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Aptivus

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Aptivus

CLINICAL PHARMACOLOGY

Mechanism Of Action

Tipranavir is an antiviral drug.

Pharmacodynamics

ECG Evaluation

The effect of APTIVUS/ritonavir on the QTcF interval was measured in a study in which 81 healthy subjects received the following treatments twice daily for 2.5 days: APTIVUS/ritonavir (500/200 mg), APTIVUS/ritonavir at a supra-therapeutic dose (750/200 mg), and placebo/ritonavir (-/200 mg). After baseline and placebo adjustment, the maximum mean QTcF change was 3.2 ms (1-sided 95% Upper CI: 5.6 ms) for the 500/200 mg dose and 8.3 ms (1-sided 95% Upper CI: 10.9 ms) for the supra-therapeutic 750/200 mg dose.

Antiviral Activity in vivo

The median Inhibitory Quotient (IQ) determined from 264 treatment-experienced adult patients was about 80 (inter-quartile range: 31-226), from the controlled clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral EC50 value, corrected for protein binding. There was a relationship between the proportion of patients with a ≥ 1 log10 reduction of viral load from baseline at week 48 and their IQ value. Among the 198 patients receiving APTIVUS/ritonavir with no new enfuvirtide use (e.g., new enfuvirtide, defined as initiation of enfuvirtide for the first time), the response rate was 23% in those with an IQ value < 80 and 59% in those with an IQ value ≥ 80. Among the 66 patients receiving APTIVUS/ritonavir with new enfuvirtide, the response rates in patients with an IQ value < 80 versus those with an IQ value ≥ 80 were 55% and 71%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints.

Pharmacokinetics

In order to achieve effective tipranavir plasma concentrations and a twice-daily dosing regimen, co-administration of APTIVUS with ritonavir is essential [see DOSAGE AND ADMINISTRATION]. Ritonavir inhibits hepatic cytochrome P450 3A (CYP 3A), the intestinal P-gp efflux pump and possibly intestinal CYP 3A. In a dose-ranging evaluation in 113 HIV-1 negative male and female volunteers, there was a 29-fold increase in the geometric mean morning steady-state trough plasma concentrations of tipranavir following APTIVUS co-administered with low-dose ritonavir (500/200 mg twice daily) compared to APTIVUS 500 mg twice daily without ritonavir. In adults the mean systemic ritonavir concentration when 200 mg of ritonavir was given with 500 mg of APTIVUS was similar to the concentrations observed when 100 mg was given with the other protease inhibitors.

Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for 30 HIV-1 infected adult patients dosed with 500/200 mg tipranavir/ritonavir for 14 days.

Figure 1 : Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration (tipranavir/ritonavir 500/200 mg BID)

Mean Steady State Tipranavir Plasma Concentrations (95% CI) with Ritonavir Co-administration - Illustration

Absorption and Bioavailability

Absorption of tipranavir in humans is limited, although no absolute quantification of absorption is available. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. In vivo data suggest that tipranavir/ritonavir, at the dose of 500/200 mg, is a P-gp inhibitor after the first dose and induction of P-gp occurs over time. Tipranavir trough concentrations at steady-state are about 70% lower than those on Day 1, presumably due to intestinal P-gp induction. Steady state is attained in most subjects after 7-10 days of dosing.

Dosing APTIVUS 500 mg with 200 mg ritonavir capsules twice daily for greater than 2 weeks and without meal restriction produced the pharmacokinetic 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)
Cptrou2h (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
AUC0-1211 (pM•h) 851±309 710±207
CL (L/h) 1.15 1.27
V (L) 7.7 10.2
t½ (h) 5.5 6.0
aPopulation pharmacokinetic parameters reported as mean ± standard deviation

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]. The effect of food on tipranavir exposure when APTIVUS capsules or oral solution is co-administered with ritonavir tablets has not been evaluated [see DOSAGE AND ADMINISTRATION]. 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 radioactivity). The most abundant urinary metabolite, at 11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.

Elimination

Administration of 14C-tipranavir to subjects (n=8) that received APTIVUS/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal.

Special Populations

Renal Impairment

APTIVUS pharmacokinetics have not been studied in patients with renal dysfunction. However, since the renal clearance of tipranavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Hepatic Impairment

In a study comparing 9 HIV-1 negative patients with mild (Child-Pugh Class A) hepatic impairment to 9 HIV-1 negative controls, the single and multiple dose plasma concentrations of tipranavir and ritonavir were increased in patients with hepatic impairment, but were within the range observed in clinical trials. No dosing adjustment is required in patients with mild hepatic impairment.

The influence of moderate hepatic impairment (Child-Pugh Class B) or severe hepatic impairment (Child-Pugh Class C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

Gender

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of APTIVUS/ritonavir 500/200 mg BID, the median plasma trough concentration of tipranavir was 43.9 μM for females and 31.1 μM for males. The difference in concentrations does not warrant a dose adjustment.

Race

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that white males generally had more variability in tipranavir concentrations than black males, but the median concentration and the range making up the majority of the data are comparable between the races.

Geriatric Patients

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the controlled clinical trials 1182.12 and 1182.48 demonstrated that there was no change in median trough tipranavir concentrations as age increased for either gender through 65 years of age. There were an insufficient number of women greater than age 65 years in the two trials to evaluate the elderly.

Pediatric Patients

Among pediatric patients in clinical trial 1182.14, steady-state plasma tipranavir trough concentrations were obtained 10 to 14 hours following study drug administration. Pharmacokinetic parameters by age group are presented in Table 6.

Table 6 : Pharmacokinetic Parametersa of tipranavir/ritonavir 375 mg/m²/150 mg/m² for HIV-1 Positive Pediatric Patients by Age

Parameter 2 to < 6 years
(n=12)
6 to < 12 years
(n=8)
12 to 18 years
(n=6)
Cptroush (μM) 59.6 ± 23.6 66.3 ± 12.5 53.3 ± 32.4
Cmax (μM) 135 ± 44 151 ± 32 138 ± 52
Tmax (h) 2.5 2.6 2.7
AUC0.12h (μM•h) 1190±332 1354± 256 1194±517
CL/F (L/h) 0.34 0.45 0.99
V (L) 4.0 4.7 5.3
t½ (h) 8.1 7.1 5.2
aPopulation pharmacokinetic parameters reported as mean ± standard deviation

Drug Interactions

Drug interaction studies were performed with APTIVUS capsules co-administered with ritonavir, and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of APTIVUS with 200 mg ritonavir on the AUC, Cmax, and Cmin of tipranavir or the co-administered drug, are summarized in Tables 7 and 8, respectively. For information regarding clinical recommendations see DRUG INTERACTIONS.

Table 7 : Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs

Co-administered Drug Co-administered Drug Dose
(Schedule)
tipranavir/ ritonavir Drug Dose
(Schedule)
n PK Ratio (90% Confidence Interval) of Tipranavir Pharmacokinetic Parameters with/without Co-administered Drug; No Effect = 1.00
Cmax AUC Cmin
Antacids
(Maalox®)
20 mL
(1 dose)
500/200 mg
(1 dose)
23 0.75
(0.63, 0.88)
0.73
(0.64, 0.84)
-
Atazanavir/ ritonavir 300/100 mg QD
(9 doses)
500/100 mg BID
(34 doses)
13 1.08
(0.98, 1.20)
1.20
(1.09, 1.32)
1.75
(1.39, 2.20)
Atorvastatin 10 mg
(1 dose)
500/200 mg BID
(14 doses)
22 0.96
(0.86, 1.07)
1.08
(1.00, 1.15)
1.04
(0.89, 1.22)
Clarithromycin 500 mg BID
(25 doses)
500/200 mg BID* 24
(68)
1.40
(1.24, 1.47)
1.66
(1.43, 1.73)
2.00
(1.58, 2.47)
Didanosine 400 mg
(1 dose)
500/100 mg BID
(27 doses)
5 1.32
(1.09, 1.60)
1.08
(0.82, 1.42)
0.66
(0.31, 1.43)
Efavirenz 600 mg QD
(8 doses)
500/100 mg BID* 21
(89)
0.79
(0.69, 0.89)
0.69
(0.57, 0.83)
0.58
(0.36, 0.86)
750/200 mg BID* 25(100) 0.97
(0.85, 1.09)
1.01
(0.85, 1.18)
0.97
(0.69, 1.28)
Ethinyl estradiol / Norethindrone 0.035/1.0 mg
(1 dose)
500/100 mg BID
(21 doses)
21 1.10
(0.98, 1.24)
0.98
(0.88, 1.11)
0.73
(0.59, 0.90)
750/200 mg BID
(21 doses)
13 1.01
(0.96, 1.06)
0.98
(0.90, 1.07)
0.91
(0.69, 1.20)
Fluconazole 100 mg QD
(12 doses)
500/200 mg BID* 20
(68)
1.32
(1.18, 1.47)
1.50
(1.29, 1.73)
1.69
(1.33, 2.09)
Loperamide 16 mg
(1 dose)
750/200 mg BID
(21 doses)
24 1.03
(0.92, 1.17)
0.98
(0.86, 1.12)
0.74
(0.62, 0.88)
Rifabutin 150 mg
(1 dose)
500/200 mg BID
(15 doses)
21 0.99
(0.93, 1.07)
1.00
(0.96, 1.04)
1.16
(1.07, 1.27)
Rosuvastatin 10 mg
(1 dose)
500/200 mg BID
(24 doses)
16 1.08
(1.00, 1.17)
1.06
(0.97, 1.15)
0.99
(0.88, 1.11)
Tadalafil 10 mg
(1 dose)
500/200 mg BID
(17 doses)
17 0.90
(0.80, 1.01)
0.85
(0.74, 0.97)
0.81
(0.70, 0.94)
Tenofovir 300 mg
(1 dose)
500/100 mg BID 22 0.83
(0.74, 0.94)
0.82
(0.75, 0.91)
0.79
(0.70, 0.90)
750/200 mg BID
(23 doses)
20 0.89
(0.84, 0.96)
0.91
(0.85, 0.97)
0.88
(0.78, 1.00)
Valacyclovir 500 mg
(1 dose)
500/200 mg BID
(23 doses)
26 1.02
(0.95, 1.10)
1.01
(0.96, 1.06)
0.98
(0.93, 1.04)
Zidovudine 300 mg
(1 dose)
500/100 mg BID 29 0.87
(0.80, 0.94)
0.82
(0.76, 0.89)
0.77
(0.68, 0.87)
750/200 mg BID
(23 doses)
25 1.02
(0.94, 1.10)
1.02
(0.92, 1.13)
1.07
(0.86, 1.34)
*steady state comparison to historical data (n)
↑ increase, ↓ decrease, ↔ no change, ⇓ unable to predict

Table 8 :Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of APTIVUS/ritonavir

Co-administered Drug Co-administered Drug Dose
(Schedule)
tipranavir/ ritonavir Drug Dose
(Schedule)
n PK Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without tipranavir/ ritonavir; No Effect = 1.00
Cmax AUC Cmin
Abacavira 300 mg BID
(43 doses)
250/200 mg BID 28 0.56
(0.48, 0.66)
0.56
(0.49, 0.63)
-
750/100 mg BID 14 0.54
(0.47, 0.63)
0.64
(0.55, 0.74)
-
1250/100 mg BID
(42 doses)
11 0.48
(0.42, 0.53)
0.65
(0.55, 0.76)
-
Acyclovirh 500 mg
(1 dose)
500/200 mg BID
(23 doses)
26 0.95
(0.88, 1.02)
1.07
(1.04, 1.09)
-
Amprenavir/ritonavira 600/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
16 0.61
(0.51, 0.73)e
0.56
(0.49, 0.64)e
0.45
(0.38, 0.53)e
74 - 0.44
(0.39, 0.49)f
Atazanavir/ritonavir 300/100 mg QD(9 doses) 500/100 mg BID(34 doses) 13 0.43
(0.38, 0.50)
0.32
(0.29, 0.36)
0.19
(0.15, 0.24)
Atorvastatin 10 mg(1 dose) 500/200 mg BID(17 doses) 22 8.61
(7.25, 10.21)
9.36
(8.02, 10.94)
5.19
(4.21, 6.40)
Orthohydroxy-atorvastatin 21, 12, 17 0.02
(0.02, 0.03)
0.11
(0.08, 0.17)
0.07
(0.06, 0.08)
Parahydroxy-atorvastatin 13, 22, 1 1.04
(0.87, 1.25)
0.18
(0.14, 0.24)
0.33
(NA)
Buprenorphine/ Naloxoneb 16/4 mg 24/6 mg
(daily)
500/200 mg BID
(16 doses)
         
Buprenorphine 10 0.86
(0.68, 1.10)
0.99
(0.80, 1.23)
0.94
(0.74, 1.19)
Carbamazepine 100 mg BID
(29 doses)
500/200 mg
(1 dose)
7 1.04
(1.00, 1.07)
1.05
(1.02, 1.09)
1.17
(1.11, 1.24)
(43 doses) (15 doses) 7 1.10
(0.85, 1.42)
1.08
(0.91, 1.27)
1.07
(0.90, 1.27)
200 mg BID
(29 doses)
500/200 mg
(1 dose)
17 1.00
(0.96, 1.04)
1.04
(1.00, 1.08)
1.16
(1.11, 1.22)
(43 doses) (15 doses) 17 1.22
(1.11, 1.34)
1.26
(1.15, 1.38)
1.35
(1.22, 1.50)
Clarithromycin 500 mg BID
(25 doses)
500/200 mg BID
(15 doses)
21 0.95
(0.83, 1.09)
1.19
(1.04, 1.37)
1.68
(1.42, 1.98)
14-OH-clarithromycin 21 0.03
(0.02, 0.04)
0.03
(0.02, 0.04)
0.05
(0.04, 0.07)
Didanosinec 200 mg BID, ≥ 60 kg 250/200 mg BID 10 0.57
(0.42, 0.79)
0.67
(0.51, 0.88)
-
125 mg BID, < 60 kg 750/100 mg BID 8 0.76
(0.49, 1.17)
0.97
(0.64, 1.47)
-
(43 doses) 1250/100 mg BID
(42 doses)
9 0.77
(0.47, 1.26)
0.87
(0.47, 1.65)
-
400 mg(1 dose) 500/100 mg BID(27 doses) 5 0.80
(0.63, 1.02)
0.90
(0.72, 1.11)
1.17
(0.62, 2.20)
Efavirenzc 600 mg QD 500/100 mg BID 24 1.09
(0.99, 1.19)
1.04
(0.97, 1.12)
1.02
(0.92, 1.12)
(15 doses) 750/200 mg BID
(15 doses)
22 1.12
(0.98, 1.28)
1.00
(0.93, 1.09)
0.94
(0.84, 1.04)
Ethinyl estradiol 0.035 mg 500/100 mg BID 21 0.52
(0.47, 0.57)
0.52
(0.48, 0.56)
-
(1 dose) 750/200 mg BID
(21 doses)
13 0.48
(0.42, 0.57)
0.57
(0.54, 0.60)
-
Fluconazole 200 mg
(Day 1) then 100 mg QD
(6 or 12 doses)
500/200 mg BID
(2 or 14 doses)
19 0.97
(0.94, 1.01)
0.99
(0.97, 1.02)
0.98
(0.94, 1.02)
19 0.94
(0.91, 0.98)
0.92
(0.88, 0.95)
0.89
(0.85, 0.92)
Lopinavir/ ritonavira 400/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
21 0.53
(0.40, 0.69)e
0.45
(0.32, 0.63)e
0.30
(0.17, 0.51)e
69 - - 0.48
(0.40, 0.58)f
Loperamide 16 mg
(1 dose)
750/200 mg BID
(21 doses)
24 0.39
(0.31, 0.48)
0.49
(0.40, 0.61)
-
N-Demethyl-Loperamide 24 0.21
(0.17, 0.25)
0.23
(0.19, 0.27)
-
Lamivudinea 150 mg BID
(43 doses)
250/200 mg BID 64 0.96
(0.89, 1.03)
0.95
(0.89, 1.02)
-
750/100 mg BID 46 0.86
(0.78, 0.94)
0.96
(0.90, 1.03)
-
1250/100 mg BID
(42 doses)
35 0.71
(0.62, 0.81)
0.82
(0.66, 1.00)
-
Methadone 5 mg
(1 dose)
500/200 mg BID
(16 doses)
14 0.45
(0.41, 0.49)
0.47
(0.44, 0.51)
0.50
(0.46, 0.54)
R-methadone 0.54
(0.50, 0.58)
0.52
(0.49, 0.56)
-
S-methadone 0.38
(0.35, 0.43)
0.37
(0.34, 0.41)
-
Nevirapinea 200 mg BID
(43 doses)
250/200 mg BID 26 0.97
(0.90, 1.04)
0.97
(0.91, 1.04)
0.96
(0.87, 1.05)
750/100 mg BID 22 0.86
(0.76, 0.97)
0.89
(0.78, 1.01)
0.93
(0.80, 1.08)
1250/100 mg BID
(42 doses)
17 0.71
(0.62, 0.82)
0.76
(0.63, 0.91)
0.77
(0.64, 0.92)
Norethindrone 1.0 mg
(1 dose)
500/100 mg BID 21 1.03
(0.94, 1.13)
1.14
(1.06, 1.22)
-
750/200 mg BID
(21 doses)
13 1.08
(0.97, 1.20)
1.27
(1.13, 1.43)
-
Raltegravir 400 mg BID 500/200 mg BID 15 0.82
(0.46, 1.46)
0.76
(0.49, 1.19)
0.45
(0.31, 0.66)g
Rifabutin 150 mg
(1 dose)
500/200 mg BID
(15 doses)
20 1.70
(1.49, 1.94)
2.90
(2.59, 3.26)
2.14
(1.90, 2.41)
25-O-desacetyl- rifabutin 20 3.20
(2.78, 3.68)
20.71
(17.66, 24.28)
7.83
(6.70, 9.14)
Rifabutin + 25-O-desacetyl-rifabutind 20 1.86
(1.63, 2.12)
4.33
(3.86, 4.86)
2.76
(2.44, 3.12)
Rosuvastatin 10 mg
(1 dose)
500/200 mg BID
(24 doses)
16 2.23
(1.83, 2.72)
1.26
(1.08, 1.46)
1.06
(0.93, 1.20)
Saquinavir/ritonavira 600/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
20 0.30
(0.23, 0.40)e
0.24
(0.19, 0.32)e
0.18
(0.13, 0.26)e
68 - - 0.20
(0.16, 0.25)f
Stavudinea 40 mg BID ≥ 60 kg 250/200 mg BID 26 0.90
(0.81, 1.02)
1.00
(0.91, 1.11)
-
30 mg BID < 60 kg
(43 doses)
750/100 mg BID 22 0.76
(0.66, 0.89)
0.84
(0.74, 0.96)
-
1250/100 mg BID
(42 doses)
19 0.74
(0.69, 0.80)
0.93
(0.83, 1.05)
-
Tadalafil 10 mg
(1 dose)
500/200 mg
(1 dose)
17 0.78
(0.72, 0.84)
2.33
(2.02, 2.69)
-
10 mg
(1 dose)
500/200 mg BID
(17 doses)
17 0.70
(0.63, 0.78)
1.01
(0.83, 1.21)
-
Tenofovir 300 mg
(1 dose)
500/100 mg BID 22 0.77
(0.68, 0.87)
0.98
(0.91, 1.05)
1.07
(0.98, 1.17)
750/200 mg BID
(23 doses)
20 0.62
(0.54, 0.71)
1.02
(0.94, 1.10)
1.14
(1.01, 1.27)
Zidovudinec 300 mg BID 250/200 mg BID 48 0.54
(0.47, 0.62)
0.58
(0.51, 0.66)
-
300 mg BID 750/100 mg BID 31 0.51
(0.44, 0.60)
0.64
(0.55, 0.75)
-
300 mg BID
(43 doses)
1250/100 mg BID
(42 doses)
23 i 0.49
(0.40, 0.59)
0.69
(0.49, 0.97)
-
300 mg
(1 dose)
500/100 mg BID 29 0.39
(0.33, 0.45)
0.57
(0.52, 0.63)
0.89
(0.81, 0.99)
750/200 mg BID
(23 doses)
25 0.44
(0.36, 0.54)
0.67
(0.62, 0.73)
1.25
(1.08, 1.44)
Zidovudine glucuronide 500/100 mg BID 29 0.82
(0.74, 0.90)
1.02
(0.97, 1.06)
1.52
(1.34, 1.71)
750/200 mg BID
(23 doses)
25 0.82
(0.73, 0.92)
1.09
(1.05, 1.14)
1.94
(1.62, 2.31)
a HIV-1 positive patients
b Buprenorphine/Naloxone maintenance patients
c HIV-1 positive patients (tipranavir/ritonavir 250 mg/200 mg, 750 mg/200 mg and 1250 mg/100 mg) and healthy volunteers (tipranavir/ritonavir 500 mg/100 mg and 750 mg/200 mg)
d Normalized sum of parent drug (rifabutin) and active metabolite (25-O-desacetyl-rifabutin)
e Intensive PK analysis
f Drug levels obtained at 8-16 hrs post-dose
g n = 14 for Cmin
hAdministered as Valacyclovir
↑ increase, ↓ decrease, ↔ no change, ⇓ unable to predict

Microbiology

Mechanism of Action

Tipranavir (TPV) is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Antiviral Activity

Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 μM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 μM and 0.233-0.522 μM, respectively. When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion inhibitor enfuvirtide. There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Resistance

In cell culture

HIV-1 isolates with a decreased susceptibility to tipranavir have been selected in cell culture and obtained from patients treated with APTIVUS/ritonavir (TPV/ritonavir). After 9 months of culture in TPV-containing media, HIV-1 isolates with 87-fold reduced susceptibility to tipranavir were selected in cell culture; these contained 10 protease substitutions that developed in the following order: L33F, I84V, K45I, I13V, V32I, V82L, M36I, A71V, L10F, and I54V/T. Changes in the Gag polyprotein CA/P2 cleavage site were also observed following drug selection. Experiments with site-directed mutants of HIV-1 showed that the presence of 6 substitutions in the protease coding sequence (I13V, V32I, L33F, K45I, V82L, I84V) conferred > 10-fold reduced susceptibility to tipranavir.

Clinical Studies of Treatment-Experienced Patients

In controlled clinical trials 1182.12 and 1182.48, multiple protease inhibitor-resistant HIV-1 isolates from 59 treatment-experienced adult patients who received APTIVUS/ritonavir and experienced virologic rebound developed amino acid substitutions that were associated with resistance to tipranavir. The most common amino acid substitutions that developed on 500/200 mg APTIVUS/ritonavir in greater than 20% of APTIVUS/ritonavir virologic failure isolates were L33V/I/F, V82T, and I84V. Other substitutions that developed in 10 to 20% of APTIVUS/ritonavir virologic failure isolates included L10V/I/S, I13V, E35D/G/N, I47V, I54A/M/V, K55R, V82L, and L89V/M. Evolution at protease gag polyprotein cleavage sites was also observed. Among 28 pediatric patients in clinical trial 1182.14 who experienced virologic failure or non-response, the emergent protease amino acid codon substitutions were similar to those observed in adult virologic failure isolates.

In clinical trials 1182.12 and 1182.48 tipranavir resistance was detected at virologic rebound after an average of 38 weeks of APTIVUS/ritonavir treatment with a median 14-fold decrease in tipranavir susceptibility. Similarly, reduced tipranavir susceptibility was associated with emergent mutations in pediatric patient isolates.

Cross-resistance

Cross-resistance among protease inhibitors has been observed. Tipranavir had < 4-fold decreased susceptibility against 90% (94/105) of HIV-1 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses which emerged in cell culture from wild-type HIV-1 had decreased susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and ritonavir but remained sensitive to saquinavir.

Baseline Genotype and Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining tipranavir susceptibility before initiation of APTIVUS/ritonavir therapy. Several analyses were conducted to evaluate the impact of specific substitutions and combination of substitutions on virologic outcome. Both the type and number of baseline protease inhibitor substitutions as well as use of additional active agents (e.g., enfuvirtide) affected APTIVUS/ritonavir response rates in controlled clinical trials 1182.12 and 1182.48 through Week 48 of treatment.

Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 treatment-experienced patients in Phase 2 and 3 trials demonstrated that amino acid substitutions at 16 codons in the HIV-1 protease coding sequence were associated with reduced virologic responses and/or reduced tipranavir susceptibility: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V.

As-treated analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor substitutions present at baseline. Response rates were reduced if five or more protease inhibitor-associated substitutions were present at baseline and subjects did not receive concomitant new enfuvirtide with APTIVUS/ritonavir. See Table 9.

Table 9 : Controlled Clinical Trials 1182.12 and 1182.48: Proportion of Responders (confirmed ≥ 1 log10 decrease at Week 48) by Number of Baseline Primary Protease Inhibitor (PI) Resistance Associated Substitutions

Number of Baseline Primary PI Mutationsa APTIVUS/ritonavir
N=578
Comparator PI/ritonavir
N=610
No New Enfuvirtideb + New Enfuvirtidec No New Enfuvirtideb + New Enfuvirtidec
Overall 38%
(180/470)
69%
(75/108)
18%
(92/524)
26%
(22/86)
1 -2 62%
(24/39)
60%
(3/5)
33%
(14/43)
0%
(0/1)
4 3 48%
(96/202)
71%
(27/38)
23%
(45/193)
38%
(13/34)
5+ 26%
(60/229)
69%
(45/65)
11%
(33/288)
18%
(9/51)
aPrimary PI mutations include any amino acid substitution at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90
bNo new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide
cNew enfuvirtide is defined as initiation of enfuvirtide for the first time

The median change from baseline in plasma HIV-1 RNA at weeks 2, 4, 8, 16, 24 and 48 was evaluated by the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or ≥ 5) in subjects who received APTIVUS/ritonavir with or without new enfuvirtide. The following observations were made:

  • Approximately 1.5 log10 decrease in HIV-1 RNA at early time points (Week 2) regardless of the number of baseline primary protease inhibitor resistance associated substitutions (1-4 or 5+).
  • Subjects with 5 or more primary protease inhibitor resistance associated substitutions in their HIV-1 at baseline who received APTIVUS/ritonavir without new enfuvirtide (n=303) began to lose their antiviral response after Week 4.
  • Early HIV-1 RNA decreases (1.5-2 log10) were sustained through Week 48 in subjects with 5 or more primary protease inhibitor resistance associated substitutions at baseline who received new enfuvirtide with APTIVUS/ritonavir (n=74).
Baseline Phenotype and Virologic Outcome Analyses

APTIVUS/ritonavir response rates were also assessed by baseline tipranavir phenotype. Relationships between baseline phenotypic susceptibility to tipranavir, mutations at protease amino acid codons 33, 82, 84 and 90, tipranavir resistance-associated mutations, and response to APTIVUS/ritonavir therapy at Week-48 are summarized in Tables 10 and 11. These baseline phenotype groups are not meant to represent clinical susceptibility breakpoints for APTIVUS/ritonavir because the data are based on the select 1182.12 and 1182.48 patient population. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to APTIVUS/ritonavir in protease inhibitor-experienced patients.

Table 10 : Response by Baseline Tipranavir Phenotype at 48 weeks in the Controlled Clinical Trials 1182.12 and 1182.48

Baseline Tipranavir Phenotype (Fold Change)” Proportion of Respondersb with No New Enfuvirtidec Use
N=211
Proportion of Respondersb with New Enfuvirtided Use
N=68
Tipranavir Susceptibility
0-3 48% (73/153) 70% (33/47) Susceptible
> 3-10 21% (10/48) 53% (8/15) Decreased Susceptibility
> 10 10% (1/10) 50% (3/6) Resistant
aChange in tipranavir EC50 value from wild-type reference
bConfirmed ≥ 1 log10 decrease at Week 48
cNo new enfuvirtide is defined as recycled or continued use of enfuvirtide or no use of enfuvirtide
dNew enfuvirtide is defined as initiation of enfuvirtide for the first time

Table 11 : Correlation of Baseline Tipranavir Phenotype to Genotype using HIV-1 isolates from Phase 2 and Phase 3 Clinical Trials

Baseline Tipranavir Phenotype (Fold Change)” # of Baseline Protease Mutations at 33, 82, 84, 90 # of Baseline Tipranavir Resistance-Associated Mutations'1 Tipranavir Susceptibilityc
0-3 0-2 0-4 Susceptible
> 3-10 3 5-7 Decreased Susceptibility
> 10 4 8+ Resistant
aChange in tipranavir EC50 value from wild-type reference
bNumber of amino acid substitutions in HIV-1 protease among L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V
cdefined by week 48 response

Analyses of pediatric clinical trial 1182.14 also demonstrated that response to therapy was influenced by the number of baseline protease inhibitor mutations present.

Animal Toxicology And/Or Pharmacology

In preclinical studies in rats, tipranavir treatment induced dose-dependent changes in coagulation parameters (increased prothrombin time, increased activated partial thromboplastin time, and a decrease in some vitamin K dependent factors). In some rats, these changes led to bleeding in multiple organs and death. The coadministration of vitamin E in the form of TPGS (d-alpha-tocopherol polyethylene glycol 1000 succinate) with tipranavir resulted in a significant increase in effects on coagulation parameters, bleeding events, and death.

In preclinical studies of tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir and vitamin E has not been studied in dogs. Clinical evaluation of coagulation effects on HIV-1-infected patients demonstrated no tipranavir plus ritonavir effect and no effect of the vitamin E-containing oral solution on coagulation parameters [see Effects on Platelet Aggregation and Coagulation].

Clinical Studies

Adult Patients

The following clinical data is derived from analyses of 48-week data from ongoing studies measuring effects on plasma HIV-1 RNA levels and CD4+ cell counts. At present there are no results from controlled studies evaluating the effect of APTIVUS/ritonavir on clinical progression of HIV-1.

APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR

The two clinical trials 1182.12 and 1182.48 (RESIST 1 and RESIST 2) are ongoing, randomized, controlled, open-label, multicenter studies in HIV-1 positive, triple antiretroviral class experienced patients. All patients were required to have previously received at least two protease inhibitor-based antiretroviral regimens and were failing a protease inhibitor-based regimen at the time of study entry with baseline HIV-1 RNA at least 1000 copies/mL and any CD4+ cell count. At least one primary protease gene mutation from among 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than two mutations at codons 33, 82, 84 or 90.

These studies evaluated treatment response at 48 weeks in a total of 1483 patients receiving either APTIVUS co-administered with 200 mg of ritonavir plus OBR versus a control group receiving a ritonavir-boosted protease inhibitor (lopinavir, amprenavir, saquinavir or indinavir) plus OBR. Prior to randomization, OBR was individually defined for each patient based on genotypic resistance testing and patient history. The investigator had to declare OBR, comparator protease inhibitor, and use of new enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of new enfuvirtide.

After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response or confirmed virologic failure had the option of discontinuing treatment and switching to APTIVUS/ritonavir in a separate roll-over study.

Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir arm and control arm. In both studies combined, the 1483 patients had a median age of 43 years (range 17-80), and were 86.3% male, 75.6% white, 12.9% black, and 0.9% Asian. The median baseline plasma HIV-1 RNA for both treatment groups was 4.8 (range 2.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 162 (range 1 to 1894) cells/mm³. Overall, 38.4% of patients had a baseline HIV-1 RNA of > 100,000 copies/mL, 58.6% had a baseline CD4+ cell count ≤ 200 cells/mm³, and 57.8% had experienced an AIDS defining Class C event at baseline.

Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. A total of 10.1% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the HIV-1 isolates were resistant to at least one protease inhibitor, 95% of the isolates were resistant to at least one NRTI, and > 75% of the isolates were resistant to at least one NNRTI.

The individually pre-selected protease inhibitor based on genotypic testing and the patient's medical history was lopinavir in 48.7%, amprenavir in 26.4%, saquinavir in 21.8% and indinavir in 3.1% of patients. A total of 85.1% were possibly resistant or resistant to the pre-selected comparator protease inhibitors. Approximately 21% of patients used enfuvirtide during the study of which 16.6% in the APTIVUS/ritonavir arm and 13.2% in the comparator/ritonavir arm represented first time use of enfuvirtide (new enfuvirtide).

Treatment response and efficacy outcomes of randomized treatment through Week 48 of studies 1182.12 and 1182.48 are shown in Table 12.

Table 12 : Outcomes of Randomized Treatment Through Week 48 (Pooled Studies 1182.12 and 1182.48)

Outcome APTIVUS/ritonavir (500/200 mg BID) + OBR
(N=746)
Comparator Protease Inhibitor*/ritonavir + OBR
(N=737)
Virologic Respondersa (confirmed at least 1 log10 HIV-1 RNA below baseline) 33.8% 14.9%
Virologic failures 55.1% 77.3%
Initial lack of virologic response by Week 8b 33.0% 57.9%
Rebound 18.9% 16.4%
Never suppressed 3.2% 3.0%
Deathc or discontinued due to adverse events 5.9% 1.9%
Death 0.5% 0.3%
Discontinued due to adverse events 5.4% 1.6%
Discontinued due to other reasonsd 5.2% 5.8%
*Comparator protease inhibitors were lopinavir, amprenavir, saquinavir or indinavir and 85.1% of patients were possibly resistant or resistant to the chosen protease inhibitors.
aPatients achieved and maintained a confirmed ≥ 1 log10 HIV-1 RNA drop from baseline through Week 48 without prior evidence of treatment failure.
bPatients did not achieve a 0.5 log10 HIV-1 RNA drop from baseline and did not have viral load < 100,000 copies/mL by Week 8.
cDeath only counted if it was the reason for treatment failure.
dIncludes patients who were lost to-follow-up, withdrawn consent, non-adherent, protocol violations, added/changed background antiretroviral drugs for reasons other than tolerability or toxicity, or discontinued while suppressed.

Through 48 weeks of treatment, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 30.3% and 13.6% respectively, and with HIV-1 RNA < 50 copies/mL was 22.7% and 10.2% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 48 was -0.64 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.22 log10 copies/mL in the comparator PI/ritonavir arm.

Among all randomized and treated patients, the median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +23 cells/mm³in patients receiving APTIVUS/ritonavir (N=740) versus +4 cells/mm³in the comparator PI/ritonavir (N=727) arm.

Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide. Among patients with new enfuvirtide use, the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 52.4% and 19.6% respectively, and with HIV-1 RNA < 50 copies/mL was 37.3% and 14.4% respectively [see CLINICAL PHARMACOLOGY]. The median change from baseline in CD4+ cell count at the last measurement up to Week 48 was +89 cells/mm³in patients receiving APTIVUS/ritonavir in combination with newly introduced enfuvirtide (N=124) and +18 cells/mm³in the comparator PI/ritonavir (N=96) arm.

Pediatric Patients

The pharmacokinetic profile, safety and activity of APTIVUS/ritonavir was evaluated in a randomized, open-label, multicenter study. This study enrolled HIV-1 infected, treatment-experienced pediatric patients (with the exception of 3 treatment-naÔve patients), with baseline HIV-1 RNA of at least 1500 copies/mL. The age ranged from 2 through 18 years and patients were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years). One hundred and ten (110) patients were randomized to receive one of two APTIVUS/ritonavir dose regimens: 375 mg/m²/150 mg/m² dose (N=55) or 290 mg/m²/115 mg/m² dose (N=55), plus background therapy of at least two non-protease inhibitor antiretroviral drugs, optimized using baseline genotypic resistance testing. All patients initially received APTIVUS oral solution. Pediatric patients who were 12 years or older and received the maximum dose of 500/200 mg BID could subsequently change to APTIVUS capsules at day 28 [see ADVERSE REACTIONS, Use In Specific Populations, CLINICAL PHARMACOLOGY, and Microbiology].

Demographics and baseline characteristics were balanced between the APTIVUS/ritonavir dose groups. The 110 randomized pediatric patients had a median age of 11.7 years (range 2 to 18), and were 57.2% male, 68.1% white, 30% black, and 1.8% Asian. The median baseline plasma HIV-1 RNA was 4.7 (range 3.0 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 379 (range 2 to 2578) cells/mm³. Overall, 37.4% of patients had a baseline HIV-1 RNA of > 100,000 copies/mL; 28.7% had a baseline CD4+ cell count ≤ 200 cells/mm³, and 48% had experienced a prior AIDS defining Class C event at baseline. Patients had prior exposure to a median of 4 NRTIs, 1 NNRTI, and 2 PIs.

Eighty three (75%) completed the 48 week period while 25% discontinued prematurely. Of the patients who discontinued prematurely, 9 (8%) discontinued due to virologic failure, and 9 (8%) discontinued due to adverse reactions.

At 48 weeks, 40% of patients had viral load < 400 copies/mL. The proportion of patients with viral load < 400 copies/mL tended to be greater (70%) in the youngest group of patients, who had less baseline viral resistance, compared to the older groups (37% and 31%). The HIV-1 RNA results are presented in Table 13.

Table 13 : Proportion of Patients with HIV-1 RNA < 400 copies/mL ( < 50 copies/mL) by age and dose*

APTIVUS/ ritonavir Dose Regimen 2 to < 6 years
(N=20)
6 to < 12 years
(N=38)
12 to 18 years
(N=52)
375 mg/m²/150 mg/m² n=10 n=19 n=26
70% (42%) 50% (39%) 33% (30%)
290 mg/m²/115 mg/m² n=10 n=19 n=26
70% (54%) 37% (32%) 31% (23%)
* The number of baseline tipranavir resistance-associated substitutions were fewer in the 2 to < 6 year old patients than the 6 to 18 year old patients enrolled in study 1182.14

The dose selection for all age groups was based on the following:

  • A greater proportion of patients receiving APTIVUS/ritonavir 375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m² achieved HIV-1 RNA < 400 and < 50 copies/mL.
  • A greater proportion of patients 6 to 18 years of age with multiple baseline protease inhibitor resistance-associated substitutions receiving APTIVUS/ritonavir 375 mg/m²/150 mg/m² achieved HIV-1 RNA < 400 copies/mL at 48 weeks compared to patients receiving APTIVUS/ritonavir 290 mg/m²/115 mg/m² .
  • No clinically significant increase in adverse event rates observed with 375 mg/m²/150 mg/m² compared to 290 mg/m²/115 mg/m² .
  • Overall, 6 (5%) patients ages 6 to 18 had AIDS defining illness during the treatment period and all received the 290 mg/m²/115 mg/m² dose.

The guidance for possible dose reduction for patients who develop intolerance or toxicity and cannot continue with APTIVUS/ritonavir 14 mg/kg/6 mg/kg (or 375 mg/m²/150 mg/m²) is based on the following:

  • The 290 mg/m²/115 mg/m² twice daily regimen provided tipranavir plasma concentrations similar to those obtained in adults receiving 500/200 mg twice daily. The 375 mg/m²/150 mg/m² twice daily regimen provided tipranavir plasma concentrations 37% higher than those obtained in adults receiving 500/200 mg twice daily.
  • The observed response rates for APTIVUS/ritonavir dose of 290 mg/m²/115 mg/m² as shown in Table 13.

Dose reduction is not appropriate for patients whose virus is resistant to more than one protease inhibitor.

When body surface area (BSA) dosing is converted to mg/kg dosing, the APTIVUS/ritonavir 375 mg/m²/150 mg/m² twice daily regimen is similar to 14 mg/kg/6 mg/kg and APTIVUS/ritonavir 290 mg/m²/115 mg/m² twice daily regimen is similar to 12 mg/kg/5 mg/kg twice daily [see DOSAGE AND ADMINISTRATION].

Last reviewed on RxList: 4/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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