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Invirase

Clinical Pharmacology
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Clinical Pharmacology

Invirase

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

A gender difference was observed, with females showing higher saquinavir exposure than males (mean AUC increase of 56%, mean Cmax increase of 26%), 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 1000-mg/ritonavir 100-mg bid).

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

Pediatric Patients

The pharmacokinetics of saquinavir when administered as INVIRASE have not been sufficiently investigated in pediatric patients.

Geriatric Patients

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

Drug Interactions

(see PRECAUTIONS: DRUG INTERACTIONS)

Several drug interaction studies have been completed with both INVIRASE and the saquinavir soft gel capsule formulation. Because 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 saquinavir soft gel capsules 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 saquinavir soft gel capsules on the Pharmacokinetics of Coadministered Drugs


Coadministered Drug Saquinavir soft gel capsules or
saquinavir soft gel capsules/ritonavir Dose 		N % Change for Coadministered Drug
AUC (95% CI) Cmax (95% CI)
Clarithromycin 500 mg bid x 7 days Clarithromycin 14-OH clarithromycin metabolite 1200 mg tid x 7 days 12V ↑45% (17-81%)
↓24% (5-40%)		 ↑39% (10-76%)
↓34% (14-50%)
Midazolam 7.5-mg oral single dose 1000/100 mg bid x 15
days		 16V ↑1144% (975-
1339%)^		 ↑327% (264-
402%)^
Ketoconazole 400 mg once daily 1200 mg tid 12V ↔ ↔
Enfuvirtide 90 mg SCq 12h (bid) for 7 days 1000/100 mg bid 12P ↔ ↔
Nelfinavir 750-mg single dose 1200 mg tid x 4 days 14P ↑18% (5-33%) ↔
Rifabutin 300 mg once daily 1200 mg tid 14P ↑44% ↑45%
Sildenafil 100-mg single dose 1200 mg tid x 8 days 27V ↑210% (150-300%) ↑140% (80-230%)
Efavirenz 600 mg 1200 mg tid 13V ↓12% ↓13%
Digoxin 0.5 mg single dose 1000/100 mg bid x 16
days		 16V ↑49% (32-69%)^ ↑27% (5-54%)^
R-Methadone 60-120 mg once daily 1000/100 mg bid x 14
days		 12M ↓19% (9-29%)^ NA
↑ 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.
^ 90% Confidence Interval
P Patient
V Healthy Volunteers
M Methadone-dependent, HIV negative patients
NA Not Available

Table 3 Effect of Coadministered Drugs on saquinavir soft gel capsules or INVIRASE Pharmacokinetics


Coadministered Drug Saquinavir soft gel capsules Dose N % Change for Saquinavir
AUC (95% CI) Cmax (95% CI)
Clarithromycin 500 mg bid x 7 days 1200 mg tid x 7 days 12V ↑177% (108-269%) ↑187% (105-300%)
Efavirenz 600 mg 1200 mg tid 13V ↓62% ↓50%
Indinavir 800 mg q8h x 2 days 1200-mg single dose 6V ↑364% (190-644%) ↑299% (138-568%)
↑171%
Ketoconazole 400 mg once daily 1200 mg tid 12V ↑190%
Nelfinavir 750 mg x 4 days 1200-mg single dose 14P ↑392% (271-553%) ↑179% (105-280%)
Rifabutin 300 mg once daily 1200 mg tid 14P ↓47% ↓39%
Ritonavir 400 mg bid x 14 days 400 mg bid x 14 days† 8V ↑121% (7-359%) ↑64%§
Lopinavir/ritonavir
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
AUC (95% CI) Cmax (95% CI)
Atazanavir 300 mg once daily 1600 mg qd + 100 mg
ritonavir qd		 18P ↑60%
(16-122%)		 ↑42%
(10-84%)
Fosamprenavir 700 mg bid 1000 mg bid + 100 mg
ritonavir bid		 18P ↓15%
(-33% to 9%)		 ↔
Rifabutin 150 mg every 3 days or 300 mg every 7 days 400 mg bid + 400 mg
ritonavir bid		 24P ↑19% ↑39%
Ritonavir 100 mg bid 1000 mg bid‡ 24P ↑1124% ↑1325%
Tenofovir 300 mg once daily 1000 mg bid + 100 mg
ritonavir bid		 18P ↔ ↔
Tipranavir 500 mg + ritonavir 200 mg bid 600 mg bid + 100 mg
ritonavir bid		 20P ↓76%
(68-81%)^		 ↓70%
(60-77%)^
Omeprazole 40 mg QD x 5 days 1000 mg/ritonavir 100
mg BID x 15 days		 19V ↑82%
(37-234%)^		 ↑75%
(31-234%)^
↑Denotes an average increase in exposure by the percentage indicated.
↓ Denotes an average decrease in exposure by the percentage indicated.
↔ Mean change < 10%
†Compared to standard saquinavir soft gel capsules 1200 mg tid regimen (n=33).
‡ Compared to standard INVIRASE 600 mg tid regimen (n=114).
§ Did not reach statistical significance.
^ 90% Confidence Interval
P Patient
V Healthy Volunteers
Brand Name: Invirase
Generic Name: Saquinavir Mesylate
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