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All about: Aptivus

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Generic Name: tipranavir
Dosage Form: Capsules

ATTENTION PHARMACIST: Detach “Patient's Instructions for Use” from package insert and dispense with product. Dispense the capsules in the unit of use container.

Prescribing Information

Warning

Aptivus CO-ADMINISTERED WITH 200 MG RITONAVIR HAS BEEN ASSOCIATED WITH REPORTS OF BOTH FATAL AND NON-FATAL INTRACRANIAL HEMORRHAGE. (SEE WARNINGS)

Aptivus CO-ADMINISTERED WITH 200 MG RITONAVIR HAS BEEN ASSOCIATED WITH REPORTS OF CLINICAL HEPATITIS AND HEPATIC DECOMPENSATION INCLUDING SOME FATALITIES. EXTRA VIGILANCE IS WARRANTED IN PATIENTS WITH CHRONIC HEPATITIS B OR HEPATITIS C CO-INFECTION, AS THESE PATIENTS HAVE AN INCREASED RISK OF HEPATOTOXICITY. (SEE WARNINGS)

Aptivus Description

Aptivus® (tipranavir) is the brand name for tipranavir (TPV), a non-peptidic protease inhibitor (PI) of HIV belonging to the class of 4-hydroxy-5,6-dihydro-2-pyrone sulfonamides.

Aptivus soft gelatin capsules are for oral administration. Each capsule contains 250 mg tipranavir. The major inactive ingredients in the capsule are dehydrated alcohol (7% w/w or 0.1 g per capsule), polyoxyl 35 castor oil, propylene glycol, mono/diglycerides of caprylic/capric acid and gelatin.

The chemical name of tipranavir is 2-Pyridinesulfonamide, N - [3 - [(1R) - 1 - [(6R) - 5,6 - dihydro - 4 - hydroxy - 2 - oxo - 6 - (2 - phenylethyl) - 6 - propyl - 2H - pyran - 3 - yl]propyl]phenyl] - 5 - (trifluoromethyl). It has a molecular formula of C31H33F3N2O5S and a molecular weight of 602.7. Tipranavir has the following structural formula and is a single stereoisomer with the 1R, 6R configuration.

Tipranavir is a white to off-white to slightly yellow solid. It is freely soluble in dehydrated alcohol and propylene glycol, and insoluble in aqueous buffer at pH 7.5.

Aptivus - Clinical Pharmacology

Microbiology

Mechanism of Action

Tipranavir (TPV) is a non-peptidic 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 vitro 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 vitro to tipranavir with EC50 values ranging from 0.164 -1 μM and 0.233-0.522 μM, respectively. Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-fold in conditions where human serum is present. When used with other antiretroviral agents in vitro, 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 fusion inhibitor enfuvirtide. There was no antagonism of the in vitro combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Resistance

In vitro: HIV-1 isolates with a decreased susceptibility to tipranavir have been selected in vitro and obtained from patients treated with Aptivus/ritonavir (TPV/ritonavir). HIV-1 isolates that were 87-fold resistant to tipranavir were selected in vitro by 9 months and contained 10 protease mutations 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 mutations in the protease coding sequence (I13V, V32I, L33F, K45I, V82L, I84V) conferred > 10-fold reduced susceptibility to tipranavir. Recombinant viruses showing ≥ 3-fold reduced susceptibility to tipranavir were growth impaired.

Clinical Studies of Treatment-Experienced Patients: In Phase 3 studies 1182.12 and 1182.48, multiple protease inhibitor-resistant HIV-1 isolates from 59 highly treatment-experienced 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, K55R, V82L, and L89V/M. 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. The resistance profile in treatment-naïve subjects has not been characterized.

Cross-resistance

Cross-resistance among protease inhibitors has been observed. Tipranavir had < 4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir. Tipranavir-resistant viruses which emerged in vitro 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 mutations and mutational patterns on virologic outcome. Both the type and number of baseline protease inhibitor mutations as well as use of additional active agents (e.g., enfuvirtide) affected Aptivus/ritonavir response rates in Phase 3 studies 1182.12 and 1182.48 through Week 24 of treatment.

Regression analyses of baseline and/or on-treatment HIV-1 genotypes from 860 highly treatment-experienced patients in Phase 2 and 3 studies demonstrated that mutations at 16 amino acid codons in the HIV protease coding sequence were associated with reduced virologic responses at 24 weeks 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.

Analyses were also conducted to assess virologic outcome by the number of primary protease inhibitor mutations present at baseline. Response rates were reduced if five or more protease inhibitor-associated mutations were present at baseline and subjects did not receive concomitant enfuvirtide with Aptivus/ritonavir. See Table 1.

Table 1 Phase 3 Studies 1182.12 and 1182.48: Proportion of Responders (confirmed ≥ 1 log10 decrease at Week 24) by Number of Baseline Primary Protease Inhibitor (PI) Mutations
Number of Baseline
Primary PI Mutationsa
Aptivus/ritonavir
N = 513
Comparator PI/ritonavir
N = 502
No Enfuvirtide + Enfuvirtide No Enfuvirtide + Enfuvirtide

a Primary PI mutations include any amino acid change at positions 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90

Overall 40%
(147/368)
64%
(93/145)
19%
(75/390)
30%
(34/112)
1 - 2 68%
(26/38)
75%
(3/4)
41%
(17/41)
100%
(2/2)
3 - 4 44%
(78/176)
64%
(39/61)
23%
(39/170)
40%
(21/52)
5+ 28%
(43/151)
64%
(51/80)
11%
(19/178)
19%
(11/57)

The median change from baseline in HIV-1 RNA at weeks 2, 4, 8, 16 and 24 was evaluated by the number of baseline primary protease inhibitor mutations (1-4 or ≥ 5) in subjects who received Aptivus/ritonavir with or without 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 mutations (1-4 or 5+).
  • Subjects with 5 or more primary protease inhibitor mutations in their HIV-1 at baseline who received Aptivus/ritonavir without enfuvirtide (n=204) began to lose their antiviral response after Week 4.
  • Early HIV-1 RNA decreases (1.5–2 log10) were sustained through Week 24 in subjects with 5 or more primary protease inhibitor mutations at baseline who received enfuvirtide with Aptivus/ritonavir (n=88).

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data.

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 24 are summarized in Table 2. 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 highly protease inhibitor-experienced patients.

Table 2 Response by Baseline Tipranavir Phenotype in the 1182.12 and 1182.48 Trials
Baseline
Tipranavir
Phenotype
(Fold Change)a
Proportion of Respondersbwith
No Enfuvirtide
Use
Proportion of Respondersbwith Enfuvirtide Use # of Baseline Protease Mutations at 33, 82, 84, 90 # of Baseline Tipranavir Resistance-Associated Mutationsc Tipranavir Susceptibility

a Change in tipranavir IC50 value from wild-type reference

b Confirmed ≥ 1 log10 decrease at Week 24

c Number of amino acid substitutions in HIV protease among L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L,

I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V

0-3 45% (74/163) 77% (46/60) 0-2 0-4 Susceptible
> 3-10 21% (10/47) 43% (12/28) 3 5-7 Decreased
Susceptibility
> 10 0% (0/8) 57% (4/7) 4 8+ Resistant

Pharmacodynamics

The median Inhibitory Quotient (IQ) determined from 301 highly treatment-experienced patients was about 75 (inter-quartile range: 29-189), from pivotal clinical trials 1182.12 and 1182.48. The IQ is defined as the tipranavir trough concentration divided by the viral IC50 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 24 and their IQ value. Among the 206 patients receiving Aptivus/ritonavir without enfuvirtide, the response rate was 23% in those with an IQ value < 75 and 55% in those with an IQ value ≥ 75. Among the 95 patients receiving Aptivus/ritonavir with enfuvirtide, the response rates in patients with an IQ value < 75 versus those with an IQ value ≥ 75 were 43% and 84%, respectively. These IQ groups are derived from a select population and are not meant to represent clinical breakpoints.

Pharmacokinetics in Adult Patients

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

Figure 1 displays mean plasma concentrations of tipranavir and ritonavir at steady state for the 500/200 mg tipranavir/ritonavir dose.

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

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 the net effect of tipranavir/ritonavir at the proposed dose regimen (500/200 mg) is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor. 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 with Aptivus 500 mg concomitant with 200 mg ritonavir twice-daily for greater than 2 weeks and without meal restriction produced the following pharmacokinetic parameters for female and male HIV-positive patients. See Table 3.

Table 3 Pharmacokinetic Parametersa of tipranavir/ritonavir 500/200 mg for HIV+ 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

Aptivus capsules co-administered with ritonavir should be taken with food. Bioavailability is increased with a high fat meal. Tipranavir capsules, administered under high fat meal conditions or with a light snack of toast and skimmed milk, were tested in a multiple dose study. High-fat meals (868 kcal, 53% derived from fat, 31% derived from carbohydrates) enhanced the extent of bioavailability (AUC point estimate 1.31, confidence interval 1.23-1.39), but had minimal effect on peak tipranavir concentrations (Cmax point estimate 1.16, confidence interval 1.09-1.24).

When Aptivus, co-administered with 200 mg ritonavir, was co-administered with 20 mL of aluminum and magnesium-based liquid antacid, tipranavir AUC12h, Cmax and C12h were reduced by 25-29%. Consideration should be given to separating tipranavir/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

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 Aptivus (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers (0.015% ± 0.006%) and HIV-positive patients (0.019% ± 0.076%). 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 tipranavir/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 tipranavir/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-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.

Pharmacokinetics in Special Populations

Renal Impairment

Aptivus pharmacokinetics has 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 patients with mild (Child-Pugh A) hepatic impairment to 9 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 B) or severe hepatic impairment (Child-Pugh C) on the multiple-dose pharmacokinetics of tipranavir administered with ritonavir has not been evaluated (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS).

Gender

Evaluation of steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the 1182.12 and 1182.48 studies demonstrated that females generally had higher tipranavir concentrations than males. After 4 weeks of tipranavir/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 1182.12 and 1182.48 studies 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 1182.12 and 1182.48 studies 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, but the trend of consistent trough tipranavir concentrations with increasing age through 80 years for men was supported.

Pediatric Patients

The pharmacokinetic profile of tipranavir in pediatric patients has not been established.

Drug Interactions

See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, Drug Interactions.

Aptivus co-administered with 200 mg of ritonavir can alter plasma exposure of other drugs and other drugs may alter plasma exposure of tipranavir.

Potential for tipranavir/ritonavir to Affect Other Drugs
  1. Aptivus co-administered with 200 mg of ritonavir at the recommended dose, is a net inhibitor of CYP 3A and may increase plasma concentrations of agents that are primarily metabolized by CYP 3A. Thus, co-administration of Aptivus/ritonavir with drugs highly dependent on CYP 3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring (see CONTRAINDICATIONS and PRECAUTIONS).
  2. Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19 and CYP 2D6. The potential net effect of tipranavir/ritonavir on CYP 2D6 is inhibition, because ritonavir is a CYP 2D6 inhibitor. The in vivo net effect of tipranavir administered with ritonavir on CYP 1A2, CYP 2C9 and CYP 2C19 is not known. Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl transferases and whether tipranavir induces CYP 1A2, CYP 2C9 and CYP 2C19.
  3. Tipranavir is a P-gp substrate, a weak P-gp inhibitor, and appears to be a potent P-gp inducer as well. Data suggest that the net effect of tipranavir co-administered with 200 mg of ritonavir is P-gp induction at steady-state, although ritonavir is a P-gp inhibitor.
  4. It is difficult to predict the net effect of Aptivus administered with ritonavir on oral bioavailability and plasma concentrations of drugs that are dual substrates of CYP 3A and P-gp. The net effect will vary depending on the relative affinity of the co-administered drugs for CYP 3A and P-gp, and the extent of intestinal first-pass metabolism/efflux.

Potential for Other Drugs to Affect tipranavir
  1. Tipranavir is a CYP 3A substrate and a P-gp substrate. Co-administration of Aptivus/ritonavir and drugs that induce CYP 3A and/or P-gp may decrease tipranavir plasma concentrations. Co-administration of Aptivus/ritonavir and drugs that inhibit P-gp may increase tipranavir plasma concentrations.
  2. Co-administration of Aptivus/ritonavir with drugs that inhibit CYP 3A may not further increase tipranavir plasma concentrations, because the level of metabolites is low following steady-state administration of Aptivus/ritonavir 500/200 mg twice daily.

Drug interaction studies were performed with Aptivus, co-administered with 200 mg of 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, are summarized in Tables 4 and 5. For information regarding clinical recommendations see PRECAUTIONS, Drug Interactions, Tables 8  and 9.

Table 4 Drug Interactions: Pharmacokinetic Parameters for Tipranavir in the Presence of Co-administered Drugs
Co-
administered
Drug
Co-
administered
Drug Dose
(Schedule)

TPV/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

*steady state comparison to historical data (n)

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*

750/200 mg BID*
21 (89)


25 (100)



0.79 (0.69, 0.89)


0.97 (0.85, 1.09)
0.69 (0.57 , 0.83)


1.01 (0.85, 1.18)
0.58 (0.36 , 0.86)


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 dose)
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)
Tenofovir 300 mg
(1 dose)
500/100 mg BID
750/200 mg BID
(23 doses)
22

20


0.83 (0.74, 0.94)

0.89 (0.84, 0.96)
0.82 (0.75, 0.91)

0.91 (0.85, 0.97)
0.79 (0.70, 0.90)

0.88 (0.78, 1.00)
Zidovudine 300 mg
(1 dose)
500/100 mg BID
750/200 mg BID
(23 doses)
29

25


0.87 (0.80, 0.94)

1.02 (0.94, 1.10)
0.82 (0.76, 0.89)

1.02 (0.92, 1.13)
0.77 (0.68, 0.87)

1.07 (0.86, 1.34)

Table 5 Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Tipranavir/Ritonavir
Co-administered Drug Co-administered
Drug Dose
(Schedule)

TPV/ritonavir
Drug Dose
(Schedule)

n

PK
Ratio (90% Confidence Interval) of Co-administered Drug Pharmacokinetic Parameters with/without TPV/ritonavir;
No Effect = 1.00
          Cmax AUC Cmin

a HIV+ patients

b HIV+ patients (TPV/ritonavir 250 mg/200 mg, 750 mg/200 mg and 1250 mg/100 mg) and healthy volunteers (TPV/ritonavir 500 mg/100 mg and 750 mg/200 mg)

c Normalized sum of parent drug (rifabutin) and active metabolite (25-O-desacetyl-rifabutin)

d Intensive PK analysis

e Drug levels obtained at 8-16 hrs post-dose

Amprenavir/RTV a 600/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
16
74

0.61 (0.51, 0.73)d
-
0.56 (0.49, 0.64)d
-
0.45 (0.38, 0.53)d
0.44 (0.39, 0.49)e
Abacavir a 300 mg BID
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 mg BID
(42 doses)
28
14
11


0.56 (0.48, 0.66)
0.54 (0.47, 0.63)
0.48 (0.42, 0.53)
0.56 (0.49, 0.63)
0.64 (0.55, 0.74)
0.65 (0.55, 0.76)
-
-
-
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)
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)
Didanosineb 200 mg BID, ≥ 60 kg
125 mg BID, < 60 kg
(43 doses)
250/200 mg BID
750/100 mg BID
1250/100 mg BID
(42 doses)
10
8
9


0.57 (0.42, 0.79)
0.76 (0.49, 1.17)
0.77 (0.47, 1.26)
0.67 (0.51, 0.88)
0.97 (0.64, 1.47)
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)
Efavirenzb 600 mg QD
(15 doses)
500/100 mg BID
750/200 mg BID
(15 doses)
24
22

1.09 (0.99, 1.19)
1.12 (0.98, 1.28)
1.04 (0.97, 1.12)
1.00 (0.93, 1.09)
1.02 (0.92, 1.12)
0.94 (0.84, 1.04)
Ethinyl estradiol 0.035 mg
(1 dose)
500/100 mg BID
750/200 mg BID
(21 doses)
21
13

0.52 (0.47, 0.57)
0.48 (0.42, 0.57)
0.52 (0.48, 0.56)
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
19

0.97 (0.94, 1.01)
0.94 (0.91, 0.98)
0.99 (0.97, 1.02)
0.92 (0.88, 0.95)
0.98 (0.94, 1.02)
0.89 (0.85, 0.92)
Lopinavir/RTVa 400/100 mg BID
(27 doses)
500/200 mg BID
(28 doses)
21
69

0.53 (0.40, 0.69)d
-
0.45 (0.32, 0.63)d
-
0.30 (0.17, 0.51)d
0.48 (0.40, 0.58)e
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

Recent Drug Updates at DrugIndexOnline:





Aranesp Aranesp
Generic Name: Darbepoetin Alfa (Polysorbate 80) (dar-be-POE-e-tin) Brand Name: AranespAranesp is used for:Treating anemia in patients with chronic kidney failure or certain types of cancers. It may also be used for other conditions as determined by your doctor. Aranesp is similar to the natura more...

Ceftazidime Ceftazidime
Some commonly used brand names are: In the U.S.— Ancef 4 Ceclor 1 Ceclor CD 1 Cedax 17 Cefadyl 23 Cefditoren 8 Cefizox 18 Cefobid 10 Cefotan 12 Ceftin 20 Cefzil 15 Ceptaz 16 Claforan 11 Duricef 2 Fortaz 16 Keflex 21 Keftab 21 Kefurox 20 Kefzol 4 Mandol 3 Maxipime 6 Mefoxin 13 Monocid 9 Om more...

Cordran Tape Tape Cordran Tape Tape
Generic Name: Flurandrenolide Tape (flure-an-DREN-oh-lide) Brand Name: Cordran TapeCordran Tape Tape is used for:Treating inflammation and itching due to certain skin conditions. It may also be used for other conditions as determined by your doctor. Cordran Tape Tape is a topical adrenocortical more...

ED-TLC ED-TLC
Some commonly used brand names are: In the U.S.— Alka-Seltzer Plus Cold and Cough 21 Alka-Seltzer Plus Cold and Cough Medicine Liqui-Gels 34 Alka-Seltzer Plus Night-Time Cold Liqui-Gels 35 Ami-Tex LA 69 Anatuss LA 70 Benylin Expectorant 54 Bromfed-DM 17 Broncholate 68 Carbinoxamine Compou more...

Fraxiparine Fraxiparine
Some commonly used brand names are: In Canada— Fraxiparine Fraxiparine Forte * Not commercially available in the U.S. Category Anticoagulant antithrombotic Description Nadroparin ( na-dro-PA-rin)is used to prevent and treat deep vein thrombosis, a condition in which harmful blood more...

Panadol Extra Strength Panadol Extra Strength
Some commonly used brand names are: In the U.S.— Aceta Elixir 1 Aceta Tablets 1 Acetaminophen Uniserts 1 Actamin 1 Actamin Extra 1 Actamin Super 2 Aminofen 1 Aminofen Max 1 Apacet Capsules 1 Apacet Elixir 1 Apacet Extra Strength Caplets 1 Apacet Extra Strength Tablets 1 Apacet, Infants' 1 more...

Plegine Plegine
Some commonly used brand names are: In the U.S.— Adipex-P 5 Adipost 4 Bontril PDM 4 Bontril Slow-Release 4 Didrex 1 Fastin 5 Ionamin 5 Mazanor 3 Melfiat 4 Obenix 5 Obezine 4 Phendiet 4 Phendiet-105 4 Phentercot 5 Phentride 5 Plegine 4 Prelu-2 4 Pro-Fast 5 PT 105 4 Sanorex 3 Tenuate 2 Tenu more...

Procrit Procrit
Generic Name: Epoetin Alfa (eh-POH-ee-tin) Brand Name: Examples include Epogen and ProcritProcrit is used for:Treating anemia in certain patients with kidney failure, HIV, or cancer. It may also be used to reduce the need for blood transfusions in some patients undergoing surgery. It may also more...