Adefovir Preveon® | PREVEON

Investigational

Indications:

•cytomegalovirus (CMV)†

•hepatitis†

•hepatitis B†

Comments:

Description: Adefovir is a nucleotide ester prodrug that is under review as an oral agent for the treatment of hepatitis B. It was originally evaluated for the treatment of HIV disease, but the manufacturer discontinued these efforts when the FDA declined to recommend it for approval for this use. It is currently under investigation at a lower dose for the treatment of hepatitis B infection. While it is currently referred to by the trade name "Preveon®", the FDA has informed the manufacturer that a different trade name should be adopted due to conflict with a different product. Gilead intends to announce a different trade name shortly before the commercial availability of adefovir. Adefovir dipivoxil was formerly known as GS 840.

Actions: is a potent inhibitor of reverse transcriptase; it is thought that, unlike nucleosides, nucleotide analogs are more resistant to the development of tolerance; data from a phase II/III trial revealed that once-daily therapy for 24 weeks was not associated with the development of resistant HIV organisms (press release 6/25/98); against the hepatitis B virus, adefovir inhibits HBV DNA polymerase.

Uses: was under review as a treatment of HIV infection, but the NDA was rejected; may also be active against cytomegalovirus (CMV) and hepatitis B virus.

Distinguishing Features: the active compound is approximately 40% bioavailable after oral administration of adefovir dipivoxil; elimination half-life ranges 4.2-5.8 hours; can be dosed once daily; should be co-administered with L-carnitine 500 mg PO to replenish body carnitine levels that may be depleted by adefovir.

Major Adverse Reactions: azotemia, weight loss, elevated hepatic enzymes, and mild GI symptoms such as nausea and anorexia have been reported; nephrotoxicity, manifest as azotemia and hypophosphatemia, was noted and the manufacturer reduced the doses being investigated from 120 mg to 60 mg and demonstrated a decrease in nephrotoxicity.

Usual Adult Dosage: in phase I/II, doses of 125 mg PO once daily for 4 weeks were studied and successfully reduced HBV viral load; doses of 120 mg or higher PO have been administered once daily for as long as 14 months; however, when the drug was rejected by the FDA for the treatment of HIV disease, the manufacturer began studying the drug at much lower doses; for the treatment of HBV, doses of 30 mg PO once daily reduced viral DNA in a phase II trial; in another phase II trial, doses of 5 mg, 30 mg, and 60 mg PO twice daily were studied; other investigations have evaluated 60 mg PO once daily and 120 mg PO once daily for HBV; still other investigations are evaluating doses of 10-30 mg PO once daily for HBV (for patients who develop nephrotoxicity, doses are reduced to 5 mg PO once daily.

Status: NDA for treatment of HIV infection was submitted 6/29/99; on 11/1/99, the Antiviral Drugs advisory committee rejected the NDA citing unimpressive efficacy combined with notable nephrotoxicity and a concern for the development of viral resistance when doses were reduced or withheld to offset nephrotoxicity (press release 11/2/99); since then, the manufacturer has dropped pursuit of the HIV indication and is studying the drug at lower doses in the treatment of HBV infection; in 11/98, the FDA granted this drug "fast-track" designation for the treatment of HIV infection; data from a phase II/III trial assessing the safety of adefovir in combination with approved antiretroviral therapies in patients with AIDS were reported 7/1/98 in Geneva at the World AIDS Conference; phase III data were also presented at the 38th ICAAC meeting in 9/98.

Manufacturer: Gilead Sciences, 353 Lakeside Drive, Foster City, CA 94404. (415)-573-4858 or (415)-574-3000.

References:

•clinical trial (HIV disease): Kahn J et al. JAMA 1999;282:2305-12.

•review: Noble S et al. Drugs 1999;58:479-87.