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Practical Perspectives on the Use of Tipranavir in Combination With Other Medications: Lessons Learned From Pharmacokinetic Studies

From the PK Research, St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom.

Address for reprints: Marta Boffito, PK Research, St. Stephen's Centre–Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, United Kingdom.

	ABSTRACT

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Drug-drug interactions are a major practical concern for physicians treating human immunodeficiency virus (HIV) because of the many medications that HIV-positive patients must take. Pharmacokinetic drug interactions can occur at different levels (absorption, distribution, metabolism, excretion) and are difficult to predict. Of all the processes that give rise to drug interactions, metabolism by cytochrome P450 (CYP3A) is the most frequent. Moreover, medications prescribed to HIV-positive patients may also be CYP3A inhibitors and inducers: Tipranavir, in the absence of ritonavir, is a CYP3A inducer, and ritonavir is a CYP3A inhibitor. Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized. This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral-treatment-related conditions such as hyperlipidemia, and side effects such as diarrhea.

Key Words: Tipranavir • ritonavir • pharmacokinetics • drug interactions

Although HIV regimens consist of 3 or 4 antiretroviral drugs, patients may receive additional medications for supportive care, management of antiretroviral-related adverse events, treatment of opportunistic infections, and immunomodulation. Furthermore, intravenous drug users may take methadone and women may take birth-control pills. HIV-infected patients, therefore, may be taking multiple drugs, creating a high potential for drug-drug interactions.

The majority of clinically relevant adverse drug interactions are related to the inhibition or induction of cytochrome (CYP) P450, in particular CYP3A.⁴ In fact, CYP3A is involved in the metabolism of more than 50% of all available drugs, including nonnucleoside reverse transcriptase inhibitors (NNRTIs) and PIs.⁴ When a drug inhibits CYP3A, metabolism of a coadministered drug may be inhibited, resulting in increased blood concentrations of that drug, possibly to toxic levels.⁴ Conversely, an inducer of CYP3A may produce suboptimal drug concentrations of other agents. Drug-drug interactions should be a major consideration, therefore, given the complexity of HIV treatment. Presented here is the first comprehensive review that provides the clinician treating HIV with practical information about the pharmacologic interactions between tipranavir, a novel nonpeptidic PI, and other medications commonly used in HIV-positive patients.

	TIPRANAVIR

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Tipranavir has demonstrated activity against HIV-1 strains that are resistant to peptidomimetic PIs.⁵ Studies have demonstrated that tipranavir is active against a wide range of patient-derived PI-resistant HIV isolates.^5-7 Like many PIs, tipranavir is taken concomitantly with ritonavir. Because ritonavir inhibits CYP3A,^8,9 the combination results in a boost in tipranavir plasma concentrations. Consequently, clinically useful plasma concentrations of tipranavir can be achieved with an acceptable pill burden—two 250-mg capsules of tipranavir twice a day, plus two 250-mg capsules of ritonavir also twice daily.¹⁰

Coadministration of tipranavir and ritonavir produces a potent antiviral response in treatment-naive and treatment-experienced HIV-infected patients.^10,11 Also, the combination produces effective and durable virologic suppression in patients who have previously failed 2 or more PI-containing regimens.¹² In recently presented phase III trials, the twice-daily combination of tipranavir/ritonavir (500 mg/200 mg) with an optimized background regimen was statistically superior to a standard-of-care PI plus an optimized background regimen.^13,14 The most common adverse events associated with tipranavir are diarrhea and nausea,^10,12 which are transient and self-limiting and usually resolve within 14 days.¹⁰

	INTERACTIONS BETWEEN TIPRANAVIR AND RITONAVIR

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
When administered alone, tipranavir is an inducer of CYP3A activity and ritonavir is a potent inhibitor of CYP3A; however, the effect of tipranavir on CYP3A activity may be amplified because of its effect on ritonavir.¹⁵ In a study of HIV-negative, healthy volunteers, combining tipranavir and ritonavir resulted in potent inhibition of CYP3A.¹⁵ Inhibition of CYP3A could alter the metabolism of other concomitantly administered drugs that are substrates of CYP3A, such as certain macrolide antibiotics, benzodiazepines, immune modulators, other PIs, NNRTIs, antihistamines, calcium channel blockers, antiarrhythmics, and 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitors.^*

Ritonavir is both an inhibitor and substrate of CYP3A.⁴ Nonetheless, recent studies demonstrated that there is a 40% decrease in plasma ritonavir concentrations in the presence of 500 mg tipranavir.¹⁵ Thus, the recommended dose of ritonavir when administered with tipranavir is higher than the recommended dose of ritonavir when it is administered in combination with other boosted PIs (200 mg vs 100 mg, respectively).

	TIPRANAVIR AS A COMPONENT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
For ritonavir-boosted tipranavir to be used in a HAART regimen, it is important to know how tipranavir interacts in combination with other antiretroviral medications and the safety of these combinations. Results from the ACTG 359 study demonstrated that antiretroviral drug interactions can be difficult to anticipate or predict when complex multidrug regimens are used.¹⁶ Pharmacokinetic parameters, such as area under the curve (AUC), maximum plasma concentration (C_max), minimum plasma concentration (C_min), and plasma concentration at 12 hours (Cp_12h), have been evaluated for tipranavir when coadministered with many drugs typically used in HAART regimens.^17,18 Also, the pharmacokinetics has been evaluated after the addition of tipranavir to ongoing HAART regimens.¹⁹ Many of these drug interactions have been evaluated both in HIV-infected patients as part of a treatment regimen and in healthy volunteers not consuming other drugs. These findings are summarized in Table I, which provides practical clinical recommendations for use when considering prescriptions for coadministered drugs.

Nucleoside Reverse Transcriptase Inhibitors
Pharmacologic interactions between tipranavir/ritonavir and nucleoside reverse transcriptase inhibitors (NRTIs) have been evaluated in HIV-positive patients on stable HAART regimens. Tipranavir/ritonavir was added to stable HAART regimens that included zidovudine, lamivudine, stavudine, didanosine, and abacavir at manufacturer-recommended doses.¹⁹

Three different doses of tipranavir/ritonavir (1250 mg/100 mg, 750 mg/100 mg, and 250 mg/200 mg twice daily) showed no clinically significant impact on the plasma concentrations of lamivudine, stavudine, or didanosine. In contrast, plasma concentrations of zidovudine were reduced in this study (AUC, –31% to –42%; C_max, –46% to –51%), as were the plasma concentrations of abacavir (AUC, –35% to –44%; C_max, –44% to –52%). Because of the add-on design of the study in patients on HAART regimens, it was not possible to evaluate the effects of NRTIs and NNRTIs on the pharmacokinetics of tipranavir/ritonavir.

The interactions between tipranavir/ritonavir and a single dose of 3 different NRTIs—zidovudine (300 mg), tenofovir disoproxil fumarate (300 mg), or didanosine enteric-coated formulation (400 mg)—have been evaluated in HIV-negative, healthy volunteers.¹⁸ Changes in the pharmacokinetic profiles of zidovudine (AUC, –33%; C_max, –56%), tenofovir disoproxil fumarate (AUC, 5%; C_max, –36%), or didanosine (AUC, –10%; C_max, –20%) were observed in this population when any of these drugs were given in combination with tipranavir/ritonavir at standard doses (500 mg/100 mg or 750 mg/200 mg twice daily). It is recommended that when the enteric-coated formulation of didanosine is used, it should be taken at least 2 hours apart from tipranavir because of an apparent interaction between the self-emulsifying drug delivery system of tipranavir and the enteric outer coat of didanosine.^18,20 Conversely, didanosine decreased the C_min (–34%) and increased the C_max (+32%) of tipranavir.

NRTIs are phosphorylated intracellularly to their active form. Intracellular concentrations of NRTIs are not directly or immediately affected by reductions in plasma drug concentrations.²¹ As a result, the clinical relevance of the observed decreases in plasma concentrations of zidovudine (AUC, –42%; C_max, –46%) and abacavir (AUC, –44%; C_max, –44%) with 250 mg/200 mg tipranavir/ritonavir twice daily are not known. Tipranavir has been extensively studied in clinical trials, and the frequency of adverse events when tipranavir/ritonavir was added to a stable HAART regimen containing an NRTI was similar to that of tipranavir/ritonavir alone.^19,22 These pharmacokinetic studies indicate that tipranavir/ritonavir may be safely used in HAART regimens that include any of these NRTIs (zidovudine, lamivudine, stavudine, abacavir, or didanosine) at standard doses; however, clinicians should be aware of the potential for alterations in plasma concentrations of zidovudine and abacavir.¹⁹ No significant changes in plasma concentrations of tipranavir/ritonavir were seen in trials involving healthy volunteers.

Nonnucleoside Reverse Transcriptase Inhibitors
Efavirenz is an inducer of CYP450 enzymes, including CYP3A. In both HIV-positive patients on stable HAART regimens and HIV-negative, healthy volunteers, adding tipranavir/ritonavir (1250 mg/100 mg, 750 mg/100 mg, 750 mg/200 mg, 500 mg/100 mg, or 250 mg/200 mg twice daily) to efavirenz (600 mg once daily) therapy had no clinically significant impact on the pharmacokinetic profile of efavirenz.^18,19 Likewise, tipranavir/ritonavir (1250 mg/100 mg, 750 mg/100 mg, or 250 mg/200 mg twice daily) had no clinically significant impact on the plasma concentrations of nevirapine (200 mg twice daily) in HIV-positive patients on stable HAART therapy.¹⁹ Efavirenz 600 mg once daily caused a 60% decrease in tipranavir systemic concentrations at 12 hours with a tipranavir/ritonavir 500 mg/100 mg dose combination, which was likely because of inconsistent ritonavir inhibition of CYP3A. No such reduction in tipranavir plasma levels was seen at the tipranavir/ritonavir 750 mg/200 mg dose, and none is anticipated at the 500 mg/200 mg dose. Likewise, nevirapine 200 mg twice daily did not have a significant effect on tipranavir systemic exposure when ritonavir was coadministered at a 200-mg level. Therefore, tipranavir/ritonavir at the 500 mg/100 mg dose can be used safely with standard doses of these NNRTIs.

Protease Inhibitors
The potential interaction between tipranavir/ritonavir and other single-boosted PIs as part of a dual-boosted PI regimen has been studied in HIV-1–infected adults.¹⁶ During the first 2 weeks of the study, 296 treatment-experienced patients were randomly assigned to receive amprenavir/ritonavir, saquinavir/ritonavir, or lopinavir/ritonavir, with a background regimen determined according to individual resistance profiles and treatment histories. After 2 weeks on the assigned PI, tipranavir/ritonavir was added to the regimen. The final twice-daily doses were tipranavir/amprenavir/ritonavir (500 mg/600 mg/200 mg), tipranavir/saquinavir/ritonavir (500 mg/1000 mg/200 mg), and tipranavir/lopinavir/ritonavir (500 mg/400 mg/200 mg).¹⁶ Plasma concentrations of ritonavir-boosted lopinavir, saquinavir, and amprenavir were decreased by the addition of tipranavir/ritonavir. C_min was reduced by 52%, 80%, and 56% for lopinavir, saquinavir, and amprenavir, respectively. All of the combinations were well tolerated with similar frequencies of adverse events and laboratory abnormalities; no unexpected adverse events were observed in this trial.¹⁶ It is interesting that even though there was a 0.2 log₁₀ to 0.4 log₁₀ decrease in the plasma concentrations of amprenavir, lopinavir, and, especially, saquinavir after tipranavir/ritonavir was added to the regimen, patients in all groups had an additional 0.8 log₁₀ to 0.9 log₁₀ decrease in the viral load.¹⁶ Dose adjustments for amprenavir, lopinavir, and saquinavir cannot be recommended at this time. Nevertheless, these ritonavir-boosted PIs provided only minimal efficacy until tipranavir was added at week 2 of the study, suggesting that, in these combinations, these PIs added little or no antiviral activity in this heavily pretreated population. The clinical value of dual-boosted PI regimens remains obscure and requires further study.

	INTERACTIONS BETWEEN TIPRANAVIR AND MEDICATIONS USED TO TREAT OPPORTUNISTIC INFECTIONS

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Although HAART is the most effective approach to preventing opportunistic infections, many patients receiving HAART require prophylactic therapy against these infections.²³ In addition, quiescent subclinical opportunistic infections unmasked during the first 2 months of HAART treatment (immune reconstitution syndrome) can be prevented with prophylactic therapy.²³ Thus, it is not unusual for patients being treated with antiretroviral medications to also require treatment for bacterial, mycobacterial, or fungal opportunistic infections.

Fluconazole
The fungistatic activity of azole antifungals (fluconazole, itraconazole, and ketoconazole) occurs via the inhibition of CYP450-mediated sterol C-14 alpha-demethylation. As CYP450 inhibitors, azole antifungals are also human CYP3A inhibitors and, thereby, are associated with a number of drug interactions. Fluconazole is a synthetic triazole antifungal medication indicated for prophylaxis and treatment of oropharyngeal and esophageal candidiasis and other serious systemic fungal infections, including those in HIV/AIDS patients. Not surprisingly, fluconazole is known to increase the AUC of a number of antiretroviral medications.²⁴

The interactions between tipranavir/ritonavir (500/200 mg twice daily) and fluconazole (100 mg once daily) were evaluated in HIV-negative, healthy individuals.²⁵ The pharmacokinetics of fluconazole was not clinically altered by single-dose or steady-state tipranavir/ritonavir. In contrast, fluconazole increased the AUC and C_max of tipranavir by 50% and 32%, respectively. Despite this increase in systemic tipranavir exposure, no dose adjustment of tipranavir/ritonavir or fluconazole is required. However, doses of fluconazole greater than 200 mg/d are not recommended.²⁰ The coadministration of fluconazole and tipranavir/ritonavir was well tolerated. Nonetheless, patients taking fluconazole together with tipranavir/ritonavir should be closely monitored.²⁶ It is also recommended that other antifungal agents, such as ketoconazole and itraconazole, be used with caution, although use in combination with tipranavir/ritonavir has not been formally studied. Similar to fluconazole, doses of ketoconazole or itraconazole greater than 200 mg/d are not recommended.²⁰

Clarithromycin
Clarithromycin is a macrolide antibiotic commonly prescribed in HIV-positive patients for streptococcus pharyngitis, sinusitis, bronchitis, and community-acquired pneumonia, as well as for prophylaxis for disseminated mycobacterium avium complex (MAC) infections.

The coadministration of tipranavir/ritonavir (500 mg/200 mg twice daily) and clarithromycin (500 mg twice daily) was evaluated in HIV-negative, healthy volunteers.²⁷ Tipranavir/ritonavir altered the pharmacokinetics of clarithromycin, resulting in almost complete inhibition of its metabolism to the metabolite 14-hydroxy-clarithromycin. This metabolite is more active than the parent drug against certain pathogens; for example, 14-hydroxy-clarithromycin is twice as active as clarithromycin against Haemophilus influenzae. Alternatives to clarithromycin should therefore be considered when selecting treatment for management of H influenzae in HIV-positive patients receiving tipranavir/ritonavir. This metabolite of clarithromycin is 4- to 7-fold less active against other organisms such as Mycobacterium avium and Mycobacterium intracellulare.²⁸ Although the pharmacokinetics of clarithromycin was altered when coadministered with tipranavir/ritonavir, clarithromycin has a wide therapeutic window, and no dosage adjustments are required in patients with normal renal function. Because the metabolic steps of clarithromycin clearance have been eliminated when tipranavir and ritonavir are coadministered, the clarithromycin dose in renal impairment should be reduced by 50% if creatinine clearance is 30 mL/min to 60 mL/min and by 75% if it is less than 30 mL/min.^20,28

Clarithromycin 500 mg twice daily increased the AUC (+66%), C_max (+40%), and C_min (+100%) of steady-state tipranavir. Because clarithromycin doubled the C_min of tipranavir, this interaction may be clinically relevant, and patients should be clinically monitored.²⁷

Rifabutin and Rifampin
Rifabutin is an antimycobacterial, which is used as a primary prophylaxis for MAC in people with advanced HIV infection and no evidence of active tuberculosis. Rifabutin induces CYP3A enzymes and is known to alter the pharmacokinetics and reduce the efficacy of standard doses of delavirdine, indinavir, nelfinavir, saquinavir, and zidovudine.²⁹

In a pharmacokinetic interaction study in HIV-negative, healthy individuals,³⁰ rifabutin had no clinically significant effects on the pharmacokinetics of tipranavir. Tipranavir/ritonavir (500 mg/200 mg twice daily) significantly increased the AUC (+190%), C_max (+70%), and C_min (+114%) of rifabutin (150 mg). Concomitantly, tipranavir/ritonavir had an even greater effect on the pharmacokinetic values (AUC, +1971%; C_max, +220%; C_min, +683%) of the active metabolite 25-O-desacetyl-rifabutin. Considering that the plasma concentration of rifabutin was increased by tipranavir/ritonavir, the dose of rifabutin should be reduced by 75% to a recommended dose of 150 mg every other day, or 3 times per week.³⁰ Patients taking tipranavir/ritonavir and rifabutin should be closely monitored for the development of rifabutin-related adverse events.³⁰

The potent CYP3A-enzyme inducer rifampin, which is structurally similar to rifabutin, is not recommended for use in combination with tipranavir/ritonavir because the combination may lead to loss of virologic response and possible resistance to tipranavir or to the class of PIs (see Table II).²⁰

	INTERACTIONS BETWEEN TIPRANAVIR AND DRUGS USED TO MANAGE ADVERSE EVENTS

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Adverse effects can have an impact on treatment adherence. One study of 345 HIV-positive patients reported that adverse events were the most common reason for discontinuation of an initial HAART regimen.³¹ Treatments for known side effects are frequently discussed at the onset of HAART therapy and are used either prophylactically or on occurrence. The interactions between tipranavir/ritonavir and a number of key medications used to treat HAART-associated adverse events have been studied and are summarized here.

Interactions Between Tipranavir and Medication Used to Treat PI-Associated Hyperlipidemia
Most PIs are associated with elevated serum cholesterol and triglyceride levels,³² possibly occurring in more than 50% of the patients taking PIs.³² In addition, the risk of developing hyperlipidemia increases with duration of use.³² Consequently, there is an increased risk of developing coronary heart disease and pancreatitis.³³ Furthermore, PI-induced hyperlipidemia is also associated with the development of lipodystrophy syndrome,³⁴ which is characterized by fat redistribution, peripheral wasting, and insulin resistance. When indicated, HMG-CoA reductase inhibitors or fibrates are typically used to treat PI-induced hyperlipidemia.³⁵

Atorvastatin
Atorvastatin is one of the most frequently used HMG-CoA reductase inhibitors, but because of its reliance on CYP3A as the major pathway to producing active metabolites and clearance, it is also associated with a high degree of drug interactions, as with other drugs in this class.²⁹ Primarily metabolized by CYP3A, atorvastatin has been shown to affect the pharmacokinetics of PI-ritonavir combinations.³² A single dose of atorvastatin had no apparent effect on the pharmacokinetics of tipranavir. Tipranavir/ritonavir (500 mg/200 mg twice daily) caused a clinically relevant 9-fold increase in the atorvastatin (10 mg) AUC in healthy volunteers,³⁶ with concomitant increases in the C_max (+761%) and C_min (+419%) values. However, because the formation pathways of atorvastatin active metabolites are inhibited, this 9-fold increase in parent-drug exposure represents only a 3-fold increase in activity. Patients requiring treatment with both tipranavir/ritonavir and atorvastatin should be closely monitored.³⁶ Because plasma concentrations of atorvastatin are increased when given with tipranavir/ritonavir, it is recommended that atorvastatin be started at the lowest possible dose.

The HMG-CoA reductase inhibitors simvastatin and lovastatin are also primarily metabolized by CYP3A.³² Concomitant use of tipranavir/ritonavir and simvastatin or lovastatin is not recommended because of an increased risk of myopathy, including rhabdomyolysis.^22,32

Interactions Between Tipranavir and a Medication Used to Treat PI-Associated Diarrhea
Gastrointestinal disturbances, such as diarrhea, nausea, and vomiting, are common side effects of antiretroviral medications. The prevalence and discomfort of these gastrointestinal side effects are the most common reason for HAART discontinuation.³¹ As with other PIs, diarrhea is the most frequent side effect seen with tipranavir/ritonavir therapy. Results from the tipranavir phase III program suggest that the incidence of these side effects is similar for tipranavir, lopinavir, indinavir, saquinavir, and amprenavir.^13,14,16

Loperamide
Loperamide, an over-the-counter synthetic opiate that does not cross the blood-brain barrier, is a common treatment for diarrhea. The pharmacokinetic interactions between tipranavir/ritonavir (750 mg/200 mg twice daily) and loperamide (16 mg) were assessed in HIV-negative, healthy volunteers.³⁷ Loperamide caused a 26% decrease in tipranavir C_min, whereas no other pharmacokinetic parameters were significantly altered.³⁷ Tipranavir/ritonavir caused large decreases in loperamide AUC (–51%) and C_max (–61%) values without a subsequent increase in metabolic concentrations. However, the clinical relevance of these findings is unclear because loperamide's primary pharmacologic activity occurs in the intestines before absorption. No clinically relevant pharmacodynamic interactions were observed, suggesting that the synthetic opiate and its metabolite did not cross the blood-brain barrier in the presence of tipranivir/ritonavir.³⁷ The authors concluded that loperamide can be safely coadministered with tipranavir/ritonavir.³⁷

Antacids
As part of antiretroviral therapy, HIV-positive patients may take antacids or their antiretroviral medication may contain antacids within the formulation, as is the case with generic indinivir (Indivir, Cipla Medpro, South Africa) or didanosine. By reducing stomach acid, the antacid may alter the absorption of drugs that require a specific gastric pH for absorption. In addition, the antacid may interact directly with the drug.

The interactions between a representative antacid (Maalox Plus, extra strength antacid/antigas liquid, 5-mL dose [aluminum hydroxide 500 mg, magnesium hydroxide 450 mg, semimethicone 40 mg]) and a single dose of 500 mg/200 mg tipranavir/ritonavir were assessed in HIV-negative, healthy volunteers.³⁵ Simultaneous ingestion of the antacid and tipranavir/ritonavir reduced the AUC, C_max, and C_min of tipranavir by 25% to 29%.³⁵ The reduced plasma concentration of tipranavir may be clinically relevant; therefore, antacid administration and tipranavir/ritonavir dosing should be separated.³⁵

	CONSIDERATIONS FOR CONCOMITANT USE WITH OTHER DRUGS

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Ritonavir is coadministered with tipranavir because, as an inhibitor of CYP3A, its concomitant use results in higher therapeutically relevant plasma concentrations. It is important to be aware that other agents metabolized by CYP3A may also be affected by ritonavir. Therefore, ritonavir is contraindicated for use with a number of agents, which are also, by association, contraindicated with ritonavir-boosted tipranavir. Important contraindicated interactions with ritonavir-boosted drugs, including tipranavir, are summarized in Table II. A number of other drug interactions are anticipated with the coadministration of ritonavir with tipranavir and are discussed below. In addition, the ritonavir prescribing information provides additional contraindications, warnings, side effects, and potential drug interactions between ritonavir and other compounds.³⁸

Phosphodiesterase Inhibitors
Phosphodiesterase (PDE5) inhibitors, eg, sildenafil, vardenafil, or tadalafil, should be used with caution in patients receiving tipranavir/ritonavir. Coadministration of tipranavir/ritonavir with PDE5 inhibitors would be expected to substantially increase PDE5 concentrations, resulting in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism.^20,39

Oral Contraceptives and Estrogens
Ethinyl estradiol is metabolized by CYP3A, and drugs that affect CYP3A metabolism can lead to loss of ethinyl estradiol effectiveness.⁴⁰ Tipranavir/ritonavir decreases the AUC and C_max of ethinyl estradiol by 50%, but does not significantly alter the pharmacokinetics of norethindrone.²⁰ Therefore, when estrogen-based oral contraceptives are coadministered with tipranavir/ritonavir, alternative or additional contraceptive measures are required, and patients should be monitored for signs of estrogen deficiency. In addition, women using estrogens may have an increased risk of nonserious rash.^20,39

Narcotic Analgesics
Tipranavir/ritonavir may interact with narcotic analgesics. Coadministration of tipranavir/ritonavir with methadone (a CYP3A inducer) would be expected to decrease methadone concentrations and may cause opiate abstinence syndrome.⁴¹ Therefore, the dosage of methadone may need to be increased. Tipranavir/ritonavir would be expected to decrease meperidine concentrations and increase normeperidine metabolite concentrations.⁴² Increasing the dose of meperidine or using meperidine long term is not recommended because the increased concentration of normeperidine would have both analgesic activity and central nervous system stimulant activity (eg, seizures).^20,39

St. John's Wort
Coadministration of tipranavir/ritonavir with St. John's wort (Hypericum perforatum), a CYP3A inducer, would be expected to substantially decrease the concentration of tipranavir/ritonavir. The possible suboptimal exposure to tipranavir/ritonavir may lead to loss of control of HIV replication and possible resistance to tipranavir or to the class of PIs. Therefore, concomitant use of tipranavir/ritonavir and St. John's Wort is not recommended.^20,39

Other Agents
It should be noted that other compounds not mentioned here that are substrates of CYP3A might have altered pharmacokinetics when coadministered with tipranavir/ritonavir. Both the ritonavir and tipranavir prescribing information contain additional contraindications, warnings, side effects, and potential drug interactions between ritonavir and other compounds.

	CONCLUSION

TOP ABSTRACT TIPRANAVIR INTERACTIONS BETWEEN TIPRANAVIR... TIPRANAVIR AS A COMPONENT... INTERACTIONS BETWEEN TIPRANAVIR... INTERACTIONS BETWEEN TIPRANAVIR... CONSIDERATIONS FOR CONCOMITANT... CONCLUSION REFERENCES

 
Optimal dosing and efficacy of tipranavir relies on the inhibition of CYP3A by ritonavir. Therefore, it is important to consider interactions between tipranavir/ritonavir and other medications in the HAART regimen, as well as the myriad other drugs an HIV-infected patient is likely to be taking. It can be difficult to predict drug interactions when complex multidrug regimens are used.¹⁷ Drug-drug interactions could have significant impact on the virologic activity of regimens administered to treatment-experienced patients. Studies demonstrate that tipranavir/ritonavir can be safely combined with 11 different antiretroviral medications. Also, adding tipranavir/ritonavir to a stable HAART regimen that included NRTIs, with or without NNRTIs, resulted in improved virologic control in many patients during 4 weeks of treatment.¹⁹ Hence, tipranavir may be an efficacious addition to a multidrug regimen for treatment-experienced patients. Fortunately, the interactions between tipranavir/ritonavir, other antiretroviral medications, and other medications commonly used in HIV-positive patients are well characterized, so tipranavir/ritonavir can be administered with confidence, even in patients with advanced disease who require complex antiretroviral regimens and other agents. The data and clinical recommendations provided in the tables should provide guidance to avoid adverse interactions that might ultimately lead to virologic failure.

^* For specific drugs that interact with CYP3A, refer to a CYP450 interaction table at the free public Web site http://medicine.iupui.edu/flockhart/.

	REFERENCES

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