VIRACEPT (nelfinavir mesylate 250 mg) Dailymed

12.1Mechanism of Action

Nelfinavir is an inhibitor of the HIV-1 protease [seeMicrobiology (12.4)].

12.2Pharmacodynamics

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 [seePharmacokinetics (12.3)].

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.

12.3Pharmacokinetics

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 [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 7.

Table 7: Summary of a Pharmacokinetic Study in HIV-positive Patients With Multiple Dosing of 1250 mg (Five 250 mg Tablets) BID for 28 Days and 750 mg (Three 250 mg Tablets) TID for 28 Days

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 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. 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 (C_max 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 × 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 × 625 mg 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 9 and Table 10, respectively.

Table 9: Increase in AUC, C_max and T_max for Nelfinavir in Fed State Relative to Fasted State Following 1250 mg VIRACEPT (5 × 250 mg Tablets)

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

Table 10: 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 VIRACEPT (5 × 250 mg Tablets)

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.

Specific Populations

Hepatic Impairment

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 C_max 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 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.

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 11.

Table 11: Summary of Steady-state AUC₂₄ of Nelfinavir in Pediatric Studies

Ctrough values are not presented in the table because they are not available for all studies
Protocol number	Dosing regimen Protocol specified dose (actual dose range)	N N: number of subjects with evaluable pharmacokinetic results	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

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 [seeDosage and Administration (2.2)].

Geriatric Patients

The pharmacokinetics of nelfinavir have not been studied in patients over 65 years of age.

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 12 summarizes the effects of nelfinavir on the geometric mean AUC, C_max and C_min of coadministered drugs. Table 13 shows the effects of coadministered drugs on the geometric mean AUC, C_max and C_min of nelfinavir.

Table 12: Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of VIRACEPT

			% Change of Coadministered Drug Pharmacokinetic Parameters ↑ Indicates increase; ↓ Indicates decrease; ↔ Indicates no change (geometric mean exposure increased, or decreased <10%) (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 DoseUsing the soft-gelatin capsule formulation of saquinavir 1200 mg	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
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%)
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 daysRifabutin 150 mg qd changes are relative to Rifabutin 300 mg qd × 8 days without coadministration with nelfinavir	750 mg q8h × 7–8 daysComparable changes in rifabutin concentrations were observed with VIRACEPT 1250 mg q12h × 7 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 qdChanges are reported for total plasma methadone; changes for the individual R-enantiomer and S-enantiomer were similar >1 month	1250 mg BID × 8 days	13	↓47%(↓42–↓51%)	↓46%(↓42–↓49%)	↓53%(↓49–↓57%)
Phenytoin 300 mg qd × 14 daysPhenytoin exposure measures are reported for total phenytoin exposure. The effect of nelfinavir on unbound phenytoin was similar	1250 mg BID × 7 days	12	↓29%(↓17–↓39%)	↓21%(↓12–↓29%)	↓39%(↓27–↓49%)

Table 13: Drug Interactions: Changes in Pharmacokinetic Parameters for Nelfinavir in the Presence of the Coadministered Drug

			% Change of Nelfinavir Pharmacokinetic Parameters ↑ Indicates increase; ↓ Indicates decrease; ↔ Indicates no change (geometric mean exposure increased or decreased <10%) (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 daysUsing the soft-gelatin capsule formulation of saquinavir 1200 mg	750 mg Single Dose	14	↑18%(↑7–↑30%)	↔	NA
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%)
Other Agents
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%)

12.4 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 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.

Resistance

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.

Cross-resistance

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.