invirase

WARNING
INVIRASE ® (saquinavir mesylate) capsules and FORTOVASE ® (saquinavir)soft gelatin capsules are not bioequivalent and cannot be used interchangeably invirase. INVIRASE may be used only if it is combined with ritonavir, which significantlyinhibits saquinavir's metabolism to provide plasma saquinavir levels at leastequal to those achieved with FORTOVASE invirase. When using saquinavir as the sole proteaseinhibitor in an antiviral regimen, FORTOVASE is the recommended formulation(see CLINICAL PHARMACOLOGY : Drug Interactions ) invirase.

Product identification in this document includes: INVIRASE in reference tosaquinavir mesylate; FORTOVASE in reference to saquinavir soft gel formulation,and saquinavir in reference to the active base invirase.

DESCRIPTION
INVIRASE brand of saquinavir mesylate is an inhibitor of the human immunodeficiencyvirus (HIV) protease invirase. INVIRASE is available as light brown and green, opaquehard gelatin capsules for oral administration in a 200-mg strength (as saquinavirfree base) invirase. Each capsule also contains the inactive ingredients lactose, microcrystallinecellulose, povidone K30, sodium starch glycolate, talc, and magnesium stearate invirase. Each capsule shell contains gelatin and water with the following dye systems:red iron oxide, yellow iron oxide, black iron oxide, FD&C Blue #2, and titaniumdioxide invirase. The chemical name for saquinavir mesylate 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 methanesulfonate with a molecular formulaC 38 H 50 N 6 O 5 ·CH 4 O 3 S and a molecular weight of 766.96 invirase. The molecularweight of the free base is 670.86 invirase.

Saquinavir mesylate is a white to off-white, very fine powder with an aqueoussolubility of 2.22 mg/mL at 25°C invirase.

MICROBIOLOGY
Mechanism of Action
Saquinavir is an inhibitor of HIV protease invirase. HIV protease is an enzyme requiredfor the proteolytic cleavage of viral polyprotein precursors into individualfunctional proteins found in infectious HIV invirase. Saquinavir is a peptide-like substrateanalogue that binds to the protease active site and inhibits the activity ofthe enzyme invirase. Saquinavir inhibition prevents cleavage of the viral polyproteinsresulting in the formation of immature noninfectious virus particles invirase.

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

Drug Resistance
HIV-1 mutants with reduced susceptibility to saquinavir have been selected duringin vitro passage invirase. Genotypic analyses of these isolates showed several substitutionsin the HIV protease gene invirase. Only the G48V and L90M substitutions were associatedwith reduced susceptibility to saquinavir, and conferred an increase in theIC 50 value of 8- and 3-fold, respectively invirase.

HIV-1 isolates with reduced susceptibility (>/=4-fold increase in the IC50 value) to saquinavir emerged in some patients treated with INVIRASE invirase. Genotypicanalysis of these isolates identified resistance conferring primary mutationsin 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 tosaquinavir invirase. Forty-one isolates from 37 patients failing therapy with INVIRASEhad a median decrease in susceptibility to saquinavir of 4.3 fold invirase.

The degree of reduction in in vitro susceptibility to saquinavir of clinicalisolates bearing substitutions G48V and L90M depends on the number of secondarymutations present invirase. In general, higher levels of resistance are associated withgreater number of mutations only in association with either or both of the primarymutations G48V and L90M invirase. No data are currently available to address the developmentof resistance in patients receiving saquinavir/ritonavir invirase.

Cross-resistance
Among protease inhibitors, variable crossresistance has been observed invirase. In oneclinical study, 22 HIV-1 isolates with reduced susceptibility (>4-fold increasein the IC 50 value) to saquinavir following therapy with INVIRASE were evaluatedfor cross-resistance to amprenavir, indinavir, nelfinavir and ritonavir invirase. Sixof 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 PIsand 4 out of the 22 isolates (18%) displayed broad cross- resistance to allPIs invirase. Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible (<4-fold)to amprenavir and indinavir, respectively invirase. Four of 16 (25%) and nine of 21 (43%)with available data remained susceptible to nelfinavir and ritonavir, respectively invirase.

After treatment failure with amprenavir, cross-resistance to saquinavir wasevaluated invirase. HIV-1 isolates from 22/22 patients failing treatment with amprenavirand containing one or more mutations M46L/I, I50V, I54L, V32I, I47V, and I84Vwere susceptible to saquinavir invirase.

CLINICAL PHARMACOLOGY
Pharmacokinetics
The pharmacokinetic properties of INVIRASE have been evaluated in healthy volunteers(n=351) and HIV-infected patients (n=270) after single- and multiple-oral dosesof 25, 75, 200, and 600 mg tid and in healthy volunteers after intravenous dosesof 6, 12, 36 or 72 mg (n=21) invirase. The pharmacokinetics of INVIRASE/ritonavir 400/400mg bid and INVIRASE/ritonavir 1000/100 mg bid have also been evaluated in HIV-infectedpatients invirase.

HIV-infected patients administered INVIRASE (600-mg TID) had AUC and maximumplasma concentration (C max ) values approximately 2-2.5 times those observedin healthy volunteers receiving the same treatment regimen invirase.

Absorption and Bioavailability in Adults

Absolute bioavailability of saquinavir administered as INVIRASE averaged 4%(CV 73%, range: 1% to 9%) in 8 healthy volunteers who received a single 600-mgdose (3 ? 200 mg) of saquinavir mesylate following a high-fat breakfast (48g protein, 60 g carbohydrate, 57 g fat; 1006 kcal) invirase. The low bioavailabilityis thought to be due to a combination of incomplete absorption and extensivefirst-pass metabolism invirase. Following single 600-mg doses, the relative bioavailabilityof saquinavir as FORTOVASE compared to saquinavir administered as INVIRASE wasestimated at 331% (95% CI 207% to 530%) invirase.

When administered as the sole protease inhibitor, it has been shown that FORTOVASE1200 mg tid provides an 8-fold increase in AUC compared with INVIRASE 600 mgtid (see Table 1) invirase.

INVIRASE in combination with ritonavir at doses of 1000/100 mg bid or 400/400mg bid provides saquinavir systemic exposures over a 24-hour period similarto or greater than those achieved with FORTOVASE 1200 mg tid (see Table 1) invirase.

Table 1 Pharmacokinetic Parameters of Saquinavir at Steady-State After Administrationof Different Regimens in HIV-Infected Patients Dosing Regimen N AUC (tau)
(ng·h/mL) AUC 24h
(ng·h/mL) C min
(ng/mL)
INVIRASE 600 mg tid (arithmetic mean, %CV) 10 866 (62) 2598 79
FORTOVASE 1200 mg tid (arithmetic mean) 31 7249 21747 216
INVIRASE 400 mg bid + ritonavir 400 mg bid (arithmetic mean ±SD) 7 16000±800032000 480±360
INVIRASE 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI) 24 14607
(10218-20882) 29214 371
(245-561)
FORTOVASE 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI) 2419085
(13943-26124) 38170 433
(301-622)
(tau) is the dosing interval (ie, 8h if tid and 12h if bid)

Food Effect

No food effect data are available for INVIRASE in combination with ritonavir invirase.

The mean 24-hour AUC after a single 600-mg oral dose (6 ? 100 mg) in healthyvolunteers (n=6) was increased from 24 ng·h/mL (CV 33%), under fastingconditions, to 161 ng·h/mL (CV 35%) when INVIRASE was given followinga high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal) invirase. Saquinavir 24-hour AUC and C max (n=6) following the administration of a highercalorie meal (943 kcal, 54 g fat) were on average 2 times higher than aftera lower calorie, lower fat meal (355 kcal, 8 g fat) invirase. The effect of food hasbeen shown to persist for up to 2 hours invirase.

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

Distribution in Adults

The mean steady-state volume of distribution following intravenous administrationof a 12-mg dose of saquinavir (n=8) was 700 L (CV 39%), suggesting saquinavirpartitions into tissues invirase. Saquinavir was approximately 98% bound to plasma proteinsover a concentration range of 15 to 700 ng/mL invirase. In 2 patients receiving saquinavirmesylate 600 mg tid, cerebrospinal fluid concentrations were negligible whencompared to concentrations from matching plasma samples invirase.

Metabolism and Elimination in Adults

In vitro studies using human liver microsomes have shown that the metabolismof saquinavir is cytochrome P450 mediated with the specific isoenzyme, CYP3A4,responsible for more than 90% of the hepatic metabolism invirase. Based on in vitro studies,saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactivecompounds invirase. In a mass balance study using 600 mg 14 C-saquinavir mesylate (n=8),88% and 1% of the orally administered radioactivity was recovered in feces andurine, respectively, within 5 days of dosing invirase. In an additional 4 subjects administered10.5 mg 14 C-saquinavir intravenously, 81% and 3% of the intravenously administeredradioactivity was recovered in feces and urine, respectively, within 5 daysof dosing invirase. In mass balance studies, 13% of circulating radioactivity in plasmawas attributed to unchanged drug after oral administration and the remainderattributed to saquinavir metabolites invirase. Following intravenous administration,66% of circulating radioactivity was attributed to unchanged drug and the remainderattributed to saquinavir metabolites, suggesting that saquinavir undergoes extensivefirst-pass metabolism invirase.

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

Special Populations
Hepatic or Renal Impairment

Saquinavir pharmacokinetics in patients with hepatic or renal impairment hasnot been investigated (see PRECAUTIONS ) invirase. Only 1% of saquinavir is excretedin the urine, so the impact of renal impairment on saquinavir elimination shouldbe minimal invirase.

Gender, Race, and Age

Pharmacokinetic data were available for 17 women in the Phase I/II studies invirase. Pooled data did not reveal an apparent effect of gender on the pharmacokineticsof saquinavir invirase.

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

Pediatric Patients

The pharmacokinetics of saquinavir when administered as INVIRASE has not beensufficiently investigated in pediatric patients invirase.

Geriatric Patients

The pharmacokinetics of saquinavir when administered as INVIRASE have not beensufficiently investigated in patients >65 years of age invirase.

Drug Interactions (see PRECAUTIONS : Drug Interactions )
Several drug interaction studies have been completed with both INVIRASE andFORTOVASE invirase. It is important to be aware that, when INVIRASE is coadministeredwith ritonavir, the occurrence and magnitude of drug interactions may differfrom those seen with FORTOVASE when administered as the sole protease inhibitor invirase. Because ritonavir is coadministered, prescribers should refer to the prescribinginformation for ritonavir regarding drug interactions associated with this drug invirase.

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