"Entry Inhibitors (including Fusion Inhibitors) and CCR5 Co-receptor Antagonist
Entry inhibitors block HIV entry into CD4+ cells.
The only drug in this class "...
Mechanism of Action
Nelfinavir is an inhibitor of the HIV-1 protease [see Microbiology].
Effects on Electrocardiogram
The effect of Viracept at the recommended dose of 1250 mg twice daily on the QTcF interval administered with a low fat meal (20% fat) was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled, crossover study in 66 healthy subjects. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction was below 10 milliseconds, the threshold of clinical concern. This finding was unchanged when a single supratherapeutic dose of Viracept 3125 mg was administered following a 3-day administration of Viracept 1250 mg twice daily. The exposure at 3125 mg was 1.4-fold that at 1250 mg. The dose of 3125 mg in this study did not achieve the anticipated exposures in patients taking a high fat meal (50% fat) or with concomitant administration of drugs that could increase nelfinavir exposure [see Pharmacokinetics].
No subject in any group had an increase in QTcF of ≥ 60 milliseconds from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 milliseconds.
The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.
Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC24], peak plasma concentrations [Cmax], morning and evening trough concentrations [Ctrough]) from a pharmacokinetic study in HIV-positive patients after multiple dosing with 1250 mg (five 250 mg tablets) twice daily (BID) for 28 days (10 patients) and 750 mg (three 250 mg tablets) three times daily (TID) for 28 days (11 patients) are summarized in Table 7.
Table 7: Summary of a Pharmacokinetic Study in HIV-positive
Patients With Multiple Dosing of 1250 mg (Five 250 me Tablets) BID for 28 Davs
and 750 me (Three 250 me Tablets) TH) for 28 Davs
Afternoon or Evening
|1250 mg BID||52.8 ± 15.7||4.0 ± 0.8||2.2 ± 1.3||0.7 ± 0.4|
|750 mg TID||43.6 ± 17.8||3.0 ± 1.6||1.4 ± 0.6||1.0 ± 0.5|
|Data are mean ± SD|
The difference between morning and afternoon or evening trough concentrations for the TID and BID regimens was also observed in healthy volunteers who were dosed at precisely 8- or 12-hour intervals.
In healthy volunteers receiving a single 1250 mg dose, the 625 mg tablet was not bioequivalent to the 250 mg tablet formulation. Under fasted conditions (n=27), the AUC and Cmax were 34% and 24% higher, respectively, for the 625 mg tablets. In a relative bioavailability assessment under fed conditions (n=28), the AUC was 24% higher for the 625 mg tablet; the Cmax was comparable for both formulations. In HIV-1 infected subjects (N=21) receiving multiple doses of 1250 mg BID under fed conditions, the 625 mg formulation was bioequivalent to the 250 mg formulation based on similarity in steady state exposure (Cmax and AUC).
Table 8 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 x 625 mg tablets) to HIV-infected patients (N=21) for 14 days.
Table 8: Summary of the Steady State Pharmacokinetic Parameters
(Mean ± SD) of Nelfinavir After Multiple Dose Administration of 1250
mg BID (2 x 625 mg Tablets) to HIV-infected Patients (N=21) for 14 Days.
|1250 mg BID||35.3 (16.4)||4.7 (1.9)||1.5(1.0)|
| AUC12: Steady state AUC
Cmax: Maximum plasma concentration at steady state
Cmin: Minimum plasma concentration at steady state
In healthy volunteers receiving a single 750 mg dose under fed conditions, nelfinavir concentrations were similar following administration of the 250 mg tablet and oral powder.
Effect of Food on Oral Absorption
Food increases nelfinavir exposure and decreases nelfinavir pharmacokinetic variability relative to the fasted state. In one study, healthy volunteers received a single dose of 1250 mg of VIRACEPT 250 mg tablets (5 tablets) under fasted or fed conditions (three different meals). In a second study, healthy volunteers received single doses of 1250 mg VIRACEPT (5 x 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 9 and Table 10, respectively.
Table 9: Increase in AUC, Cmax and Tmax for Nelfinavir in
Fed State Relative to Fasted State Following 1250 mg VIRACEPT (5 x 250 me Tablets)
|Number of Kcal||% Fat||Number of subjects|| AUC fold
| Cmax fold
| Increase in
Table 10: Increase in Nelfinavir AUC, Cmax and Tmax in Fed
Low Fat (20%) versus High Fat (50%) State Relative to Fasted State Following
1250 me VIRACEPT (5 x 250 me Tablets)
|Number of Kcal||% Fat||Number of subjects||AUC fold increase|| Cmax fold
| Increase in
Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with VIRACEPT.
A food effect study has not been conducted with the 625 mg tablet. However, based on a cross-study comparison (n=26 fed vs. n=26 fasted) following single dose administration of nelfinavir 1250 mg, the magnitude of the food effect for the 625 mg nelfinavir tablet appears comparable to that of the 250 mg tablets. VIRACEPT should be taken with a meal.
The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. Nelfinavir in serum is extensively protein-bound (>98%).
Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.
The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14C-nelfinavir was recovered in the feces; fecal radioactivity consisted of numerous oxidative metabolites (78%) and unchanged nelfinavir (22%). Only 1-2% of the dose was recovered in urine, of which unchanged nelfinavir was the major component.
The steady-state pharmacokinetics of nelfinavir (1250 mg BID for 2 weeks) was studied in HlV-seronegative subjects with mild (Child-Pugh Class A; n=6) or moderate (Child-Pugh Class B; n=6) hepatic impairment. When compared with subjects with normal hepatic function, the Cmax and AUC of nelfinavir were not significantly different in subjects with mild hepatic impairment but were increased by 22% and 62%, respectively, in subjects with moderate hepatic impairment. The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-seronegative subjects with severe hepatic impairment.
The steady-state pharmacokinetics of nelfinavir has not been studied in HIV-positive patients with any degree of hepatic impairment.
The pharmacokinetics of nelfinavir have not been studied in patients with renal impairment.
Gender and Race
No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.
The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving VIRACEPT three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 11.
Table 11: Summary of Steady-state AUC24 of Nelfinavir
in Pediatric Studies
|Protocol number||Dosing regimen*||N†||Age|| AUC24 (mg·hr/L)
arithmetic mean ± SD
|AG1343-524||20 (19-28) mg/kg TID||14||2-13 years||56.1 ± 29.8|
|PACTG-725||55 (48-60) mg/kg BID||6||3-11 years||101.8 ± 56.1|
|PENTA 7||40 (34-43) mg/kg TID||4||2-9 months||33.8 ± 8.9|
|PENTA 7||75 (55-83) mg/kg BID||12||2-9 months||37.2 ± 19.2|
|PACTG-353||40 (14-56) mg/kg BID||10||6 weeks||44.1 ± 27.4|
|1 week||45.8 ± 32.1|
*Protocol specified dose (actual dose range)
† N: number of subjects with evaluable pharmacokinetic results
Ctrough values are not presented in the table because they are not available for all studies
Pharmacokinetic data are also available for 86 patients (age 2 to 12 years) who received VIRACEPT 25-35 mg/kg TID in Study AG1343-556. The pharmacokinetic data from Study AG1343-556 were more variable than data from other studies conducted in the pediatric population; the 95% confidence interval for AUC24 was 9 to 121 mg·hr/L.
Overall, use of VIRACEPT in the pediatric population is associated with highly variable drug exposure. The high variability may be due to inconsistent food intake in pediatric patients [see DOSAGE AND ADMINISTRATION].
The pharmacokinetics of nelfinavir have not been studied in patients over 65 years of age.
CYP3A and CYP2C19 appear to be the predominant enzymes that metabolize nelfinavir in humans. The potential ability of nelfinavir to inhibit the major human cytochrome P450 enzymes (CYP3A, CYP2C19, CYP2D6, CYP2C9, CYP1A2 and CYP2E1) has been investigated in vitro. Only CYP3A was inhibited at concentrations in the therapeutic range. Specific drug interaction studies were performed with nelfinavir and a number of drugs. Table 12 summarizes the effects of nelfinavir on the geometric mean AUC, Cmax and Cmin of coadministered drugs. Table 13 shows the effects of coadministered drugs on the geometric mean AUC, Cmax and Cmin of nelfinavir.
Table 12: Drug Interactions: Changes in Pharmacokinetic Parameters
for Coadministered Drue in the Presence of VIRACEPT
|Coadministered Drug||Nelfinavir Dose||N|| % Change of Coadministered Drug
Pharmacokinetic Parameters* (90% CI)
|Indinavir 800 mg Single Dose||750 mg q8h x 7 days||6|| ↑51%
|Ritonavir 500 mg Single Dose||750 mg q8h x 5 doses||10||↔||↔||NA|
|Saquinavir 1200 mg Single Dose†||750 mg TID x 4 days||14|| ↑392%
|Amprenavir 800 mg TID x 14 days||750 mg TID x 14 days||6||↔|| ↓14%
|Nucleoside Reverse Transcriptase Inhibitors|
|Lamivudine 150 mg Single Dose||750 mg q8h x 7-10 days||11|| ↑10%
|Zidovudine 200 mg Single Dose||750 mg q8h x 7-10 days||11|| ↓35%
|Non-nucleoside Reverse Transcriptase Inhibitors|
|Efavirenz 600 mg qd x 7 days||750 mg q8h x 7 days||10|| ↓12%
|Delavirdine 400 mg q8h x 14 days||750 mg q8h x 7 days||7|| ↓31%
|Rifabutin 150 mg qd x 8 days§||750 mg q8h x7-8 days¶||12|| ↑83%
|Rifabutin 300 mg qd x 8 days||750 mg q8h x 7-8 days||10|| ↑207%
|Azithromycin 1200 mg Single Dose||750 mg TID x 11 days||12|| ↑112%
|HMG-CoA Reductase Inhibitors|
|Atorvastatin 10 mg qd x 28 days||1250 mg BID x 14 days||15|| ↑74%
|Simvastatin 20 mg qd x 28 days||1250 mg BID x 14 days||16|| ↑505%
|Ethinyl estradiol 35 µg qd x 15 days||750 mg q8h x 7 days||12|| ↓47%
|Norethindrone 0.4 mg qd x 15 days||750 mg q8h x 7 days||12|| ↓18%
|Methadone 80 mg ± 21 mg qd#>1 month||1250 mg BID x 8 days||13|| ↓47%
|Phenytoin 300 mg qd x 14 daysþ||1250 mg BID x 7 days||12|| ↓29%
|NA: Not relevant for single-dose treatment; ND: Cannot be
* ↑Indicates increase; ↓ Indicates decrease; ↔ Indicates no change (geometric mean exposure increased, or decreased <10%)
† Using the soft-gelatin capsule formulation of saquinavir 1200 mg
§ Rifabutin 150 mg qd changes are relative to Rifabutin 300 mg qd x 8 days without coadministration with nelfinavir
¶ Comparable changes in rifabutin concentrations were observed with VIRACEPT 1250 mg q12h x 7 days
# Changes are reported for total plasma methadone; changes for the individual R-enantiomer and S-enantiomer were similar
thorn Phenytoin exposure measures are reported for total phenytoin exposure. The effect of nelfinavir on unbound phenytoin was similar
Table 13: Drug Interactions: Changes in Pharmacokinetic Parameters
for Nelfinavir in the Presence of the Coadministered Drug
|% Change of Nelfinavir Pharmacokinetic
Parameters* (90% CI)
|Coadministered Drug||Nelfinavir Dose||N||AUC||Cmax||Cmin|
|Indinavir 800 mg q8h x 7 days||750 mg Single Dose||6|| ↑83%
|Ritonavir 500 mg q12h x 3 doses||750 mg Single Dose||10|| ↑152%
|Saquinavir 1200 mg TID x 4 days†||750 mg Single Dose||14||↑18%
|Nucleoside Reverse Transcriptase Inhibitors|
|Didanosine 200 mg Single Dose||750 mg Single Dose||9||↔||↔||NA|
| Zidovudine 200 mg +
Lamivudine 150 mg Single Dose
|Non-nucleoside Reverse Transcriptase Inhibitors|
|Efavirenz 600 mg qd x 7 days||750 mg q8h x 7 days||7|| ↑20%
| Nevirapine 200 mg qd x 14 days
followed by 200 mg BID x 14 days
|750 mg TID x 36 days||23||↔||↔|| ↓32%
|Delavirdine 400 mg q8h x 7 days||750 mg q8h x 14 days||12|| ↑107%
|Ketoconazole 400 mg qd x 7 days||500 mg q8h x 5-6 days||12|| ↑35%
|Rifabutin 150 mg qd x 8 days||750 mg q8h x 7-8 days||11 11|| ↓23%
|1250 mg q!2h x 7-8 days||↔||↔||↓15%
|Rifabutin 300 mg qd x 8 days||750 mg q8h x 7-8 days||10|| ↓32%
|Rifampin 600 mg qd x 7 days||750 mg q8h x 5-6 days||12|| ↓83%
|Azithromycin 1200 mg Single Dose||750 mg tid x 9 days||12|| ↓15%
|Phenytoin 300 mg qd x 7 days||1250 mg BID x 14 days||15||↔||↔|| ↓18%
| Omeprazole 40 mg qd x 4 days administered
30 minutes before nelfinavir
|1250 mg BID x 4 days||19|| ↓36%
|NA: Not relevant for single-dose treatment
* ↑ Indicates increase; ↓ Indicates decrease; ↔ Indicates no change (geometric mean exposure increased or decreased <10%)
†Using the soft-gelatin capsule formulation of saquinavir 1200 mg
Mechanism of Action
Nelfinavir is an inhibitor of the HIV-1 protease. Inhibition of the viral protease prevents cleavage of the gag and gag-pol polyprotein resulting in the production of immature, non-infectious virus.
Antiviral Activity in Cell Culture
The antiviral activity of nelfinavir has been demonstrated in both acute and/or chronic HIV infections in lymphoblastoid cell lines, peripheral blood lymphocytes, and monocytes/macrophages. Nelfinavir was found to be active against several laboratory strains and clinical isolates of HIV-1, and the HIV-2 strain ROD. The EC95 (95% effective concentration) of nelfinavir ranged from 7 to 196 nM. Drug combination studies with other HIV-1 protease inhibitors showed nelfinavir had antagonistic interactions with indinavir, additive interactions with ritonavir or saquinavir, and synergistic interactions with amprenavir and lopinavir. Minimal to no cellular cytotoxicity was observed with any of these protease inhibitors alone or in combination with nelfinavir. In combination with reverse transcriptase inhibitors, nelfinavir demonstrated additive (didanosine or stavudine) to synergistic (abacavir, delavirdine, efavirenz, emtricitabine, lamivudine, nevirapine, tenofovir, zalcitabine, or zidovudine) antiviral activity without enhanced cytotoxicity. Nelfinavir's anti-HIV activity was not antagonized by the anti-HCV drug ribavirin.
HIV-1 isolates with reduced susceptibility to nelfinavir have been selected in cell culture. HIV-1 isolates from selected patients treated with nelfinavir alone or in combination with reverse transcriptase inhibitors were monitored for phenotypic (n=19) and genotypic (n=195, 157 of which were evaluable) changes in clinical trials over a period of 2 to 82 weeks. One or more viral protease mutations at amino acid positions 30, 35, 36,46, 71,77, and 88 were detected in the HIV-1 of >10% of patients with evaluable isolates. The overall incidence of the D30N substitution in the viral protease of evaluable isolates (n=157) from patients receiving nelfinavir monotherapy or nelfinavir in combination with zidovudine and lamivudine or stavudine was 54.8%. The overall incidence of other substitutions associated with primary protease inhibitor resistance was 9.6% for the L90M substitution, whereas substitutions at 48, 82, or 84 were not observed. Of the 19 clinical isolates for which both phenotypic and genotypic analyses were performed, 9 showed reduced susceptibility (5- to 93-fold) to nelfinavir in cell culture. All 9 isolates possessed one or more mutations in the viral protease gene. Amino acid position 30 appeared to be the most frequent mutation site.
Non-clinical Studies: Patient-derived recombinant HIV-1 isolates containing the D30N substitution (n=4) and demonstrating high-level (> 10-fold) nelfinavir-resistance remained susceptible ( <2.5-fold resistance) to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Patient-derived recombinant HIV-1 isolates containing the L90M substitution (n=8) demonstrated moderate to high-level resistance to nelfinavir and had varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir in cell culture. Most patient-derived recombinant isolates with phenotypic and genotypic evidence of reduced susceptibility (>2.5-fold) to amprenavir, indinavir, lopinavir, and/or saquinavir demonstrated high-level cross-resistance to nelfinavir. Amino acid substitutions associated with resistance to other protease inhibitors (e.g., G48V, V82A/F/T, I84V, L90M) appeared to confer high-level cross-resistance to nelfinavir. Following ritonavir therapy 6 of 7 clinical isolates with decreased ritonavir susceptibility (8- to 113-fold) compared to baseline also exhibited decreased susceptibility to nelfinavir (5- to 40-fold). Cross-resistance between nelfinavir and reverse transcriptase inhibitors is unlikely because different enzyme targets are involved. Clinical isolates (n=5) with decreased susceptibility to lamivudine, nevirapine, or zidovudine remain fully susceptible to nelfinavir.
Clinical Studies: There have been no controlled or comparative studies evaluating the virologic response to subsequent protease inhibitor-containing regimens in subjects who have demonstrated loss of virologic response to a nelfinavir-containing regimen. However, virologic response was evaluated in a single-arm prospective study of 26 subjects with extensive prior antiretroviral experience with reverse transcriptase inhibitors (mean 2.9) who had received nelfinavir for a mean duration of 59.7 weeks and were switched to a ritonavir (400 mg BID)/saquinavir hard-gel (400 mg BID)-containing regimen after a prolonged period of nelfinavir failure (median 48 weeks). Sequence analysis of HIV-1 isolates prior to switch demonstrated a D30N or an L90M substitution in 18 and 6 subjects, respectively. Subjects remained on therapy for a mean of 48 weeks (range 40 to 56 weeks) where 17 (65%) and 13 (50%) of the 26 subjects were treatment responders with HIV-1 RNA below the assay limit of detection ( <500 HIV-1 RNA copies/mL, Chiron bDNA) at 24 and 48 weeks, respectively.
Last reviewed on RxList: 4/20/2012
This monograph has been modified to include the generic and brand name in many instances.
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