethoprim/sulfamethoxazole, and acetaminophen, the effects of coadministration of adefovir dipivoxil with drugs that are excreted renally, or other drugs known to affect renal function have not been evaluated.

The effect of adefovir on cyclosporine concentrations is not known.

No drug interaction studies have been performed in adolescent patients 12 to less than 18 years of age.

Special Populations

Gender

The pharmacokinetics of adefovir were similar in male and female patients.

Race

The pharmacokinetics of adefovir have been shown to be comparable in Caucasians and Asians. Pharmacokinetic data are not available for other racial groups.

Geriatric Patients

Pharmacokinetic studies have not been conducted in the elderly.

Pediatric Patients

The pharmacokinetics of adefovir were assessed from drug plasma concentrations in 53 HBeAg positive hepatitis B pediatric patients with compensated liver disease. The exposure of adefovir following a 48 week daily treatment with adefovir dipivoxil 10 mg tablet in pediatric patients 12 to less than 18 years of age (Cmax = 23.3 ng/mL and AUC0–24 = 248.8 ng h/mL) was comparable to that observed in adult patients.

Renal Impairment

In adults with moderately or severely impaired renal function or with end-stage renal disease (ESRD) requiring hemodialysis, Cmax, AUC, and half-life (T1/2 ) were increased compared to adults with normal renal function. It is recommended that the dosing interval of adefovir dipivoxil be modified in these patients [See Dosage and Administration (2.2)].

The pharmacokinetics of adefovir in non-chronic hepatitis B patients with varying degrees of renal impairment are described in Table 3. In this study, subjects received a 10 mg single dose of adefovir dipivoxil.

Table 3 Pharmacokinetic Parameters (Mean ± SD) of Adefovir in Patients with Varying Degrees of Renal Function
Renal Function Group Unimpaired Mild Moderate Severe
Baseline creatinine clearance (mL/min) >80(N=7) 50 to 80(N=8) 30 to 49(N=7) 10 to 29(N=10)
Cmax (ng/mL) 17.8 ± 3.22 22.4 ± 4.04 28.5 ± 8.57 51.6 ± 10.3
AUC 0–∞ (ng∙h/mL) 201 ± 40.8 266 ± 55.7 455 ± 176 1240 ± 629
CL/F (mL/min) 469 ± 99.0 356 ± 85.6 237 ± 118 91.7 ± 51.3
CLrenal (mL/min) 231 ± 48.9 148 ± 39.3 83.9 ± 27.5 37.0 ± 18.4

A four-hour period of hemodialysis removed approximately 35% of the adefovir dose. The effect of peritoneal dialysis on adefovir removal has not been evaluated.

The pharmacokinetics of adefovir have not been studied in adolescent patients with renal dysfunction [See Use in Specific Populations (8.4)].

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