Nelfinavir Mesylate
Nelvir Oral Powder, Nelvir Tablets(cipla)
DESCRIPTION
NELVIR ® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease. NELVIR Tablets are available for oral administration as a light blue, capsule-shaped tablet with a clear film coating in 250 mg strength (as nelfinavir free base) and as a white oval tablet with a clear film coating in 625 mg strength (as nelfinavir free base). Each tablet contains the following common inactive ingredients: calcium silicate, crospovidone, magnesium stearate, hypromellose, and triacetin. In addition, the 250 mg tablet contains FD&C blue #2 powder and the 625 mg tablet contains colloidal silicon dioxide. NELVIR Oral Powder is available for oral administration in a 50 mg/g strength (as nelfinavir free base) in bottles. The oral powder also contains the following inactive ingredients: microcrystalline cellulose, maltodextrin, dibasic potassium phosphate, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural and artificial flavor. The chemical name for nelfinavir mesylate is [3 S -[2 (2 S* , 3 S* ), 3a, 4aß, 8aß]] - N - (1, 1 - dimethylethyl) decahydro - 2 - [2 - hydroxy - 3 - [(3 - hydroxy - 2 - methylbenzoyl) amino] - 4 - (phenylthio) butyl]-3-isoquinoline carboxamide monomethanesulfonate (salt) and the molecular weight is 663.90 (567.79 as the free base). Nelfinavir mesylate has the following structural formula:
Nelfinavir mesylate is a white to off-white amorphous powder, slightly soluble in water at pH=4 and freely soluble in methanol, ethanol, 2-propanol and propylene glycol.
MICROBIOLOGY
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 Vitro : The antiviral activity of nelfinavir in vitro 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 EC 95 (95% effective concentration) of nelfinavir ranged from 7 to 196 nM. Drug combination studies with 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, lamivudine, nevirapine, tenofovir, zalcitabine or zidovudine) antiviral activity in vitro without enhanced cytotoxicity.
Drug Resistance : HIV-1 isolates with reduced susceptibility to nelfinavir have been selected in vitro . HIV 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 mutation 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 mutations 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 vitro . All 9 patient isolates possessed one or more mutations in the viral protease gene. Amino acid position 30 appeared to be the most frequent mutation site.
Cross-resistance: Non-clinical Studies- Patient-derived recombinant HIV isolates containing the D30N mutation (n=4) and demonstrating high-level (>10-fold) NFV-resistance remained susceptible (<2.5-fold resistance) to amprenavir, indinavir, lopinavir, and saquinavir, in vitro . Patient-derived recombinant HIV isolates containing the L90M mutation (n=8) demonstrated moderate to high-level resistance to NFV and had varying levels of susceptibility to amprenavir, indinavir, lopinavir, and saquinavir, in vitro . 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, in vitro . Mutations associated with resistance to other PIs (e.g. G48V, V82A/F/T, I84V, L90M) appeared to confer high-level cross-resistance to NFV. Following ritonavir therapy 6 of 7 clinical isolates with decreased ritonavir susceptibility (8- to 113-fold) in vitro compared to baseline also exhibited decreased susceptibility to nelfinavir in vitro (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 in vitro .
Clinical Studies - There have been no controlled or comparative studies evaluating the virologic response to subsequent protease inhibitor-containing regimens in patients 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 patients with extensive prior antiretroviral experience with reverse transcriptase inhibitors (mean 2.9) who had received NELVIR 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 NELVIR failure (median 48 weeks). Sequence analysis of HIV-1 isolates prior to switch demonstrated a D30N or an L90M substitution in 18 and 6 patients, respectively. Subjects remained on therapy for a mean of 48 weeks (range 40 to 56 weeks) where 17 of 26 (65%) subjects and 13 of 26 (50%) subjects were treatment responders with HIV RNA below the assay limit of detection (<500 HIV RNA copies/mL, Chiron bDNA) at 24 and 48 weeks, respectively.
CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetic properties of nelfinavir were evaluated in healthy volunteers and HIV-infected patients; no substantial differences were observed between the two groups.
Absorption: Pharmacokinetic parameters of nelfinavir (area under the plasma concentration-time curve during a 24-hour period at steady-state [AUC 24 ], peak plasma concentrations [C max ], morning and evening trough concentrations [C trough ]) 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 1.
Table 1
Summary of a Pharmacokinetic Study in HIV-positive Patients with Multiple Dosing of 1250 mg BID for
28 days and 750 mg TID for 28 days
Regimen AUC 24 C max C trough C trough
mg.h/L mg/L Morning mg/L Afternoon or Evening
mg/L
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 C max 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 C max was comparable for both formulations. (See ADVERSE REACTIONS .)
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 NELVIR 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 NELVIR (5 × 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 2 and Table 3, respectively.
Table 2
Increase in AUC, C max and T max for Nelfinavir in Fed State Relative to Fasted State Following 1250
mg NELVIR (5 × 250 mg tablets)
Number of Kcal % Fat Number of subjects AUC fold increase C max fold increase Increase in T max (hr)
125 20 n=21 2.2 2.0 1.00
500 20 n=22 3.1 2.3 2.00
1000 50 n=23 5.2 3.3 2.00
Table 3
Increase in Nelfinavir AUC, C max and T max in Fed Low Fat (20%) versus High Fat (50%) State Relative
to Fasted State Following 1250 mg NELVIR (5 × 250 mg tablets)
Number of Kcal % Fat Number of subjects AUC fold increase C max fold increase Increase in T max (hr)
500 20 n=22 3.1 2.5 1.8
500 50 n=22 5.1 3.8 2.1
Nelfinavir exposure can be increased by increasing the calorie or fat content in meals taken with NELVIR.
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. NELVIR should be taken with a meal.
Distribution: The apparent volume of distribution following oral administration of nelfinavir was 2-7 L/kg. Nelfinavir in serum is extensively protein-bound (>98%).
Metabolism: Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14 C-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.
Elimination: The terminal half-life in plasma was typically 3.5 to 5 hours. The majority (87%) of an oral 750 mg dose containing 14 C-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.
Special Populations
Hepatic Insufficiency: The multi-dose pharmacokinetics of nelfinavir have not been studied in HIV-positive patients with hepatic insufficiency.
Renal Insufficiency: The pharmacokinetics of nelfinavir have not been studied in patients with renal insufficiency; however, less than 2% of nelfinavir is excreted in the urine, so the impact of renal impairment on nelfinavir elimination should be minimal.
Gender and Race: No significant pharmacokinetic differences have been detected between males and females. Pharmacokinetic differences due to race have not been evaluated.
Pediatrics: The pharmacokinetics of nelfinavir have been investigated in 5 studies in pediatric patients from birth to 13 years of age either receiving NELVIR three times or twice daily. The dosing regimens and associated AUC 24 values are summarized in Table 4.
Table 4
Summary of Steady-state AUC 24 of Nelfinavir in Pediatric Studies
Protocol no. Dosing regimen 1 N 2 Age AUC 24 (mg.hr/L)
arithmetic mean ± SD
AG1343-524 20 (19-28) mg/kg 14 2-13 years 56.1 ± 29.8
TID
PACTG-725 55 (48-60) mg/kg 6 3-11 years 101.8 ± 56.1
BID
PENTA 7 40 (34-43) mg/kg 4 2-9 months 33.8 ± 8.9
TID
PENTA 7 75 (55-83) mg/kg 12 2-9 months 37.2 ± 19.2
BID
PACTG-353 40 (14-56) mg/kg 10 6 weeks 44.1 ± 27.4
BID
1 weeks 45.8 ± 32.1
1 Protocol specified (actual dose range)
2 N: number of subjects with evaluable pharmacokinetic results
C trough 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 NELVIR 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 AUC 24 was 9 to 121 mg.hr/L.
Overall, use of NELVIR 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 PRECAUTIONS: Pediatric Use , DOSAGE AND ADMINISTRATION .)
Geriatric Patients: The pharmacokinetics of nelfinavir have not been studied in patients over 65 years of age.
Drug Interactions (also see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS: Drug Interactions )
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 5 summarizes the effects of nelfinavir on the geometric mean AUC, C max and C min of coadministered drugs. Table 6 shows the effects of coadministered drugs on the geometric mean AUC, C max and C min of nelfinavir.
Table 5: Drug Interactions:
Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of NELVIR
% Change of Coadministered Drug Pharmacokinetic
Parameters 1 (90% CI)
Coadministered Drug Nelfinavir Dose N AUC C max C min
HIV-Protease Inhibitors
Indinavir 800 mg Single Dose 750 mg q8h × 7 days 6 ?51% ?10% NA
(?29-?77%) (?28-?13%)
Ritonavir 500 mg Single Dose 750 mg q8h × 5 doses 10 ? ? NA
Saquinavir 1200 mg Single Dose 2 750 mg tid × 4 days 14 ?392% ?179% NA
(?291-?521%) (?117-?259%)
Amprenavir 800 mg tid × 14 days 750 mg tid × 14 days 6 ? ?14% ?189%
(?38-?20%) (?52-?448%)
Nucleoside Reverse Transcriptase Inhibitors
Lamivudine 150 mg Single Dose 750 mg q8h × 7-10 days 11 ?10% ?31% NA
(?2-?18%) (?9-?56%)
Stavudine 30-40 mg bid × 56 days 750 mg tid × 56 days 8 See footnote 3
Zidovudine 200 mg Single Dose 750 mg q8h × 7-10 days 11 ?35% ?31% NA
(?29-?40%) (?13-?46%)
Non-Nucleoside Reverse Transcriptase Inhibitors
Efavirenz 600 mg qd × 7 days 750 mg q8h × 7 days 10 ?12% ?12% ?22%
(?31-?12%) (?29-?8%) (?54-?32%)
Nevirapine 200 mg qd × 14 days 3
Followed by 200 mg bid × 14 days 750 mg tid × 36 days 23 See footnote 3
Delavirdine 400 mg q8h × 14 days 750 mg q8h × 7 days 7 ?31% ?27% ?33%
(?57-?10%) (?49-?4%) (?70-?49%)
Anti-infective Agents
Rifabutin 150 mg qd × 8 days 4 750 mg q8h × 7-8 days 5 12 ?83% ?19% ?177%
(?72-?96%) (?11-?28%) (?144-?215%)
Rifabutin 300 mg qd × 8 days 750 mg q8h × 7-8 days 10 ?207% ?146% ?305%
(?161-?263%) (?118-?178%) (?245-?375%)
Azithromycin 1200 mg Single Dose 750 mg tid × 11 days 12 ?112% ?136% NA
(?80-?150%) (?77-?215%)
HMG-CoA Reductase Inhibitors
Atorvastatin 10 mg qd × 28 days 1250 mg bid × 14 days 15 ?74% ?122% ?39%
(?41-?116%) (?68-?193%) (?21-?145%)
Simvastatin 20 mg qd × 28 days 1250 mg bid × 14 days 16 ?505% ?517% ND
(?393-?643%) (?367-?715%)
Other Agents
Ethinyl estradiol 35 µg qd × 15 days 750 mg q8h × 7 days 12 ?47% ?28% ?62%
(?42-?52%) (?16-?37%) (?57-?67%)
Norethindrone 0.4 mg qd × 15 days 750 mg q8h × 7 days 12 ?18% ? ?46%
(?13-?23%) (?38-?53%)
Methadone 80 mg + / -
21 mg qd 6 > 1 month 1250 mg bid × 8 days 13 ?47% ?46% ?53%
(?42-?51%) (?42-?49%) (?49-?57%)
Phenytoin 300 mg qd × 14 days 7 1250 mg bid × 7 days 12 ?29% ?21% ?39%
(?17-?39%) (?12-?29%) (?27-?49%)
NA : Not relevant for single-dose treament; ND: Cannot be determined
1 ? Indicates increase ? Indicates decrease ? Indicates no change (geometric mean exposure increased or decreased < 10%)
2 Using the soft-gelatin capsule formulation of saquinavir 1200 mg
3 Based on non-definitive cross-study comparison, drug plasma concentrations appeared to be unaffected by coadministration
4 Rifabutin 150 mg qd changes are relative to Rifabutin 300 mg qd × 8 days without coadministration with nelfinavir
5 Comparable changes in rifabutin concentrations were observed with NELVIR 1250 mg q12h × 7 days
6 Changes are reported for total plasma methadone; changes for the individual R-enantiomer and S-enantiomer were similar
7 Phenytoin exposure measures are reported for total phenytoin exposure. The effect of nelfinavir on unbound phenytoin was similar
Table 6: Drug Interactions:
Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of Coadministered Drug
% Change of Nelfinavir Pharmacokinetic
Parameters 1 (90% CI)
Coadministered Drug Nelfinavir Dose N AUC C max C min
HIV-Protease Inhibitors
Indinavir 800 mg q8h × 7 days 750 mg Single Dose 6 ?83% ?31% NA
(?42-?137%) (?16-?48%)
Ritonavir 500 mg q12h × 3 doses 750 mg Single Dose 10 ?152% ?44% NA
(?96-?224%) (?28-?63%)
Saquinavir 1200 mg tid × 4 days 2 750 mg Single Dose 14 ?18% ? NA
(?7-?30%)
Amprenavir 800 mg tid × 14 days 750 mg tid × 14 days 6 See footnote 3
Nucleoside Reverse Transcriptase Inhibitors
Didanosine 200 mg Single Dose 750 mg Single Dose 9 ? ? NA
Zidovudine 200 mg +
Lamivudine 150 mg Single Dose 750 mg q8h × 7-10 days 11 ? ? ?
Non-Nucleoside Reverse Transcriptase Inhibitors
Efavirenz 600 mg qd × 7
days 750 mg q8h × 7 days 7 ?20% ?21% ?
(?8-?34%) (?10-?33%)
Nevirapine 200 mg qd ×
14 days Followed by 200 mg bid
× 14 days 750 mg tid × 36 days 23 ? ? ?32%
(?50-?5%)
Delavirdine 400 mg q8h × 7 days 750 mg q8h × 14 days 12 ?107% ?88% ?136%
(?83-?135%) (?66-?113%) (?103-?175%)
Anti-infective Agents
Ketoconazole 400 mg qd x 7 days 500 mg q8h × 5-6 days 12 ?35% ?25% ?14%
(?24-?46%) (?11-?40%) (?23-?69%)
Rifabutin 150 mg qd x 8 days 750 mg q8h × 7-8 days 11 ?23% ?18% ?25%
(?14-?31%) (?8-?27%) (?8-?39%)
1250 mg q12h × 7-8 days 11 ? ? ?15%
(?43-?27%)
Rifabutin 300 mg qd x 8 days 750 mg q8h × 7-8 days 10 ?32% ?24% ?53%
(?15-?46%) (?10-?36%) (?15-?73%)
Rifampin 600 mg qd x 7 days 750 mg q8h × 5-6 days 12 ?83% ?76% ?92%
(?79-?86%) (?69-?82%) (?86-?95%)
Azithromycin 1200 mg Single Dose 750 mg tid × 9 days 12 ?15% ?10% ?29%
(?7-?22%) (?19-?1%) (?19-?38%)
HMG-CoA Reductase Inhibitors
Atorvastatin 10 mg qd × 28 days 1250 mg bid × 14 days 15 See footnote 3
Simvastatin 20 mg qd x 28 days 1250 mg bid × 14 days 16 See footnote 3
Other Agents
Methadone 80 mg + / -
21 mg qd > 1 month 1250 mg bid × 8 days 13 See footnote 3
Phenytoin 300 mg qd x 7 days 1250 mg bid × 14 days 15 ? ? ?18%
(?45-?23%)
NA: Not relevant for single-dose treament
1 ? Indicates increase ? Indicates decrease ? Indicates no change (geometric mean exposure increased or decreased < 10%)
2 Using the soft-gelatin capsule formulation of saquinavir 1200 mg
3 Based on non-definitive cross-study comparison, nelfinavir plasma concentrations appeared to be unaffected by coadministration
For information regarding clinical recommendations see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS: Drug Interactions .
INDICATIONS AND USAGE
NELVIR in combination with other antiretroviral agents is indicated for the treatment of HIV infection.
Description of Studies
In the clinical studies described below, efficacy was evaluated by the percent of patients with plasma HIV RNA < 400 copies/mL (Studies 511 and 542) or < 500 copies/mL (Study ACTG 364), using the Roche RT-PCR (Amplicor) HIV-1 Monitor or < 50 copies/mL, using the Roche HIV-1 Ultrasensitive assay (Study Avanti 3). In the analysis presented in each figure, patients who terminated the study early for any reason, switched therapy due to inadequate efficacy or who had a missing HIV-RNA measurement that was either preceded or followed by a measurement above the limit of assay quantification were considered to have HIV-RNA above 400 copies/mL, above 500 copies/mL, or above 50 copies/mL at subsequent time points, depending on the assay that was used.
a. Studies in Antiretroviral Treatment Naïve Patients
Study 511: NELVIR + zidovudine + lamivudine versus zidovudine + lamivudine
Study 511 was a double-blind, randomized, placebo controlled trial comparing treatment with zidovudine (ZDV; 200 mg TID) and lamivudine (3TC; 150 mg BID) plus 2 doses of NELVIR (750 mg and 500 mg TID) to zidovudine (200 mg TID) and lamivudine (150 mg BID) alone in 297 antiretroviral naive HIV-1 infected patients (median age 35 years [range 21 to 63], 89% male and 78% Caucasian). Mean baseline CD4 cell count was 288 cells/ mm 3 and mean baseline plasma HIV RNA was 5.21 log 10 copies/mL (160,394 copies/mL). The percent of patients with plasma HIV RNA < 400 copies/mL and mean changes in CD4 cell count are summarized in Figures 1 and 2, respectively.
Study 542: NELVIR BID + stavudine + lamivudine compared to NELVIR TID + stavudine + lamivudine
Study 542 is an ongoing, randomized, open-label trial comparing the HIV RNA suppression achieved by NELVIR 1250 mg BID versus NELVIR 750 mg TID in patients also receiving stavudine (d4T; 30-40 mg BID) and lamivudine (3TC; 150 mg BID). Patients had a median age of 36 years (range 18 to 83), were 84% male, and were 91% Caucasian. Patients had received less than 6 months of therapy with nucleoside transcriptase inhibitors and were naïve to protease inhibitors. Mean baseline CD4 cell count was 296 cells/mm 3 and mean baseline plasma HIV RNA was 5.0 log 10 copies/mL (100,706 copies/mL).
Results showed that there was no significant difference in mean CD4 cell count among treatment groups; the mean increases from baseline for the BID and TID arms were 150 cells/mm 3 at 24 weeks and approximately 200 cells/ mm 3 at 48 weeks.
The percent of patients with HIV RNA < 400 copies/mL is summarized in Figure 3. The outcomes of patients through 48 weeks of treatment are summarized in Table 7.
Table 7
Outcomes of Randomized Treatment Through 48 Weeks
Outcome NELVIR 1250 mg BID Regimen NELVIR 750 mg TID Regimen
Number of patients evaluable * 323 192
HIV RNA < 400 copies/mL 198 (61%) 111 (58%)
HIV RNA = 400 copies/mL 46 (14%) 22 (11%)
Discontinued due to NELVIR toxicity ** 9 (3%) 2 (1%)
Discontinued due to other antiretroviral agents' toxicity ** 3 (1%) 3 (2%)
Others *** 67 (21%) 54 (28%)
*Twelve patients in the BID arm and fourteen patients in the TID arm had not yet reached 48 weeks of therapy.
**These rates only reflect dose-limiting toxicities that were counted as the initial reason for treatment failure in the analysis (see ADVERSE REACTIONS for a description of the safety profile of these regimens).
***Consent withdrawn, lost to follow-up, intercurrent illness, noncompliance or missing data; all assumed as failures.
Study Avanti 3: NELVIR TID + zidovudine + lamivudine compared to zidovudine + lamivudine
Study Avanti 3 was a placebo-controlled, randomized, double-blind study designed to evaluate the safety and efficacy of NELVIR (750 mg TID) in combination with zidovudine (ZDV; 300 mg BID) and lamivudine (3TC; 150 mg BID) (n=53) versus placebo in combination with ZDV and 3TC (n=52) administered to antiretroviral-naive patients with HIV infection and a CD4 cell count between 150 and 500 cells/µL. Patients had a mean age of 35 (range 22- 59), were 89% male, and 88% Caucasian. Mean baseline CD4 cell count was 304 cells/mm 3 and mean baseline plasma HIV RNA was 4.8 log 10 copies/mL (57,887 copies/ mL). The percent of patients with plasma HIV RNA < 50 copies/mL at 52 weeks was 54% for the NELVIR + ZDV + 3TC treatment group and 13% for the ZDV + 3TC treatment group.
b. Studies in Antiretroviral Treatment Experienced Patients
Study ACTG 364: NELVIR TID + 2NRTIs compared to efavirenz + 2NRTIs compared to NELVIR + efavirenz + 2NRTIs
Study ACTG 364 was a randomized, double-blind study that evaluated the combination of NELVIR 750 mg TID and/or efavirenz 600 mg QD with 2 NRTIs (either didanosine [ddI] + d4T, ddI + 3TC, or d4T + 3TC) in patients with prolonged prior nucleoside exposure who had completed 2 previous ACTG studies. Patients had a mean age of 41 years (range 18 to 75), were 88% male, and were 74% Caucasian. Mean baseline CD4 cell count was 389 cells/mm 3 and mean baseline plasma HIV RNA was 3.9 log 10 copies/mL (7,954 copies/mL).
The percent of patients with plasma HIV RNA < 500 copies/mL at 48 weeks was 42%, 62%, and 72% for the NELVIR (n=66), EFV (n=65), and NELVIR + EFV (n=64) treatment groups, respectively. The 4-drug combination of NELVIR + EFV + 2 NRTIs was more effective in suppressing plasma HIV RNA in these patients than either 3-drug regimen.
CONTRAINDICATIONS
NELVIR is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Coadministration of NELVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 8.