"Entry Inhibitors (including Fusion Inhibitors) and CCR5 Co-receptor Antagonist
Entry inhibitors block HIV entry into CD4+ cells.
The only drug in this class "...
Mechanism of Action
INVIRASE is an antiviral agent [see Microbiology]
QTcS interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 59 healthy adults, with ECG measurements on Day 3. The maximum mean (95% upper confidence bound) differences in QTcS interval from placebo after baseline-correction were 18.9 (22.0) and 30.2 (33.4) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily of INVIRASE/ritonavir, respectively. There is a delayed effect between QTc interval change and drug concentrations, with the maximum placebo-adjusted baseline-corrected QTcS observed at about 12-20 h post-dose. INVIRASE/ritonavir 1500/100 mg twice daily resulted in a Day 3 mean Cmax of INVIRASE approximately 1.4-fold higher than the mean Cmax observed on Day 3 with the approved therapeutic dose in healthy volunteers (within the same study). QTcS in this study was QT/RR0.319 for males and QT/RR0.337 for females, which are similar to Fridericia's correction (QTcF=QT/RR0.3333).
PR and QRS interval prolongations were also noted in subjects receiving INVIRASE/ritonavir in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 28.6 (31.6) and 38.4 (41.4) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily saquinavir/ritonavir respectively. The maximum mean (95% upper confidence bound) difference from placebo in QRS interval after baseline correction were 2.9 (3.9) and 4.4 (5.3) ms for 1000/100 mg twice daily and supratherapeutic 1500/100 mg twice daily INVIRASE/ritonavir respectively. In this study using healthy subjects, PR interval prolongation of > 200 ms was also observed in 40% and 47% of subjects receiving INVIRASE/ritonavir 1000/100 mg bid and 1500/100 mg bid, respectively, on Day 3. Three (3%) of subjects in the active control moxifloxacin arm and 5% in the placebo arm experienced PR prolongation of > 200 ms.
The pharmacokinetics of INVIRASE/ritonavir 1000/100 mg twice daily have been evaluated in HIV-1-infected subjects and healthy subjects. Steady-state saquinavir AUC, Cmax, and Cmin in healthy subjects are approximately 50% higher than observed in HIV-1-infected subjects.
Absorption and Bioavailability in Adults
Similar bioavailability was demonstrated when INVIRASE 500 mg film-coated tablet (2 x 500 mg) and INVIRASE 200 mg capsule (5 x 200 mg) were administered with low-dose ritonavir (100 mg) under fed conditions. The ratio of mean exposures (90% confidence intervals) of tablets vs capsules was 1.10 (1.04-1.16) for AUC0-∞ and 1.19 (1.14-1.25) for Cmax.
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 saquinavir mesylate following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). The low bioavailability is thought to be due to a combination of incomplete absorption and extensive first-pass metabolism.
INVIRASE in combination with ritonavir at a dose of 1000/100 mg twice daily provides saquinavir systemic exposures over a 24-hour period that are similar to those achieved with saquinavir soft gel capsules with ritonavir 1000/100 mg twice daily and greater than that achieved with saquinavir soft gel capsules 1200 mg three times daily (see Table 4).
Table 4 : Pharmacokinetic Parameters of Saquinavir at
Steady-State After Administration of Different Regimens in HIV-1-Infected
|Dosing Regimen||N||AUC τ (ng•h/mL)||AUC24h (ng•h/mL)||Cmin (ng/mL)|
|INVIRASE 600 mg tid (arithmetic mean, %CV)||10||866 (62)||2598||79|
|Saquinavir soft gel capsules 1200 mg tid (arithmetic mean)||31||7249||21747||216|
|INVIRASE 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI)||24||14607 (10218-20882)||29214||371 (245-561)|
|Saquinavir soft gel capsules 1000 mg bid + ritonavir 100 mg bid (geometric mean and 95% CI)||24||19085 (13943-26124)||38170||433 (301-622)|
|τ is the dosing interval (i.e., 8h if three times daily and 12h if twice daily)|
The mean 24-hour AUC after a single 600-mg oral dose (6 x 100 mg) in healthy volunteers (n=6) was increased from 24 ng·h/mL (CV 33%), under fasting conditions, to 161 ng·h/mL (CV 35%) when INVIRASE was given following a high-fat breakfast (48 g protein, 60 g carbohydrate, 57 g fat; 1006 kcal). Saquinavir 24-hour AUC and Cmax (n=6) following the administration of a higher calorie meal (943 kcal, 54 g fat) were on average 2 times higher than after a lower calorie, lower fat meal (355 kcal, 8 g fat). The effect of food has been shown to persist for up to 2 hours.
INVIRASE/ritonavir should be taken within 2 hours after a meal.
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. Saquinavir was approximately 98% bound to plasma proteins over a concentration range of 15 to 700 ng/mL. In 2 subjects receiving saquinavir mesylate 600 mg three times daily, cerebrospinal fluid concentrations were negligible when compared to concentrations from matching plasma samples.
Metabolism and Elimination
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 dihydroxylated 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).
Saquinavir pharmacokinetics in patients with renal impairment has not been investigated. Only 1% of saquinavir is excreted in the urine, so the impact of renal impairment on saquinavir elimination would likely be minimal. However, subjects with severe renal impairment or end-stage renal disease (ESRD) have not been studied, and concentrations of saquinavir may be elevated in these populations.
The effect of hepatic impairment on the steady state pharmacokinetics of INVIRASE/ritonavir (1000/100 mg bid for 14 days) was investigated in 7 HIV-1-infected subjects with moderate liver impairment (6 with Child-Pugh score of 7 and 1 with Child-Pugh score of 9). The study included a control group consisting of 7 HIV-1infected subjects with normal hepatic function matched with hepatically impaired subjects for age, gender, weight and tobacco use. The mean (% coefficient of variation in parentheses) values for INVIRASE AUC0-12 and Cmax were 24.3 (102%) μg·hr/mL and 3.6 (83%) μg/mL, respectively, for HIV-1-infected subjects with moderate hepatic impairment. The corresponding values in the control group were 28.5 (71%) μg·hr/mL and 4.3 (68%) μg/mL. The geometic mean ratio (ratio of pharmacokinetic parameters in hepatically impaired subjects to subjects with normal liver function) (90% confidence interval) was 0.7 (0.3 to 1.6) for both AUC0-12 and Cmax, which suggests approximately 30% reduction in saquinavir exposure in subjects with moderate hepatic impairment. No dose adjustment is warranted for INVIRASE in HIV-1-infected patients with mild or moderate hepatic impairment [see WARNINGS AND PRECAUTIONS].
Gender, Race, and Age
A gender difference was observed, with females showing higher saquinavir exposure than males (mean AUC 56% higher, mean Cmax 26% higher), in the relative bioavailability study comparing INVIRASE 500 mg film-coated tablets to the INVIRASE 200 mg capsules in combination with ritonavir. There was no evidence that age and body weight explained the gender difference in this study. A clinically significant difference in safety and efficacy between men and women has not been reported with the approved dosage regimen (saquinavir 1000mg/ritonavir 100-mg twice daily).
The effect of race on the pharmacokinetics of saquinavir has not been investigated.
The pharmacokinetics of saquinavir have not been evaluated in the elderly.
Steady-state pharmacokinetic information is available from HIV-1 infected pediatric subjects from study NV20911. In this study, 5 subjects less than 2 years of age and 13 subjects between 2 and less than 6 years of age received 50 mg per kg saquinavir twice daily (not to exceed 1000 mg twice daily) boosted with ritonavir at 3 mg/kg for subjects with body weight ranging from 5 to < 15 kg or 2.5 mg per kg for subjects with body weight ranging from 15 to 40 kg (not to exceed 100 mg twice daily). For subjects unable to swallow the INVIRASE capsules, the contents of INVIRASE 200 mg capsules were mixed with sugar syrup, or sorbitol syrup (for subjects with Type I diabetes or glucose intolerance), jam, or baby formula. The mean steady state saquinavir PK parameters for pediatric subjects 2 to less than 6 years of age were: AUC0-12h 37269 ±18232 ng·h/mL; Ctrough 1811 ±998 ng/mL; Cmax 5464 ±2782 ng/mL, and day 3 exposures may be within the range of exposure associated with QT and PR prolongation [see CLINICAL PHARMACOLOGY: Pharmacodynamics]. The subject number was too low and the pharmacokinetic data too variable in the subjects less than 2 years to establish an appropriate dosing recommendation for this age group. Pharmacokinetic data for subjects ages 6 to 16 years were not available for comparisons with observations from NV20911 [see Use in Specific Populations: Pediatric Use] as the data from HIVNAT 017 could not be validated.
Table 5 summarizes the effect of saquinavir soft gel capsules and INVIRASE with and without ritonavir on the geometric mean AUC and Cmax of coadministered drugs. Table 6 summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.
Table 5 : Effect of Saquinavir (+/- Ritonavir) on the
Pharmacokinetics of Coadministered Drugs
|Coadministered Drug||Saquinavir soft gel capsules or saquinavir soft gel capsules/ ritonavir
|N||% Change for Coadministered Drug|
|Clarithromycin 500 mg bid x 7 days Clarithromycin 14-OH clarithromycin metabolite||1200 mg tid x 7 days||12V||↑45%
|Enfuvirtide 90 mg SC q12h
(bid) for 7 days
|1000/100 mg bid||12S||↔||↔|
|Sildenafil 100-mg single dose||1200 mg tid x 8 days||27V||↑210%
|Efavirenz 600 mg qd||1200 mg tid||13V||↓12%||↓13%|
|Digoxin 0.5 mg single dose||1000/100 mg bid x 16 days||16V||↑49%
|R-Methadone 60-120 mg qd||1000/100 mg bid x 14 days||12M||↓19%
|Ketoconazole 200 mg/day||1000/100 mg bid||12V||↑168%
|Midazolam 7.5 mg oral single dose||1000/100 mg bid||16V||↑1144%
|Rifabutin 150 mg q4d||1000/100 mg bid||11V||↑60%†*
(-10 to 13%)^
|↑ Denotes an average increase in exposure by the percentage
↓ Denotes an average decrease in exposure by the percentage indicated.
↔ Denotes no statistically significant change in exposure was observed.
* Compared to rifabutin 150 mg QD
^ 90% Confidence Interval
† AUC0-96hr and Cmax of the active moiety
(rifabutin + 25-O-desacetyl rifabutin)
§ AUC0-96hr and Cmax for rifabutin only
V Healthy Volunteers
M Methadone-dependent, HIV negative subjects
NA Not Available
Table 6 : Effect of Coadministered Drugs on Saquinavir
|Coadministered Drug||Saquinavir soft gel capsules
|N||% Change for Saquinavir|
|Clarithromycin 500 mg bid x 7 days||1200 mg tid x 7 days||12V||↑177%
|Efavirenz 600 mg qd||1200 mg tid||13V||↓62%||↓50%|
|Indinavir 800 mg q8h x 2 days||1200 mg single dose||6V||↑364%
|Ritonavir 400 mg bid x 14 days||400 mg bid x 14 days†||8V||↑121%
Evidence from several clinical trials indicates that saquinavir concentrations achieved with saquinavir 1000 mg + lopinavir/ritonavir 400/100 mg BID are similar to those achieved following saquinavir/ritonavir 1000/100 mg BID.
|Coadministered Drug||INVIRASE or INVIRASE/ritonavir Dose||N||% Change for Saquinavir|
|Atazanavir 300 mg qd||1600/100 mg qd||18S||↑60%
|Fosamprenavir 700 mg bid||1000 mg bid/100 mg bid||18S||↓15%
(-33% to 9%)
|Ritonavir 100 mg bid||1000 mg bid‡||24S||↑1124%||↑1325%|
|Tenofovir 300 mg qd||1000 mg bid/100 mg bid||18S||↔||↔|
|Tipranavir 500 mg + ritonavir 200 mg bid||600 mg bid/100 mg bid||20S||↓76%
|Omeprazole 40 mg qd x 5 days||1000/100 mg bid x 15 days||19V||↑82%
|Ketoconazole 200 mg/day||1000 mg bid/100 mg bid||20V||↔^||↔|
|Rifabutin 150 mg q3d||1000 mg bid/100 mg bid||19V||↓13%
(-31% to 9%)^
(-32% to 7%)^
|↑ Denotes an average increase in exposure by the percentage
↓ Denotes an average decrease in exposure by the percentage indicated.
↔ Mean change < 10%
† Compared to saquinavir soft gel capsules 1200 mg tid regimen
‡ Compared to INVIRASE 600 mg tid regimen
§ Did not reach statistical significance.
^ 90% Confidence Interval
V Healthy Volunteers
Mechanism of Action
Saquinavir is an inhibitor of HIV-1 protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of viral polyprotein precursors into individual functional proteins found in HIV-1 particles. 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 viral particles
The antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes in cell culture. Saquinavir inhibited HIV-1 activity in both acutely and chronically infected cells. EC50 and EC90 values (50% and 90% inhibitory concentrations) ranged from 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean EC50 of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7±5 nM representing a 4-fold increase in the EC50 value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity. Saquinavir displayed antiviral activity in cell culture against HIV-1 clades A-H (EC50 values ranged from 0.9 to 2.5 nM). The EC50 and EC90 values of saquinavir against HIV-2 isolates in cell culture ranged from 0.25 nM to 14.6 nM and 4.65 nM to 28.6 nM, respectively.
HIV-1 isolates with reduced susceptibility to saquinavir have been selected during passage in cell culture. Genotypic analyses of these isolates showed several amino acid substitutions in the HIV-1 protease. Only the G48V and L90M substitutions were associated with reduced susceptibility to saquinavir, and conferred an increase in the EC50 value of 8- and 3-fold, respectively.
HIV-1 isolates with reduced susceptibility ( ≥ 4-fold increase in the EC50 value) to saquinavir emerged in some subjects treated with INVIRASE. Genotypic analysis of these isolates identified resistance conferring primary amino acid substitutions in the protease G48V and L90M, and secondary substitutions L10I/R/V, I54V/L, A71V/T, G73S, V77I, V82A and I84V that contributed additional resistance to saquinavir. Forty-one isolates from 37 subjects failing therapy with INVIRASE had a median decrease in susceptibility to saquinavir of 4.3fold.
The degree of reduction in cell culture susceptibility to saquinavir of clinical isolates bearing substitutions G48V and L90M depends on the number of secondary substitutions present. In general, higher levels of resistance are associated with greater number of substitutions only in association with either or both of the primary substitutions G48V and L90M. No data are currently available to address the development of resistance in patients receiving saquinavir/ritonavir.
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 EC50 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 protease inhibitors and 4 out of the 22 isolates (18%) displayed broad cross-resistance to all protease inhibitors. Sixteen (73%) and 11 (50%) of the 22 isolates remained susceptible ( < 4fold) to amprenavir and indinavir, respectively. Four of 16 (25%) and nine 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 subjects failing treatment with amprenavir and containing one or more substitutions M46L/I, I50V, I54L, V32I, I47V, and I84V were susceptible to saquinavir.
Description of Clinical Studies in Adults
In a randomized, double-blind clinical study NV14256 in zidovudine-experienced, HIV-1-infected adult subjects, INVIRASE in combination with zalcitabine2 was shown to be superior to either INVIRASE or zalcitabine monotherapy in decreasing the cumulative incidence of clinical disease progression to AIDS-defining events or death. In another randomized study ACTG229/NV14255, subjects with advanced HIV-1 infection with history of prolonged zidovudine treatment were administered INVIRASE 600 mg (three times daily) + zidovudine + zalcitabine. Subjects receiving this regimen experienced greater increases in CD4+ cell counts as compared to those who received INVIRASE + zidovudine or zalcitabine + zidovudine. It should be noted the HIV treatment regimens that were used in these clinical trials are no longer considered standard of care.
In the MaxCmin1 trial, saquinavir gel capsule 1000 mg twice daily coadministered with ritonavir 100 mg twice daily was evaluated in a heterogeneous population of 148 HIV-1-infected subjects. A total of 42 subjects enrolled were treatment-na´ve, and 106 subjects were treatment-experienced (of which 52 subjects had HIV-1 RNA < 400 copies/mL at baseline). Results showed that 91/148 (61%) subjects achieved and/or sustained an HIV-1 RNA < 400 copies per mL at the completion of 48 weeks treatment.
2No longer available in the US.
Last reviewed on RxList: 12/18/2012
This monograph has been modified to include the generic and brand name in many instances.
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