Pharmacology Update

Nelfinavir Mesylate Tablets and Powder

By William T. Elliott, MD, and James Chan, PharmD, PhD

The fda has approved nelfinavir (viracept, Agouron), an inhibitor of the human immunodeficiency virus protease. The pharmaceutical company Agouron received accelerated approval for nelfinavir, a process whereby a drug is approved on the basis of improvement in surrogate markers such as viral load and CD4 counts pending clinical data on disease progression or mortality. The drug is similar to the other three currently available protease inhibitors—indinavir, saquinavir, and ritonavir. The drug was also given approval for use in children, an indication that was also recently given to ritonavir.

Indications

Nelfinavir is indicated for the treatment of HIV infections when antiretroviral therapy is warranted.

Potential Advantages

In antiretroviral naïve patients (mean baseline CD4 cell count of 283 and mean HlV RNA of 152,511 copies/mL), triple combination of nelfinavir with zidovudine and lamivudine produces a mean decline in viral load of about 2 log (assay sensitivity of 500 copies/mL) and a mean increase in CD4 counts of about 150 cells at 24 weeks.1 In a group of mainly antiretroviral experienced patients (mean baseline CD4 of 279 and plasma HlV RNA of 141,369 copies/mL), combination of nelfinavir with stavudine produces about a 1 log decline in viral load and increase in CD4 counts of about 100 cells at 24 weeks.2

Nelfinavir may have a different pattern of resistance than other protease inhibitors. The most common mutation site involving drug resistance is position 30 in the protease gene. This is different than the common mutation sites observed with other protease inhibitors. Limited in vitro and in vivo data suggest that nelfinavir-resistant strains have remained sensitive to indinavir, ritonavir, and saquinavir.2-4 Nelfinavir appears to be fairly well tolerated. The most common adverse event is diarrhea (20-32%), which is generally mild to moderate in intensity and can be controlled with OTC antidiarrheals. Diarrhea led to discontinuation in less than 2% of patients in clinical trials.2

Potential Disadvantages

Despite the possibility of differences in resistance patterns, the potential for the development of cross resistance between nelfinavir and other protease inhibitors has not been fully explored. In particular, it is not clear whether strains resistant to other protease inhibitors are sensitive to nelfinavir. Further study is required to resolve this issue.

Nelfinavir requires taking nine tablets per day (3 ´ 250 mg tid) with food. The drug is metabolized in part by cytochrome P450 CYP3A4. Coadministration with terfenadine, rifampin, astemizole, and cisapride should be avoided. The dose of rifabutin should be reduced by 50% if coadministered with nelfinavir. Conversely, plasma concentrations of oral contraceptives may be decreased by nelfinavir. Anticonvulsants (e.g., carbamazine, phenobartbitol, phenytoin) may decrease plasma concentrations of nelfinavir.2

Dosing Information

The drug is supplied in 250 mg tablets and 50 mg/1 g scoop powder. The adult dose is 750 mg tid with a meal or light snack. Pediatric doses for children 2-13 years old is 20-30 mg/kg per dose tid with a meal or light snack.

Comments

Nelfinavir joins saquinavir, ritonavir, and indinavir as the fourth protease inhibitor to be approved by the FDA. Inhibition of HlV protease prevents the cleavage of the gag-pol polyprotein precursor resulting in immature, noninfectious particles, thus interrupting the replication cycle of HlV. There are currently no data on the effectiveness of nelfinavir on clinical progression end points in HIV infections such as survival or the incidence of opportunistic infections. Agouron has initiated a one-year comparative trial (n = 1300) with ritonavir in combination with nucleoside analogues to assess clinical end points.5

Clinical Implications

Protease inhibitors represent a major advance in the management of HIV disease; however, the development of resistance remains problematic. Even with highly effective triple therapy, resistance is a concern. Appropriate use of these potent agents is essential. The following points are critical in the use of these protease inhibitors: 1) Do not use them as monotherapy; 2) do not add to a failing regimen; 3) do not reduce the dose due to side effects; and 4) do not interrupt therapy.6,7 Nelfinavir offers a useful alternative to current protease inhibitors. Although more research is needed, the apparent lack of overlapping mutations with other protease inhibitors, tolerability, and limited drug interactions make nelfinavir a useful addition to the current arsenal. The wholesale acquisition cost of nelfinavir is $15.48 per day, which is more expensive than indinavir and similar to ritonavir.

References

1. Henry K, et al. (abstract) 4th Conference on Retroviruses and Opportunistic Infections: 1997 January 22-26; Washington.

2. Viracept Product Information. Agouron; March 1997.

3. Patick AK, et al. (abstract) 5th Workshop on HIV Drug Resistance: 1996 July 3-6; Whistler, Canada.

4. Mascoline M. J Inter Assoc Phys AIDS Care 1996;2: 29-34, 36-56.

5. The Pink Sheet. F-D-C Reports. March 17, 1997.

6. Bartlett JG. Ann Intern Med 1996;124:1086-1087.

7. Carpenter CCJ, et al. JAMA 1996;276:146-154.