Adefovir Dipivoxil: PHARMACOKINETICS

In: Main

24 Jun 2010

Adefovir DipivoxilFrom a 10-mg single dose of Hep-sera™, the approximate bioavailability of adefovir is 59%. After oral administration of a 10-mg single dose of Hepsera™ to patients with chronic hepatitis B, the peak adefovir plasma concentration has been 18.4 + 6.26 ng/ml, occurring between 0.58 and 4.00 hours after a dose. The adefovir area under the plasma con­centration-time curve is 220 + 70.0 ng • hour/ml. Plasma adefovir concentrations decline in a biexponential manner, with a terminal elimination half-life of 7.48 + 1.65 hours.

Adefovir dipivoxil is rapidly converted to adefovir after oral administration. Following a 10-mg dose of Hepsera™, 45% of the dose is recovered as adefovir in the urine over 24 hours at a steady state. It is excreted renally by a combination of glomerular filtration and active tubular secretion.
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Table 1 Dosing Interval Adjustment of Adefovir Dipivoxil (ADV) in Patients with Renal Impairment

Creatinine Clearance (ml/min)*

Hemodialysis

>50

20-49

10-19

Patients

Recommended dose

10 mg

10 mg

10 mg

10 mg

and dosing interval

every

every

every

every 7 days

24 hours

48 hours

72 hours

following dialysis

Following a 10-mg dose of Hepsera™, the pharmacokinetics of adefovir varies in patients with moderately or severely impaired renal function or with end-stage renal disease (ESRD) and who need hemodialysis. For these patients, the plasma concentration, the area under the plasma-time curve, and the half-life are greater than in patients with normal renal function.

The recommended dosage and dosing interval adjustments for patients with renal impairment are listed in Table 1. The safety and effectiveness of these dosing interval adjustment guidelines have not been clinically evaluated. In addition, these guidelines were derived from data in patients with pre-existing renal impairment at baseline values and might not be appropriate for patients in whom renal insufficiency evolves during treatment.
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Table 2 Efficacy of Adefovir Dipivoxil (ADV) 10 mg Once Daily, Compared with Placebo, After 48 Weeks of Treatment

ADV

10 mg*

Placebo

Parameter

(n = 172)

(n = 170)

P Value
Histology improvement*

53%

25%

P < .001
Necroinflammatory improvement

71%

41%

P < .001
Fibrosis improvement

41%

26%

P < .001
HBeAg seroconversion!

12%

6%

P < .001
HBeAg loss

23%

17%

P < .001
Median reduction in HBV DNA
(log,0copies/ml)!

-3.52%

-0.55

P < .001
HBV DNA < 400 copies/ml

21%

0%

P < .001
Median reduction in ALT levels (lU/liter)

-51

-17

P < .001
Percentage of patients achieving
normal ALT Levels

48%

16%

P < .001

Efficacy The Marcellin Trial

Marcellin et al. evaluated the safety and efficacy of adefovir dipivoxil (10 mg and 30 mg), once daily, compared with placebo in a two-year trial (study 437) of 515 patients. These patients had hepatitis B early antigen (HBeAg) with chronic HBV infection, and the median age was 33 years. During the first 48 weeks of the study, 172 patients received adefovir dipivoxil 10 mg, 173 received adefovir dipivoxil 30 mg, and 170 received placebo. Although the 30-mg dose of adefovir dipivoxil had greater efficacy than the 10-mg dose, it showed increased toxicity. It was necessary to reduce the dose in 25% of the patients taking the 30-mg dose; a dose reduction was warranted in only 3% of those taking the 10-mg dose.

These study results demonstrated that higher baseline alanine aminotransferase (ALT) values are associated with signifi­cant increases in histological improve­ment and HbeAg seroconversion (Table 2). Continued treatment with adefovir dipivoxil 10 mg once daily for 72 weeks resulted in continued maintenance of mean reductions in the serum HBV DNA observed at week 48.

The Hadziyannis Trial

An ongoing clinical trial (study 438), conducted by Hadziyannis et al., has enrolled 185 patients with pre-core mutant HBV (HBeAg-negative, anti-HBe-positive, and HBV-DNA-positive). The median age of these patients is 46 years. Patients were randomly assigned to re ceive adefovir dipivoxil 10 mg once a day (n = 123) or placebo (n = 62) for 48 weeks. Following the first 48 weeks of treatment, the patients who had received adefovir dipivoxil were randomly reassigned (2:1) to receive either ade-fovir dipivoxil 10 mg or placebo for a second year. Patients who had initially received placebo have now been receiving adefovir dipivoxil 10 mg for the second 48 weeks of the study. Detailed results are presented in Table 3, and results from Kaplan-Meier estimates beyond 48 weeks are presented in Table 4.

Table 3 Comparison of Adefovir Dipivoxil (ADV) 10 mg Once Daily with Placebo After 48 Weeks of Therapy

Parameter

ADV

(n = 123)

Placebo (n = 61) P Value
Histology improvement*

64%

33%

P < .001
Necroinflammatory improvement

80%

42%

P < .001
Necroinflammatory worsening

3%

51%

P < .001
Fibrosis improvement

48%

25%

P < .001
Fibrosis worsening

4%

38%

P < .001
Median reduction in HBV DNA
(logl0 copies/ml)!

-3.91

-l.35

P < .001
HBV DNA < 400 copies/ml

51%

0%

P < .001

Median reduction in ALT levels (lU/liter)     -55

-38

P < .001
Percentage of patients achieving
normal ALT levels

72%

29%

P < .001
*lmprovement in the Kneel score of at least 2 points or greater and no worsening of theKnodell fibrosis score. fRoche Amplicor Monitor® Test (PCR [polymerase chain reaction]). ALT = alanine aminotransferase; HBV = hepatitis B virus; DNA = deoxyribonucleic acid;

lU = lnternational Units. Data from Hadziyannis S, et al. Oral presentation at the 37th Annual Meeting of the European

Association for the Study of the Liver. Madrid, Spain, April 17-21, 2002.9

The Benhamou Study

Benhamou and colleagues assessed the safety and efficacy of adefovir 10 mg once daily in 35 patients co-infected with HIV and HBV (mean age, 41 years). Four patients withdrew early, two for adverse events (diabetes mellitus and insomnia), one for poor compliance, and one for personal reasons. The patients had controlled HIV ribonucleic acid (RNA), adequate renal function, and detectable HBV DNA despite Epivir-HBV® therapy. Adefovir 10 mg daily was added to the existing anti-HIV therapeutic regimen. Changes to treatment regimens were permitted, and all patients continued to take Epivir-HBV®. The patients were seen monthly for safety and efficacy evaluations.

Table 4 Efficacy of Adefovir Dipivoxil 10 mg Once Daily Beyond 48 Weeks (Studies 437 and 438)

Parameter Study 437 (n = 309) Study 438 (n = 183)
Week 48       Week 72

Week 48    Week 72

HBV DNA < 400 copies/ml* 26%

46%

66%         80%

ALT normalization* 67%

78%

76%         8l%

HBeAg loss* 23%

44%

NA         NA

HBeAg seroconversion* 14%

23%

NA         NA

*Kaplan-Meier estimates for all patients who completed 48 and 72 weeks of treatment.
ALT = alanine aminotransferase; DNA = deoxyribonucleic acid; HBeAg = hepatitis B early anti-
gen; HBV = hepatitis B virus.
Data from Brosgart C. Oral presentation at the Food and Drug Administration Antiviral Advi-
sory Committee Meeting, August 6, 2002.8

In this ongoing study, the use of ade-fovir 10 mg once daily, when added to Epivir-HBV® for 88 weeks, resulted in continued significant antiviral activity against ®-resistant HBV. Twelve percent of the co-infected patients experienced histological improvement and HBeAg seroconversion. No adefovir-related HBV or HIV mutations occurred, and there was no any laboratory or clinical evidence of nephrotoxicity.

 


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