Tipranavir (TPV) is a non-peptidic protease inhibitor (PI) with proven potency against multiple PI-resistant HIV mutants. To achieve appropriate pharmacokinetic levels, tipranavir needs to be boosted with ritonavir (RTV, Norvir) at a dose of 200 mg twice a day. Coadministration with ritonavir increases tipranavir plasma C_max and area under the curve (AUC) at least 4-fold, and C_min at least 20-fold, when compared with tipranavir monotherapy.

The efficacy and safety of ritonavir-boosted tipranavir in HIV-infected, treatment-experienced patients will be discussed when the preliminary phase 3 results of the RESIST-1 trial are presented later at this conference.

Tipranavir is both an inducer and a substrate of cytochrome P450 3A4 (CYP3A4). Ritonavir also has a complex interaction with cytochrome P450, but for the most part it is a potent inhibitor of CYP3A4. With all these cytochrome interactions, it is important to measure the pharmacokinetic levels of other drugs that are also metabolized by the same system. This way, clinicians can reduce the occurrence of complications in patients who may be taking several of these drugs concomitantly.

With tipranavir getting ready for prime time (it will hopefully receive American and European approval next year), this ICAAC featured an influx of studies looking at different pharmacokinetic parameters of tipranavir when coadministered with other agents.

Impact of Boosted Tipranavir on Clarithromycin Pharmacokinetics

One of these studies (Abstract A-457) examined the interaction between clarithromycin (CLR, Biaxin) and ritonavir-boosted tipranavir. Clarithromycin is a macrolide antibiotic frequently used for both prophylaxis and treatment of mycobacterial infections and other common respiratory pathogens. It is known that clarithromycin is extensively metabolized in the liver by CYP3A4 to at least 8 metabolites, including a metabolite called 14-OH-CLR. Thus, the potential exists for drug-drug interaction if clarithromycin and boosted tipranavir are used together.

This study was designed to evaluate the effect of single-dose and steady-state ritonavir-boosted tipranavir on the steady-state pharmacokinetics of clarithromycin and the 14-OH-CLR metabolite. The study was conducted in 24 healthy, HIV-uninfected volunteers.

In a nutshell, no significant effect on clarithromycin was found after a single dose of ritonavir-boosted tipranavir. The pharmacokinetic data did not show a significant effect on clarithromycin AUC (0-12 hours), but did show a decreased C_max and an increased C (12 hours).

This means that the increased exposure to clarithromycin caused by the coadministration of ritonavir-boosted tipranavir is not expected to be clinically relevant in patients with normal renal function. Therefore no dose adjustment of clarithromycin is required when combined with ritonavir-boosted tipranavir.

Interestingly, the investigators also observed a significant inhibition of the formation of the 14-OH-CLR metabolite. This inhibition is important because 14-OH-CLR is twice as active as clarithromycin itself against certain pathogens, such as H. influenza, but 4 to 7 times less active against other mycobacterial pathogens.

Impact of Clarithromycin on Pharmacokinetics of Boosted Tipranavir

What about the effect of clarithromycin on ritonavir-boosted tipranavir? During coadministration of twice-daily clarithromycin 500 mg, the geometric mean steady-state tipranavir AUC (0-12 hours), C_max and C (12 hours) were increased by 59%, 43% and 112%, respectively, when compared with historical controls. (The historical data was obtained from a previous study also conducted on healthy, HIV-uninfected volunteers who took tipranavir 500 mg with ritonavir 200 mg at steady-state.) The moderate effect of clarithromycin on the steady-state pharmacokinetics of tipranavir is something that will probably require further investigation, but in the meantime clinical monitoring of patients on this combination is warranted.

Both the ritonavir-boosted tipranavir and clarithromycin were well tolerated in this study. All adverse events were mild to moderate; the most frequent adverse events were gastrointestinal and central nervous system symptoms, but none led to study discontinuation. For the most part, ritonavir-boosted tipranavir's adverse event profile was consistent with that of other boosted PIs.

Pharmacokinetic Interactions Between Boosted Tipranavir and Rifabutin

A similar study (Abstract A-456) was conducted to determine the pharmacokinetic interactions between ritonavir-boosted tipranavir and rifabutin (RFB, Mycobutin), which is used in the prevention of Mycobacterium avium complex. Rifabutin is a semi-synthetic ansamycin antibiotic derived from rifamycin S, which, like clarithromycin, is a substrate of CYP3A4. Like the clarithromycin study, this study was designed to determine the pharmacokinetic interaction between a single dose of rifabutin and steady-state boosted tipranavir in HIV-uninfected, healthy volunteers. The same team of researchers who conducted the clarithromycin study conducted this study as well.

The investigators found that the coadministration of steady-state ritonavir-boosted tipranavir with single-dose rifabutin caused statistically significant increases in all 3 primary pharmacokinetic parameters -- AUC, C_max and C (12 hours) -- for both rifabutin and its main metabolite, but that a single dose of rifabutin did not have a clinically relevant effect on the steady-state pharmacokinetics of ritonavir-boosted tipranavir.

This is a pharmacokinetic dynamic that has been observed with other PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) -- a dynamic that has resulted in updated recommendations by the U.S. Centers for Disease Control and Prevention to reduce the dose of rifampin (Rifadin, Rimactane) or rifabutin when treating tuberculosis in HIV-infected patients who are taking PIs or NNRTIs. Similarly, this study suggests that patients taking ritonavir-boosted tipranavir with rifabutin should receive a reduced rifabutin dose (150 mg) 3 times weekly. These patients also need to be monitored closely for potential emergence of adverse events associated with rifabutin therapy, including fever, gastrointestinal problems, rash and sore throat.

Ritonavir-Boosted Tipranavir Excretion Mass Balance and Metabolite Profile

In another study (Abstract A-455), investigators aimed to characterize the steady-state excretion mass balance, major metabolites and pharmacokinetics of ritonavir-boosted tipranavir.

The researchers administered tipranavir labeled with radioactive C-14 to 12 healthy, HIV-uninfected volunteers, and then performed extensive analyses of serum, urine and feces to determine the rate of excretion. They found that unchanged tipranavir represented 98.4% to 99.7% of the plasma radioactivity. Most of the elimination of radioactive tipranavir was via feces. The most common form of excreted radioactivity was generally unchanged tipranavir, but one metabolite, H-3 glucoronide, was the most common form recovered in the urine.

In this study, steady-state plasma concentration of twice-daily tipranavir 500 mg coadministered with twice-daily ritonavir 200 mg was achieved by day 7. As with most other boosted PIs, a dose adjustment to the ritonavir-boosted tipranavir will likely not be needed in patients with renal insufficiency.