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Tipranavir: new protease inhibitor approved by the FDA for patients with extensive treatment-experience
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Report by Jules Levin
Tipranavir was approved by the FDA on June 22, 2005 for patients with extensive treatment-experience. Tipranavir is a potent drug & useful for patients with resistance to protease inhibitors and other HIV antiretroviral drugs. There are however a number of important points of interest to keep in mind when considering use of tipranavir including potential hepatoxicity, rash, drug interactions, and potential for increased lipids. Nontheless, if a patient has extensive HIV drug resistance and is highly treatment experienced tipranavir can be useful in reducing HIV viral load and increasing CD4 count. Here are excerpts from the FDA Package Insert addressing important information related to tipranavir. The Package Insert however contains much more information than I can report here. You can easily acquire a Package Insert from your pharmacy.
The recommended dose of APTIVUS (tipranavir) Capsules is 500 mg (two 250 mg capsules), coadministered with 200 mg of ritonavir, twice daily.
APTIVUS Capsules, co-administered with 200 mg of ritonavir should be taken with food. Bioavailability is increased with a high fat meal.
Effects of Food and Antacids 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 low-dose 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.
APTIVUS capsules should be stored in a refrigerator 2°-8°C (36°-46°F) prior to opening the bottle. After opening the bottle, the capsules may be stored at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) and must be used within 60 days.
Tipranavir (TPV) was studied in highly treatment-experienced patients (studies described below), in comparison to patients who received different boosted protease inhibitors. After 24 weeks of treatment, patients receiving tipranavir had better viral responses: a viral response was defined as achieving a 1 log or greater reduction in viral load, and 40% receiving TPV achieved this vs 18% receiving other PI regimens; the proportion of patients in the APTIVUS/ritonavir arm compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/mL was 34% and 16% respectively, and with HIV-1 RNA < 50 copies/mL was 23% and 9% respectively. The addition of Fuzeon (T-20) improved viral responses quite a bit. Analysis of response was conducted looking at patients with phenotypic or genotypic resistance at baseline. The tables showing viral responses stratified by baseline phenotypic or genotypic resistance are displayed below. For patients with TPV phenotypic change (resistance) of 0-3, the proportion of responders with NO Fuzeon use was 45% but the proportion of responders with Fuzeon use was 77%. Regardless of the level of resistance at baseline adding T20 improved response rates. Of note, patients with >10-fold tipranavir resistance did not achieve a viral response (0/8) unless T20 was also used, and then 57% (4/7) of patients achieved a viral response, although the number of patients in this analysis is small. Overall, regardless of baseline resistance profile, taking T20 along with tipranavir increased viral response rates by >50%: from 40% to 65% when doing analysis based on baseline genotypic resistance, and from 45% to 77% when basing analysis on phenotypic baseline resistance. Clearly, the message is to take TPV along with a new drug (or drugs to which you are sensitive to), one you have never taken before, and for many patients T-20 is the only drug they have not taken.
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 (1.52 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.
APTIVUS is associated with hepatotoxicity (elevated liver enzymes) and clinical hepatitis, and contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency. (see details below)
APTIVUS (tipranavir), co-administered with 200 mg of ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.
This indication is based on analyses of plasma HIV-1 RNA levels in two controlled studies of APTIVUS/ritonavir of 24 weeks duration. Both studies were conducted in clinically advanced, 3-class antiretroviral (NRTI, NNRTI, PI) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The use of other active agents with APTIVUS/ritonavir is associated with a greater likelihood of treatment response. The use of T-20 (Fuzeon) along with tipranavir showed in studies much better responses in terms of viral load reductions.
Genotypic or phenotypic testing and/or treatment history should guide the use of
APTIVUS/ritonavir. The number of baseline primary protease inhibitor mutations affects the virologic response to APTIVUS/ritonavir.
Liver function tests should be performed at initiation of therapy with APTIVUS/ritonavir and monitored frequently throughout the duration of treatment. Use caution when prescribing APTIVUS/ritonavir to patients with elevated transaminases, hepatitis B or C co-infection or other underlying hepatic impairment.
APTIVUS co-administered with 200 mg of ritonavir can alter plasma exposure of other drugs and other drugs may alter plasma exposure of tipranavir.
The extensive drug-drug interaction potential of APTIVUS/ritonavir when co-administered with multiple classes of drugs must be considered prior to and during APTIVUS/ritonavir use. In the text of this report below there is discussion of interactions reported by the FDA with ddI, abacavir, and protease inhibitors. But you should speak to your doctor about potential interactions with other drugs. TPV/r dosing should be separated by at least 2 hours from ddI. See discussion below on PIs & NRTIs.
Oral contraceptives/Estrogens:
Tipranavir reduces Ethinyl estradiol concentrations by 50%
Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with tipranavir and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non serious rash.
The risk-benefit of APTIVUS/ritonavir has not been established in treatment-naïve adult patients or pediatric patients.
Cross-resistance:
Cross-resistance among protease inibitors has been observed. Tipranavir had < 4-fold decreased susceptibility against 90% (94/105) of HIV-1 isolates (in vitro) 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.
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.
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. AUC 0-12h was 851 for females & 710 uM.h for men.
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.
Description of Clinical Studies and Antiviral Potency
The following clinical data is derived from analyses of 24-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.
Summary: Virologic responders were defined in the study as patients with at least 1 log reduction from baseline in HIV viral load: 40% of the patients receiving tipranavir/r achieved this goal vs 18% of the patients receiving different protease inhibitor regimens (boosted by ritonavir). After 8 weeks in the study patients receiving the other protease inhibitor regimen could switch to tipranavir/r.
Through 24 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 34% and 16% respectively, and with HIV-1 RNA < 50 copies/mL was 23% and 9% respectively. Among all randomized and treated patients, the median change from baseline in HIV-1 RNA at the last measurement up to Week 24 was -0.80 log10 copies/mL in patients receiving APTIVUS/ritonavir versus -0.25 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 24 was +34 cells/mm3 in patients receiving tipranavir/ritonavir (N = 582) versus +4 cells/mm3 in the comparator PI/ritonavir (N = 577) arm. Patients in the APTIVUS/ritonavir arm achieved a significantly better virologic outcome when APTIVUS/ritonavir was combined with enfuvirtide (Fuzeon, T20).
Treatment-Experienced Patients
Studies 1182.12 and 1182.48: APTIVUS/ritonavir 500/200 mg BID + optimized background regimen (OBR) vs. Comparator Protease Inhibitor/ritonavir BID + OBR
Studies 1182.12 and 1182.48 are ongoing, randomized, controlled, open-label, multicenter studies in HIV-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 24 weeks in a total of 1159 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 enfuvirtide prior to randomization. Randomization was stratified by choice of comparator protease inhibitor and use of enfuvirtide.
After Week 8, patients in the control group who met the protocol defined criteria of initial lack of virologic response had the option of discontinuing treatment and switching over 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 1159 patients had a median age of 43 years (range 17-80), were 88% male, 73% white, 14% black and 1% Asian. The median baseline plasma HIV-1 RNA was 4.82 (range 2 to 6.8) log10 copies/mL and median baseline CD4+ cell count was 155 (range 1 to 1893) cells/mm3. Forty percent (40%) of the patients had baseline HIV-1 RNA of 100,000 copies/mL, 61% had a baseline CD4+ cell count < 200 cells/mm3, and 57% 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 12% of patients had previously used enfuvirtide. In baseline patient samples (n=454), 97% of the 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 patients medical history was lopinavir in 50%, amprenavir in 26%, saquinavir in 20% and indinavir in 4% of patients. A total of 86% were possibly resistant or resistant to the pre-selected comparator protease inhibitors.
Approximately 25% of patients used enfuvirtide during study. There were differences between Studies 1182.12 and 1182.48 in the use of the protease inhibitors and in the use of enfuvirtide.
Drugs within Class that are Contraindicated with APTIVUS,
Co-administered with 200 mg of ritonavir (this list is limited, speak to your doctor about potential interactions)
Antiarrhythmics: Amiodarone, bepridil, flecainide, propafenone, quinidine
Antihistamines: Astemizole, terfenadine
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI motility agent: Cisapride
Neuroleptic: Pimozide
Sedatives/hypnotics: Midazolam, triazolam
ALERT: Find out about medicines that should NOT be taken with APTIVUS. This statement is included on the products bottle label.
Hepatic Impairment and Toxicity
APTIVUS co-administered with 200 mg of ritonavir, has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications. A causal relationship to APTIVUS/ritonavir could not be established. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with APTIVUS/ritonavir, and frequently throughout the duration of treatment.
Patients with chronic hepatitis B or hepatitis C co-infection or elevations in transaminases are at approximately 2.5-fold risk for developing further transaminase elevations or hepatic decompensation. Additionally, Grade 3 and 4 increases in hepatic transaminases were observed in 6% of healthy volunteers in Phase 1 studies and 6% of subjects receiving APTIVUS/ritonavir in Phase 3 studies.
Tipranavir is principally metabolized by the liver. Therefore caution should be exercised when administering APTIVUS/ritonavir to patients with hepatic impairment because tipranavir concentrations may be increased. APTIVUS/ritonavir is contraindicated in patients with moderate to severe (Child-Pugh Class B and Child-Pugh Class C) hepatic insufficiency.
Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. For information on the multi-dose pharmacokinetics of tipranavir in hepatically impaired patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Hepatic Impairment).
PRECAUTIONS
Sulfa Allergy
APTIVUS (tipranavir) should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir is unknown.
Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported in subjects receiving APTIVUS/ritonavir. In Phase 2 and 3 trials rash was observed in 14% of females and in 8-10% of males receiving APTIVUS/ritonavir. Additionally, in one drug interaction trial in healthy female volunteers administered a single dose of ethinyl estradiol followed by APTIVUS/ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women receiving APTIVUS/ritonavir.
Lipid Elevations
Treatment with APTIVUS co-administered with 200 mg of ritonavir has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating APTIVUS/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.
Information for Patients
Patients should be informed that APTIVUS co-administered with 200 mg of ritonavir, has been associated with severe liver disease, including some deaths. Patients with signs or symptoms of clinical hepatitis should discontinue APTIVUS/ritonavir treatment and seek medical evaluation. Symptoms of hepatitis include fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Extra vigilance is needed for patients with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity.
Liver function tests should be performed prior to initiating therapy with tipranavir and 200 mg of ritonavir, and frequently throughout the duration of treatment. Patients with chronic hepatitis B or C co-infection or elevations in liver enzymes prior to treatment are at increased risk (approximately 2.5-fold) for developing further liver enzyme elevations or severe liver disease. Caution should be exercised when administering APTIVUS/ritonavir to patients with liver enzyme abnormalities or history of chronic liver disease. Increased liver function testing is warranted in these patients.
APTIVUS should not be given to patients with moderate to severe liver disease.
Mild to moderate rash has been reported in HIV-infected men and women receiving APTIVUS/ritonavir.
Women receiving estrogen-based hormonal contraceptives should be instructed that additional or alternative contraceptive measures should be used during therapy with APTIVUS/ritonavir. There may be an increased risk of rash when APTIVUS is given with hormonal contraceptives.
APTIVUS may interact with some drugs; therefore, patients should be advised to report to their health care provider the use of any other prescription, non-prescription medication or herbal products, particularly St. Johns wort.
APTIVUS should be taken with food to enhance absorption.
Drug Interactions
Tipranavir administered with ritonavir can alter plasma exposure of other drugs and other drugs can alter plasma exposure of tipranavir and ritonavir.
Tipranavir co-administered with 200 mg of ritonavir at the recommended dosage 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 tipranavir/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 should be contraindicated. Co-administration with other CYP 3A substrates may require a dose adjustment or additional monitoring.
Table 9. Established and Other Potentially Significant Drug Interactions:
Alterations in Dose or Regimen May be Recommended Based on Drug
Interaction Studies or Predicted Interaction
It is recommended not to combine tipranavir with other protease inhibitors.
Effect on Concentration of Tipranavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
Nucleoside reverse transcriptase inhibitors:
_ Abacavir AUC by approximately 40%
Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.
_ Didanosine
Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from TPV/ritonavir dosing by at least 2 hours.
_ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.
Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease inhibitors (co-administered with 200 mg of ritonavir):
_ Amprenavir,
_ Lopinavir,
_ Saquinavir
Combining amprenavir, lopinavir or saquinavir with APTIVUS/ritonavir is not recommended. No formal drug interaction data are currently available for the concomitant use of APTIVUS, co-administered with 200 mg of ritonavir, with protease inhibitors other than those listed above.
RESISTANCE
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 500/200mg 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.
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