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Fortovase (Saquinavir) - Description and Clinical Pharmacology

 
 



FORTOVASE®
(saquinavir)
SOFT GELATIN CAPSULES

Product identification in this document includes: INVIRASE® in reference to saquinavir mesylate; FORTOVASE in reference to saquinavir, and saquinavir in reference to the active base.

DESCRIPTION

FORTOVASE brand of saquinavir is an inhibitor of the human immunodeficiency virus (HIV) protease. FORTOVASE is available as beige, opaque, soft gelatin capsules for oral administration in a 200-mg strength (as saquinavir free base). Each capsule also contains the inactive ingredients medium chain mono- and diglycerides, povidone and dl-alpha tocopherol. Each capsule shell contains gelatin and glycerol 85% with the following colorants: red iron oxide, yellow iron oxide, and titanium dioxide. The chemical name for saquinavir is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide which has a molecular formula C38H50N6O5 and a molecular weight of 670.86. Saquinavir has the following structural formula:

Saquinavir is a white to off-white powder and is insoluble in aqueous medium at 25°C.

MICROBIOLOGY

Mechanism of Action

Saquinavir is an inhibitor of HIV protease. HIV protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in infectious HIV. Saquinavir is a peptide-like substrate analogue that binds to the protease active site and inhibits the activity of the enzyme. Saquinavir inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious virus particles.

Antiviral Activity

In vitro antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes. Saquinavir inhibited HIV activity in both acutely and chronically infected cells. IC50 and IC90 values (50% and 90% inhibitory concentrations) were in the range of 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean IC50 of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7 ± 5 nM, representing a 4-fold increase in IC50 value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine, zalcitabine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity.

Drug Resistance

HIV-1 mutants with reduced susceptibility to saquinavir have been selected during in vitro passage. Genotypic analyses of these isolates showed several substitutions in the HIV protease gene. Only the G48V and L90M substitutions were associated with reduced susceptibility to saquinavir, and conferred an increase in the IC50 value of 8- and 3-fold, respectively.

HIV-1 isolates with reduced susceptibility (≥4-fold increase in the IC50 value) to saquinavir emerged in some patients treated with INVIRASE. Genotypic analysis of these isolates identified resistance conferring primary mutations in the protease gene G48V and L90M, and secondary mutations L10I/R/V, I54V/L, A71V/T, G73S, V77I, V82A and I84V that contributed additional resistance to saquinavir. Forty-one isolates from 37 patients failing therapy with INVIRASE had a median decrease in susceptibility to saquinavir of 4.3 fold.

The degree of reduction in in vitro susceptibility to saquinavir of clinical isolates bearing substitutions G48V and L90M depends on the number of secondary mutations present. In general, higher levels of resistance are associated with greater number of mutations only in association with either or both of the primary mutations G48V and L90M. No data are currently available to address the development of resistance in patients receiving saquinavir/ritonavir.

Cross-resistance

Among protease inhibitors, variable cross-resistance has been observed. In one clinical study, 22 HIV-1 isolates with reduced susceptibility (>4-fold increase in the IC50 value) to saquinavir following therapy with INVIRASE were evaluated for cross-resistance to amprenavir, indinavir, nelfinavir and ritonavir. Six of the 22 isolates (27%) remained susceptible to all 4 protease inhibitors, 12 of the 22 isolates (55%) retained susceptibility to at least one of the PIs and 4 out of the 22 isolates (18%) displayed broad cross-resistance to all PIs.

Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible (<4-fold) to amprenavir and indinavir, respectively. Four of 16 (25%) and 9 of 21 (43%) with available data remained susceptible to nelfinavir and ritonavir, respectively.

After treatment failure with amprenavir, cross-resistance to saquinavir was evaluated. HIV-1 isolates from 22/22 patients failing treatment with amprenavir and containing one or more mutations M46L/I, I50V, I54L, V32I, I47V, and I84V were susceptible to saquinavir.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The pharmacokinetic properties of saquinavir when administered as FORTOVASE have been evaluated in healthy volunteers (n=207) and HIV-infected patients (n=91) after single-oral doses (range: 300 mg to 1200 mg) and multiple-oral doses (range: 400 mg to 1200 mg tid). The disposition properties of saquinavir have been studied in healthy volunteers after intravenous doses of 6, 12, 36 or 72 mg (n=21).

HIV-infected patients administered FORTOVASE (1200 mg tid) had AUC and maximum plasma concentration (Cmax) values approximately twice those observed in healthy volunteers receiving the same treatment regimen. The mean AUC values at week 1 were 4159 (CV 88%) and 8839 (CV 82%) ng∙h/mL, and Cmax values were 1420 (CV 81%) and 2477 (CV 76%) ng/mL for healthy volunteers and HIV-infected patients, respectively.

Absorption and Bioavailability in Adults

The absolute bioavailability of saquinavir administered as FORTOVASE has not been assessed. However, following single 600-mg doses, the relative bioavailability of saquinavir as FORTOVASE compared to saquinavir administered as INVIRASE was estimated as 331% (95% CI: 207% to 530%). The absolute bioavailability of saquinavir administered as INVIRASE averaged 4% (CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600-mg dose (3 x 200 mg) of INVIRASE following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). In healthy volunteers receiving single doses of FORTOVASE (300 mg to 1200 mg) and in HIV-infected patients receiving multiple doses of FORTOVASE (400 mg to 1200 mg tid), a greater than dose-proportional increase in saquinavir plasma concentrations has been observed.

Comparison of pharmacokinetic parameters between single- and multiple-dose studies shows that following multiple dosing of FORTOVASE (1200 mg tid) in healthy male volunteers (n=18), the steady-state AUC was 80% (95% CI: 22% to 176%) higher than that observed after a single 1200-mg dose (n=30).

Saquinavir plasma concentrations remained stable over a 60-week period of continued treatment in patients in a phase III substudy.

When administered as the sole protease inhibitor, it has been shown that FORTOVASE 1200 mg tid provides an 8-fold increase in AUC compared with INVIRASE 600 mg tid.

FORTOVASE in combination with ritonavir at doses of 400/400 mg bid, or 1000/100 mg bid provide saquinavir systemic exposures over a 24-hour period similar to or greater than those achieved with FORTOVASE 1200 mg tid.

Table 1 Pharmacokinetic Parameters of Saquinavir at Steady-State After Administration of Different Regimens in HIV-Infected Patients
Dosing RegimennAUC0-τ
(ng∙h/mL)
AUC0–24h
(ng∙h/mL)
Cmin
(ng/mL)
τ is the dosing interval (ie, 8h if tid and 12h if bid).
FORTOVASE 1200 mg tid (arithmetic mean)31724921747216
INVIRASE 400 mg bid + ritonavir 400 mg bid (arithmetic mean± SD)716000±800032000480±360
INVIRASE 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI)2414607
(10218-20882
29214371
(245-561)
FORTOVASE 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI)2419085
(13943-26124)
38170433
(301-622)

Food Effect

The mean 12-hour AUC after a single 800-mg oral dose of saquinavir in healthy volunteers (n=12) was increased from 167 ng∙h/mL (CV 45%), under fasting conditions, to 1120 ng∙h/mL (CV 54%) when FORTOVASE was given following a high-fat breakfast (45 g protein, 76 g carbohydrate, 55 g fat; 961 kcal). The effect of food with INVIRASE has been shown to persist for up to 2 hours. The mean 12-hour AUC after a single 1200-mg oral dose of FORTOVASE in healthy volunteers (n=12) was increased from 952 ng∙h/mL, following a light meal (21 g protein, 50 g carbohydrate, 28 g fat; 524 kcal) to 1388 ng∙h/mL when FORTOVASE was given following a high-fat breakfast (45 g protein, 76 g carbohydrate, 55 g fat; 961 kcal).

Saquinavir exposure was similar when FORTOVASE plus ritonavir (1000-mg/100-mg bid) was administered following a high-fat (45 g fat) or moderate-fat (20 g fat) breakfast.

Distribution in Adults

The mean steady-state volume of distribution following intravenous administration of a 12-mg dose of saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavir partitions into tissues. It has been shown that saquinavir, up to 30 µg/mL, is approximately 97% bound to plasma proteins.

Metabolism and Elimination in Adults

In vitro studies using human liver microsomes have shown that the metabolism of saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4, responsible for more than 90% of the hepatic metabolism. Based on in vitro studies, saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactive compounds. In a mass balance study using 600 mg 14C-saquinavir mesylate (n=8), 88% and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In an additional 4 subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in feces and urine, respectively, within 5 days of dosing. In mass balance studies, 13% of circulating radioactivity in plasma was attributed to unchanged drug after oral administration and the remainder attributed to saquinavir metabolites. Following intravenous administration, 66% of circulating radioactivity was attributed to unchanged drug and the remainder attributed to saquinavir metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism.

Systemic clearance of saquinavir was rapid, 1.14 L/h/kg (CV 12%) after intravenous doses of 6, 36, and 72 mg. The mean residence time of saquinavir was 7 hours (n=8).

Special Populations

Hepatic or Renal Impairment

Saquinavir pharmacokinetics in patients with hepatic or renal impairment has not been investigated (see PRECAUTIONS). Only 1% of saquinavir is excreted in the urine, so the impact of renal impairment on saquinavir elimination should be minimal.

Gender, Race and Age

The effect of gender was investigated in healthy volunteers receiving single 1200-mg doses of FORTOVASE (n=12 females, 18 males). No effect of gender was apparent on the pharmacokinetics of saquinavir in this study.

The effect of race on the pharmacokinetics of saquinavir has not been investigated.

Pediatric Patients

The pharmacokinetics of saquinavir in pediatric patients differs significantly from that in adults. Children have a markedly higher apparent clearance than adults and administration of saquinavir alone will not give consistently therapeutic plasma levels. The pharmacokinetics of saquinavir when coadministered with ritonavir to pediatric patients is under investigation.

Geriatric Patients

The pharmacokinetics of saquinavir when administered as FORTOVASE have not been sufficiently investigated in patients >65 years of age.

Drug Interactions

(see PRECAUTIONS: Drug Interactions)

It is important to be aware that, when coadministered with ritonavir, the occurrence and magnitude of drug interactions may differ from those seen with FORTOVASE when administered as the sole protease inhibitor. When ritonavir is coadministered, prescribers should refer to the prescribing information for ritonavir regarding drug interactions associated with this drug.

Table 2 summarizes the effect of FORTOVASE on the geometric mean AUC and Cmax of coadministered drugs. Table 3 summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.

Table 2 Effect of FORTOVASE on the Pharmacokinetics of Coadministered Drugs
Coadministered DrugFORTOVASE or FORTOVASE/ritonavir
Dose
N% Change for Coadministered Drug
AUC (95%CI)Cmax (95%CI)
↑  Denotes an average increase in exposure by the percentage indicated.
↓  Denotes an average decrease in exposure by the percentage indicated.
↔ Denotes no statistically significant change in exposure was observed.
P   Patient
V  Healthy Volunteers
Φ No longer marketed in the US.
Clarithromycin 500 mg bid × 7 days
     Clarithromycin
    14-OH clarithromycin
    metabolite
1200 mg tid × 7days12V
↑45% (17-81%)
↓24% (5-40%)

↑39% (10-76%)
↓34% (14-50%)
Midazolam 7.5-mg oral single dose1200 mg tid × 5days6V↑514%↑235%
Nelfinavir 750-mg single dose1200 mg tid × 4days14P↑18%(5-33%)
Rifabutin 300 mg once daily1200 mg tid14P↑44%↑45%
Ritonavir 400 mg bid × 14 days400 mg bid × 14 days8V
Sildenafil 100-mg single dose1200 mg tid × 8 days27V↑210%(150-300%)↑140%(80-230%)
TerfenadineΦ 60 mg bid × 11 days  FORTOVASE should not be coadministered with terfenadine (see PRECAUTIONS: Drug Interactions).
     Terfenadine
    Terfenadine acid metabolite
1200 mg tid × 4 days12V
↑368% (257-514%)
↑120% (89-156%)

↑253% (164-373%)
↑93% (59-133%)
Efavirenz 600 mg1200 mg tid13V↓12%↓13%
Ketoconazole 400 mg once daily1200 mg tid12V
Enfuvirtide 90 mg SC q12h (bid) for 7 days1000/100 mg bid 12 P
Table 3 Effect of Coadministered Drugs on FORTOVASE Pharmacokinetics
Coadministered DrugFORTOVASE
Dose
N% Change for Saquinavir
AUC (95%CI)Cmax (95%CI)
↑  Denotes an average increase in exposure by the percentage indicated.
↓  Denotes an average decrease in exposure by the percentage indicated.
P   Patient
V  Healthy Volunteers
Clarithromycin 500 mg bid × 7 days1200 mg tid × 7days12V↑177% (108-269%)↑187% (105-300%)
Efavirenz 600 mg1200 mg tid13V↓62%↓50%
Indinavir 800 mg q8h × 2 days1200-mg single dose6V↑364% (190-644%)↑299% (138-568%)
Ketoconazole 400 mg once daily1200 mg tid12V↑190%↑171%
Nelfinavir 750 mg × 4 days1200-mg single dose14P↑392% (271-553%)↑179% (105-280%)
Rifabutin 300 mg once daily1200 mg tid14P↓47%↓31%
Rifampin 600 mg once daily1200 mg tid × 14 days14V↓70%↓65%
Ritonavir 100 mg bid1000 mg bid 1 24P↑176%↑153%
Ritonavir 400 mg bid × 14 daysWhen ritonavir was combined with the same dose of either INVIRASE or FORTOVASE, actual mean plasma exposures (AUC0-12, 18200 ng∙h/mL, 20000 ng∙h/mL, respectively) were not significantly different.400 mg bid × 14 days8V↑121% (7-359%)↑64%§
Lopinavir/ritonavir
   400/100 mg bid, 15 days

800 mg bid, 10 days combo vs. 1200 mg tid, 5 days alone

14V

↑9.62-fold
(8.05, 11.49) 2

↑6.34-fold
(5.32, 7.55)
   400/100 mg bid, 20 days1200 mg bid, 5 days combo vs. 1200 mg tid 5 days alone10V↑9.91-fold
(8.28, 11.86)
↑6.44-fold
(5.59, 7.41)

1   Compared to standard FORTOVASE 1200 mg tid regimen (n=33).
2 90% CI reported

For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions, Table 6.

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