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 Regimen | n | AUC0-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) | 31 | 7249 | 21747 | 216 |
INVIRASE 400 mg bid + ritonavir 400 mg bid (arithmetic mean± SD) | 7 | 16000±8000 | 32000 | 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) | 24 | 19085 (13943-26124) | 38170 | 433 (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 Drug | FORTOVASE 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 × 7days | 12V | ↑45% (17-81%) ↓24% (5-40%) | ↑39% (10-76%) ↓34% (14-50%) |
Midazolam 7.5-mg oral single dose | 1200 mg tid × 5days | 6V | ↑514% | ↑235% |
Nelfinavir 750-mg single dose | 1200 mg tid × 4days | 14P | ↑18%(5-33%) | ↔ |
Rifabutin 300 mg once daily | 1200 mg tid | 14P | ↑44% | ↑45% |
Ritonavir 400 mg bid × 14 days | 400 mg bid × 14 days | 8V | ↔ | ↔ |
Sildenafil 100-mg single dose | 1200 mg tid × 8 days | 27V | ↑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 days | 12V | ↑368% (257-514%) ↑120% (89-156%) | ↑253% (164-373%) ↑93% (59-133%) |
Efavirenz 600 mg | 1200 mg tid | 13V | ↓12% | ↓13% |
Ketoconazole 400 mg once daily | 1200 mg tid | 12V | ↔ | ↔ |
Enfuvirtide 90 mg SC q12h (bid) for 7 days | 1000/100 mg bid | 12 P | ↔ | ↔ |
Table 3 Effect of Coadministered Drugs on FORTOVASE Pharmacokinetics Coadministered Drug | FORTOVASE 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 days | 1200 mg tid × 7days | 12V | ↑177% (108-269%) | ↑187% (105-300%) |
Efavirenz 600 mg | 1200 mg tid | 13V | ↓62% | ↓50% |
Indinavir 800 mg q8h × 2 days | 1200-mg single dose | 6V | ↑364% (190-644%) | ↑299% (138-568%) |
Ketoconazole 400 mg once daily | 1200 mg tid | 12V | ↑190% | ↑171% |
Nelfinavir 750 mg × 4 days | 1200-mg single dose | 14P | ↑392% (271-553%) | ↑179% (105-280%) |
Rifabutin 300 mg once daily | 1200 mg tid | 14P | ↓47% | ↓31% |
Rifampin 600 mg once daily | 1200 mg tid × 14 days | 14V | ↓70% | ↓65% |
Ritonavir 100 mg bid | 1000 mg bid
| 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 days | 8V | ↑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)
| ↑6.34-fold (5.32, 7.55) |
400/100 mg bid, 20 days | 1200 mg bid, 5 days combo vs. 1200 mg tid 5 days alone | 10V | ↑9.91-fold (8.28, 11.86) | ↑6.44-fold (5.59, 7.41) |
For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions, Table 6.
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