nelfinavir mesylate
Dosage Form: tablets and oral powder
Viracept®
(nelfinavir mesylate)
TABLETS and ORAL POWDER
Viracept Description
Viracept® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease. Viracept 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. Viracept 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 [3S-[2(2S*, 3S*), 3α,4aβ,8aβ]] - N - (1,1 - dimethylethyl)decahydro - 2 - [2 - hydroxy - 3 - [(3 - hydroxy - 2 - methylbenzoyl)amino] - 4 - (phenylthio)butyl] - 3 - isoquinoline carboxamide mono-methanesulfonate (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 EC95 (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, emtricitabine, lamivudine, nevirapine, tenofovir, zalcitabine or zidovudine) antiviral activity in vitro without enhanced cytotoxicity. Nelfinavir's anti-HIV activity was not antagonized by the anti-HCV drug ribavirin.
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 Viracept 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 Viracept 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.
Viracept - 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 [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 1.
| Regimen | AUC24 mg.h/L | Cmax mg/L | Ctrough Morning mg/L | Ctrough Afternoon or Evening mg/L |
|---|---|---|---|---|
| data are mean ± SD | ||||
| 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 |
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 2 shows the summary of the steady state pharmacokinetic parameters (mean ± SD) of nelfinavir after multiple dose administration of 1250 mg BID (2 × 625 tablets) to HIV-infected patients (N = 21) for 14 days.
| Regimen | AUC12 mg.h/L | Cmax mg/L | Cmin mg/L |
|---|---|---|---|
| AUC12: Steady state AUC | |||
| Cmax: Maximum plasma concentration at steady state | |||
| Cmin: Minimum plasma concentration at steady state | |||
| 1250 mg BID | 35.3 (16.4) | 4.7 (1.9) | 1.5 (1.0) |
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 × 250 mg tablets) under fasted or fed conditions (two different fat content meals). The results from the two studies are summarized in Table 3 and Table 4, respectively.
| Number of Kcal | % Fat | Number of subjects | AUC fold increase | Cmax fold increase | Increase in Tmax (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 |
| Number of Kcal | % Fat | Number of subjects | AUC fold increase | Cmax fold increase | Increase in Tmax (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 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.
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 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.
Elimination
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.
Special Populations
Hepatic Insufficiency
The steady-state pharmacokinetics of nelfinavir (1250 mg BID for 2 weeks) was studied in HIV-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.
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 Viracept three times or twice daily. The dosing regimens and associated AUC24 values are summarized in Table 5.
| Protocol no. | Dosing regimen* | N† | Age | AUC24 (mg.hr/L) arithmetic mean ± SD |
|---|---|---|---|---|
| Ctrough values are not presented in the table because they are not available for all studies | ||||
| ||||
| 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 | |||
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 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 6 summarizes the effects of nelfinavir on the geometric mean AUC, Cmax and Cmin of coadministered drugs. Table 7 shows the effects of coadministered drugs on the geometric mean AUC, Cmax and Cmin of nelfinavir.
| % Change of Coadministered Drug Pharmacokinetic Parameters* (90% CI) | |||||
|---|---|---|---|---|---|
| Coadministered Drug | Nelfinavir Dose | N | AUC | Cmax | Cmin |
| NA: Not relevant for single-dose treatment; ND: Cannot be determined | |||||
| |||||
| HIV-Protease Inhibitors | |||||
| Indinavir 800 mg Single Dose | 750 mg q8h × 7 days | 6 | ↑51% (↑29–↑77%) | ↓10% (↓28–↑13%) | NA |
| Ritonavir 500 mg Single Dose | 750 mg q8h × 5 doses | 10 | ↔ | ↔ | NA |
| Saquinavir 1200 mg Single Dose † | 750 mg tid × 4 days | 14 | ↑392% (↑291–↑521%) | ↑179% (↑117–↑259%) | NA |
| Amprenavir 800 mg tid × 14 days | 750 mg tid × 14 days | 6 | ↔ | ↓14% (↓38–↑20%) | ↑189% (↑52–↑448%) |
| Nucleoside Reverse Transcriptase Inhibitors | |||||
| Lamivudine 150 mg Single Dose | 750 mg q8h × 7–10 days | 11 | ↑10% (↑2–↑18%) | ↑31% (↑9–↑56%) | NA |
| Stavudine 30–40 mg bid × 56 days | 750 mg tid × 56 days | 8 | See footnote ‡ | ||
| Zidovudine 200 mg Single Dose | 750 mg q8h × 7–10 days | 11 | ↓35% (↓29–↓40%) | ↓31% (↓13–↓46%) | NA |
| Non-Nucleoside Reverse Transcriptase Inhibitors | |||||
| Efavirenz 600 mg qd × 7 days | 750 mg q8h × 7 days | 10 | ↓12% (↓31–↑12%) | ↓12% (↓29–↑8%) | ↓22% (↓54–↑32%) |
| Nevirapine 200 mg qd × 14 days ‡ Followed by 200 mg bid × 14 days | 750 mg tid × 36 days | 23 | See footnote ‡ | ||
| Delavirdine 400 mg q8h × 14 days | 750 mg q8h × 7 days | 7 | ↓31% (↓57–↑10%) | ↓27% (↓49–↑4%) | ↓33% (↓70–↑49%) |
| Anti-infective Agents | |||||
| Rifabutin 150 mg qd × 8 days § | 750 mg q8h × 7–8 days ¶ | 12 | ↑83% (↑72–↑96%) | ↑19% (↑11–↑28%) | ↑177% (↑144–↑215%) |
| Rifabutin 300 mg qd × 8 days | 750 mg q8h × 7–8 days | 10 | ↑207% (↑161–↑263%) | ↑146% (↑118–↑178%) | ↑305% (↑245–↑375%) |
| Azithromycin 1200 mg Single Dose | 750 mg tid × 11 days | 12 | ↑112% (↑80–↑150%) | ↑136% (↑77–↑215%) | NA |
| HMG-CoA Reductase Inhibitors | |||||
| Atorvastatin 10 mg qd × 28 days | 1250 mg bid × 14 days | 15 | ↑74% (↑41–↑116%) | ↑122% (↑68–↑193%) | ↑39% (↓21–↑145%) |
| Simvastatin 20 mg qd × 28 days | 1250 mg bid × 14 days | 16 | ↑505% (↑393–↑643%) | ↑517% (↑367–↑715%) | ND |
| Other Agents | |||||
| Ethinyl estradiol 35 µg qd × 15 days | 750 mg q8h × 7 days | 12 | ↓47% (↓42–↓52%) | ↓28% (↓16–↓37%) | ↓62% (↓57–↓67%) |
| Norethindrone 0.4 mg qd × 15 days | 750 mg q8h × 7 days | 12 | ↓18% (↓13–↓23%) | ↔ | ↓46% (↓38–↓53%) |
| Methadone 80 mg + / - 21 mg qd # > 1 month | 1250 mg bid × 8 days | 13 | ↓47% (↓42–↓51%) | ↓46% (↓42–↓49%) | ↓53% (↓49–↓57%) |
| Phenytoin 300 mg qd × 14 days Þ | 1250 mg bid × 7 days | 12 | ↓29% (↓17–↓39%) | ↓21% (↓12–↓29%) | ↓39% (↓27–↓49%) |
| % Change of Nelfinavir Pharmacokinetic Parameters* (90% CI) | |||||
|---|---|---|---|---|---|
| Coadministered Drug | Nelfinavir Dose | N | AUC | Cmax | Cmin |
| NA: Not relevant for single-dose treatment | |||||
| |||||
| HIV-Protease Inhibitors | |||||
| Indinavir 800 mg q8h × 7 days | 750 mg Single Dose | 6 | ↑83% (↑42–↑137%) | ↑31% (↑16–↑48%) | NA |
| Ritonavir 500 mg q12h × 3 doses | 750 mg Single Dose | 10 | ↑152% (↑96–↑224%) | ↑44% (↑28–↑63%) | NA |
| Saquinavir 1200 mg tid × 4 days † | 750 mg Single Dose | 14 | ↑18% (↑7–↑30%) | ↔ | NA |
| Amprenavir 800 mg tid × 14 days | 750 mg tid × 14 days | 6 | See footnote ‡ | ||
| 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% (↑8–↑34%) | ↑21% (↑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% (↑83–↑135%) | ↑88% (↑66–↑113%) | ↑136% (↑103–↑175%) |
| Anti-infective Agents | |||||
| Ketoconazole 400 mg qd × 7 days | 500 mg q8h × 5–6 days | 12 | ↑35% (↑24–↑46%) | ↑25% (↑11–↑40%) | ↑14% (↓23–↑69%) |
| Rifabutin 150 mg qd × 8 days | 750 mg q8h × 7–8 days | 11 | ↓23% (↓14–↓31%) | ↓18% (↓8–↓27%) | ↓25% (↓8–↓39%) |
| 1250 mg q12h × 7–8 days | 11 | ↔ | ↔ | ↓15% (↓43–↑27%) | |
| Rifabutin 300 mg qd × 8 days | 750 mg q8h × 7–8 days | 10 | ↓32% (↓15–↓46%) | ↓24% (↓10–↓36%) | ↓53% (↓15–↓73%) |
| Rifampin 600 mg qd × 7 days | 750 mg q8h × 5–6 days | 12 | ↓83% (↓79–↓86%) | ↓76% (↓69–↓82%) | ↓92% (↓86–↓95%) |
| Azithromycin 1200 mg Single Dose | 750 mg tid × 9 days | 12 | ↓15% (↓7–↓22%) | ↓10% (↓19–↑1%) | ↓29% (↓19–↓38%) |
| HMG-CoA Reductase Inhibitors | |||||
| Atorvastatin 10 mg qd × 28 days | 1250 mg bid × 14 days | 15 | See footnote ‡ | ||
| Simvastatin 20 mg qd × 28 days | 1250 mg bid × 14 days | 16 | See footnote ‡ | ||
| Other Agents | |||||
| Methadone 80 mg + / - 21 mg qd > 1 month | 1250 mg bid × 8 days | 13 | See footnote ‡ | ||
| Phenytoin 300 mg qd × 7 days | 1250 mg bid × 14 days | 15 | ↔ | ↔ | ↓18% (↓45–↑23%) |
| Omeprazole 40 mg qd × 4 days administered 30 minutes before nelfinavir | 1250 mg bid × 4 days | 19 | ↓36% (↓20–↓49%) | ↓37% (↓23–↓49%) | ↓39% (↓15–↓57%) |
For information regarding clinical recommendations see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions.
Indications and Usage for Viracept
Viracept 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 Naive Patients
Study 511: Viracept + 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 Viracept (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/mm3 and mean baseline plasma HIV RNA was 5.21 log10 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.
Figure 1
Study 511: Percentage of Patients With HIV RNA Below 400 Copies/mL
Figure 2
Study 511: Mean Change From Baseline in CD4 Cell Counts
Study 542: Viracept BID + stavudine + lamivudine compared to Viracept TID + stavudine + lamivudine
Study 542 is an ongoing, randomized, open-label trial comparing the HIV RNA suppression achieved by Viracept 1250 mg BID versus Viracept 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/mm3 and mean baseline plasma HIV RNA was 5.0 log10 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/mm3 at 24 weeks and approximately 200 cells/mm3 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 8.
Figure 3
Study 542: Percentage of Patients With HIV RNA Below 400 Copies/mL
| Outcome | Viracept 1250 mg BID Regimen | Viracept 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 Viracept toxicity† | 9 (3%) | 2 (1%) |
| Discontinued due to other antiretroviral agents' toxicity† | 3 (1%) | 3 (2%) |
| Others‡ | 67 (21%) | 54 (28%) |
Study Avanti 3: Viracept 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 Viracept (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/mm3 and mean baseline plasma HIV RNA was 4.8 log10 copies/mL (57,887 copies/mL). The percent of patients with plasma HIV RNA < 50 copies/mL at 52 weeks was 54% for the Viracept + ZDV + 3TC treatment group and 13% for the ZDV + 3TC treatment group.
b. Studies in Antiretroviral Treatment Experienced Patients
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