acokinetic parameters for male and female HIV-1 positive patients presented in Table 5.
Table 5 Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV-1 Positive Patients by Gender
|
|
Females
(n=14) |
Males
(n=106) |
|
a Population pharmacokinetic parameters reported as mean ± standard deviation |
|
Cptrough (μM) |
41.6 ± 24.3 |
35.6 ± 16.7 |
|
Cmax (μM) |
94.8 ± 22.8 |
77.6 ± 16.6 |
|
Tmax (h) |
2.9 |
3.0 |
|
AUC0-12h (μM•h) |
851 ± 309 |
710 ± 207 |
|
CL (L/h) |
1.15 |
1.27 |
|
V (L) |
7.7 |
10.2 |
|
t1/2 (h) |
5.5 |
6.0 |
Effects of Food on Oral Absorption
For APTIVUS capsules or oral solution co-administered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir Cmax, Cp12h, and AUC were observed under fed conditions (500-682 Kcal, 23-25% calories from fat) compared to fasted conditions [see Dosage and Administration (2)]. The effect of food on tipranavir exposure when APTIVUS capsules or oral solution is co-administered with ritonavir tablets has not been eva luated [see Dosage and Administration (2)]. For information on the effect of food on the bioavailability of ritonavir tablets, please refer to the ritonavir tablet prescribing information.
Distribution
Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and α-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 μM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range.
No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal fluid or semen.
Metabolism
In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.
The oral clearance of tipranavir decreased after the addition of ritonavir, which may represent diminished first-pass clearance of the drug at the gastrointestinal tract as well as the liver.
The metabolism of tipranavir in the presence of 200 mg ritonavir is minimal. Administration of 14C-tipranavir to subjects that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that unchanged tipranavir accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or 12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2% or less of the plasma radioactivity). In feces, unchanged tipranavir represented the majority of fecal radioactivity (79.9% of fecal radioactivity). The most abundant fecal metabolite, at 4.9% of fecal radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir was found in trace amounts (0.5% of urine radio
