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Goodnight, Gracie!
Quirky PK of BI's Tipranavir May Confine Its Use to Limited Rescue Role

By Rob Camp

June 2004

Penned in by PK

Advances in HIV pharmacology can theoretically lead to improvements in HIV care. The monitoring of antiretroviral drugs including virologic, immunologic and pharmacologic surveillance can form an integral component in the care of patients living with HIV. At the 5th International Workshop on Clinical Pharmacology of HIV Therapy (April 1-3), lots of this and more were presented in posters and orally. This month, writes Rob Camp, I will just be looking at new drugs in the pipeline and their pharmacokinetic (PK) properties, but in upcoming articles, I will report on the clinical pharmacology of NRTIs, drug-drug interactions of already approved drugs, as well as the latest in therapeutic drug monitoring.

What Is a Salvage Drug? A Look at BI's "51" Study

One of the most important studies presented at the Pharmacology Workshop was the first analysis of Boehringer-Ingelheim's Phase III trial ("BI 1182.51") which looked at the interaction between tipranavir/r and three other protease inhibitors. The results have important implications.

Tipranavir is dosed at 500 mg and boosted with 200 mg ritonavir, both twice daily. BI's "51" study was designed to look at the PK interaction with a second full dose protease inhibitor: saquinavir, amprenavir or lopinavir/r. Whereas ritonavir is a potent inhibitor of CYP3A4, tipranavir is an inducer (as are the NNRTIs and the TB drug rifampin) of the same enzyme.

Enrollment criteria for 1182.51 included triple-class experience and three or more "universal" protease-associated mutations (at codons 33, 82, 84 and 90). The median viral load for study participants at baseline was around 100,000 copies/mL, while the median CD4 count stood at 140 cells/mL (range 0-867 cells/mL). Tipranavir/r was added to a steady-state optimized background (OB) regimen of each of the three protease regimens (SQV, AMP, LPV/r) after two weeks and compared to a tipranavir/r only + OB regimen.

One immediate comment is that while these were "extra" people from other trials (people who enrolled in this study were "too resistant" to enroll in the large RESIST tipranavir/r trials) who in fact needed a new regimen, this new regimen could have been better designed. For example, to find out the interactions of TPV/r and other protease inhibitors, a PK study could have been nested within a larger study of TPV/r + OB vs. TPV/r + a second active agent + OB, where the OB could have included the other PIs. As it turns out, 300 people with major resistance patterns were generally given just one new drug. Yes, approximately 15% of patients were able to add T-20 to the mix, but this was not facilitated, simply "allowed." A weird attitude in a salvage therapy trial.

BI "51" Safety and PK Analyses

Results from 296 patients were included in the safety data set. Two hundred ninety in the PK trough data set and 86 (out of 134 patients in the intensive PK substudy) had evaluable data at two visits to be reported on here.

The addition of tipranavir/r at Week 2 caused concentrations of the other PIs to fall well below target for the majority of patients, although a small number of people did achieve therapeutic concentrations. Trough, peak and total drug exposure of saquinavir, amprenavir, or lopinavir/r were significantly decreased when TPV/r was added to the regimen. TPV trough levels did not appear to differ significantly between the treatment arms. Unfortunately, no precise dosing recommendations can be made for these second protease inhibitors when used with TPV/r. Additional studies are necessary to define the magnitude of these drug interactions and their appropriate doses. Very disappointing.

At Week 8, 55-60% of people in each study arm reported at least one side effect. Of these, diarrhea (5.3% saquinavir, 15.8% amprenavir, 10.1% lopinavir/r, 13.6% tipranavir/r) and nausea were the most common. Incidence of laboratory abnormalities was similar in all study arms, with elevated triglycerides the most commonly reported lab event at Week 8.

Virologic efficacy in the study was driven by TPV/r, with people in all groups achieving a median HIV-RNA reduction of >1.0 log by Week 4, (after tipranavir/r was added). In this highly experienced group, viral load drops proved transient, and by Week 8 median viral load was already heading back to baseline. The 24-week analysis is due to be presented at Bangkok in July, and we will see if this trend continues.

Dwindling PI concentrations were at least partially the cause of these viral rebounds. Adding tipranavir at Week 2 cut lopinavir's trough by about 45%, amprenavir's by about 50%, and saquinavir's by about 80%. Peak concentrations and AUCs also fell when teamed up with tipranavir. The CYP3A4-inducing effect of tipranavir may have undercut the inhibiting effect of ritonavir, although in a study of healthy volunteers a single dose of tipranavir/r (500/200 mg) nearly completely inhibited hepatic CYP3A4 activity (by 96%, see below).

(Another potential issue is the in-house combination of nevirapine and TPV/r. Both are BI drugs. But both are also inducers of CYP3A4. It doesn't look hopeful.)

The preliminary conclusions from this large (~300 people) PK study at eight weeks were that:

  1. TPV/r alone or in combo with other PIs is well tolerated for up to 4 weeks,

  2. The PK parameters of all 3 PIs are reduced in the presence of TPV/r (although dosing adjustments can't be made at this time), and

  3. The clinical utility of dual-boosted PI regimens containing TPV (/r) may have been reduced by these adverse PK reactions.

What Is a Salvage Drug?

So maybe we should ask, "What is a salvage drug?" Answer: One that works well after various treatment failures, including other drugs of the same class. Salvage drugs don't actually exist (maybe Kaletra is the closest), so it is a hard thing to criticize TPV/r about. When Boehringer-Ingelheim felt that TPV/r had a place in salvage treatment, they went whole hog to show it -- and failed! (Well, at least in this study; there is another study, BI 1182.52, where the data might be better; but here, efficacy seems limited.)

Does Tipranavir Fit the Bill?

For TPV/r to be effective in a salvage setting, the person needs at least one other active drug (and, especially in the case of TPV/r, this needs to be from another drug class); therefore, tipranavir is not a true salvage drug.

Is It Time for Expanded Access?

Is expanded access for TPV/r needed right now? The combined use of at least one drug that still works from another drug class (including the entry class, but this begs the question: How to access T-20? Why are there no studies with TPV/r and an entry inhibitor?) is the absolute minimum needed in order to stand a chance of meaningful viral suppression with TPV/r in a salvage setting. Some people in 1182.51 were, in fact, taking Fuzeon (18% in the TPV/r arm, 12% in the TPV/r/amprenavir arm, 11% in the TPV/r/saquinavir arm, and 14% in the TPV/r/lopinavir/r arm), but investigators provided no information on how these patients' T cells performed. That would be very interesting data to see.

Further complicating things, potential TPV/r takers of a tipranavir expanded access program will likely need to pay exorbitant sums for the ritonavir component (BI is not ready to foot that bill), putting it out of reach for many. Some might think this BI's responsibility; after all, tipranavir doesn't work without it.

TPV/r and Atorvastatin or Antacids

Tipranavir/r (500/200 mg BID) skyrocketed exposure of atorvastatin nearly nine times, while the antacid Maalox lowered tipranavir concentrations by up to 29% in a study of twenty-three healthy volunteers in Ottawa. The three drugs were looked at in twelve women and eleven men with a median age of 32 years.

Atorvastatin had no apparent effect on tipranavir levels. But the author did rate the atorvastatin surges "clinically relevant" and recommended close monitoring of people who take it with tipranavir/r.

TPV/r plus antacid compared to tipranavir/r alone showed substantial drops in tipranavir exposure. Because the antacid lowers tipranavir levels, clinicians prescribing these drugs with TPV/r will have to consider the timing of the antacid dose; e.g., Maalox should be taken 1 hour before or 2 hours after the administration of TPV.

These volunteers must have been glad when the study ended because all but one of them suffered some kind of gastrointestinal distress. During treatment with TPV/r alone, 17 (74%) had diarrhea, 11 (48%) had nausea, and 9 (39%) had abdominal pain. Sixteen people (70%) reported some central nervous system complaint, including headache and loss of taste. These problems were reported as mild. There was one clinically relevant lab abnormality, a grade 3 ALT gain (within 23 days). This study also showed that single-dose TPV/r reduced hepatic CYP3A4 activity by 96%, so why it had the effects it did have on other PIs is a mystery.

In one poster looking at the effect of TPV/r 500/200 mg twice daily on the PK of fluconazole 100 mg in HIV-negative volunteers, fluconazole plasma concentrations were not affected by TPV/r; the TPV 12-hour concentration, however, increased 104%. The clinical relevance of this interaction is "unclear" and needs to be further explored.

TMC114/r and Food

In a study of 50 PI-experienced people on a failing PI regimen, TMC114/r doses of 300/100 or 600/100 twice daily or 900/100 mg once daily lowered median viral loads from 1.24 to 1.50 logs over 8 weeks. In that period no one changed the nucleosides in their baseline regimen. Food interactions were shown on a new 400-mg solid formulation of TMC114 and an oral solution, both given with ritonavir.

The four-way crossover study design called for 16 healthy volunteers to take the tablet or oral solution with or without a standard breakfast. They also took 100 mg of ritonavir twice daily from 2 days before to 1 day after dosing of TMC114. One person withdrew consent during the washout after the first dosing period. Others reported mild or moderate nausea, vomiting, dyspepsia, and headache.

Intake of food with the tablet formulation increased the amount of drug in the body or AUC approximately 42%. No differences in systemic exposure were noted for the oral solution between the fasted and fed states.

Tibotec concludes that the TMC114 tablet formulation should be taken with food.

Note: After the sad results of TPV/r, the community is asking en force that double-investigative trials of both TMC compounds, the NNRTI and the PI, get under way tout suite. Tibotec is talking about early next year, by which time, the same disappointing results will have been seen individually in the tested salvage populations (of successive monotherapy) that it is being looked at in.

Elvucitabine (ACH-443)

Is it time to start thinking about once-weekly therapy? At the pharmacology workshop, we saw a glimmer of a drug that might be just -- the nucleoside analog elvucitabine from Achillion Pharmaceuticals.

In vitro work (PK/PD modeling) shows that elvucitabine has 5- to 10-fold greater antiviral activity than 3TC against wild-type HIV and HBV at 50% inhibitory concentrations of 4.8 and 1.0 nM. At doses of 50 mg or more daily, the nucleoside also slowed replication of 3TC-resistant M184V mutant virus, but the daily dosing up to now has caused bone marrow toxicity in the HIV-negative and HBV-positive volunteers studied.

Achillion has thus opened a safe and secure therapeutic window of a steady-state 24-hour AUC of 300 µg o h/mL and a Cmin of at least 2 µg/L. To prevent bone marrow toxicity the Cmin must stay below 23 µg/L, which would keep peak concentrations under 40 µg/L in bone marrow.

With an estimated elimination half-life of 175 hours, elvucitabine might be a candidate for once-weekly therapy. Computer PK simulations settled on three once-weekly doses that yielded a Cmin, Cmax, and AUC within the therapeutic window: 40, 50, and 75 mg, respectively.

These hematologic toxicities, including neutropenia, may affect neutrophil function, and there are no plans to look at them right now. Mitochondrial DNA damage will also need to be assessed.

AMD070 Dosing

A phase I study of AMD070, an orally bio-available CXCR4 antagonist, showed a dose response effect, with most 12-hour concentrations of the 400 mg dose above the protein binding-adjusted EC90 of 125 nM.

AMD070 levels were looked at in HIV-negative men taking single daily doses of 50, 100, 200, or 400 mg, twice daily doses of 100 or 200 mg, and a single daily 400 mg dose with food. Food had no impact on the drug's bio-availability.

The Cmax and AUC proved dose-proportional across doses, although inter-individual variation was wide among the 12 volunteers. White blood cell gains, a possible marker of CXCR4 inhibition, ranged from 1.3- to 1.6-fold with the 50 mg dose and from 1.5- to 2.9-fold with 400 mg. AMD070 concentrations 12 hours after a single 400 mg dose ranged from 79 to 155 nM, although two thirds of the people at that dose had a concentration above the EC90. Multiple dosing did not result in drug accumulation. Some volunteers reported mild headaches.

UK-427 and CYP3A4

The CYP3A4 inducers rifampin and efavirenz lower levels of the CCR5 antagonist UK-427, according to Pfizer. Doubling the dose of UK-427 compensates for this inducing effect.

The placebo-controlled, two-group study involved 36 HIV-negative men who took 100 mg of UK-427 twice daily from study days 1 through 21. On days 8 through 21, they also took 600 mg of rifampin once daily, 600 mg of efavirenz once daily, or placebo. By comparing UK-427 troughs on days 7 and 17, they gauged the effect of the CYP3A4 inducers and adjusted the dose of the antagonist if necessary on days 22 through 28.

Pfizer calculates a 6.6-fold increase in CYP3A4 induction with rifampin and a 2.4-fold increase with efavirenz. Both drugs substantially lowered UK-427 exposure compared with placebo. By Day 28 the dose adjustment had lifted UK-427 exposure back to levels comparable with UK-427 plus placebo. So UK-427 will need to be dose-doubled if administered with either rifampicin or efavirenz.

In two other abstracts, the effects of UK-427 on CYP3A4 substrates and the effects of CYP3A4 inhibitors on UK-427 were looked at. The combination of UK-427 + midazolam, a substrate for 3A4, was looked at, and midazolam AUC and Cmax both increased slightly (118% and 121%) There were no clinically relevant differences in Tmax or t1/2 in either the males or females studied. Also, UK-427 did not show signs of inducing 3A4, which was measured by looking at the 6B-hydrocortisol/cortisol ratio only in men.

3A4 inhibitors' effects on UK-427 were looked at through the co-administration of ketoconazole and saquinavir. UK-427 Cmax was raised by some 338% with ketoconazole and 332% with saquinavir, while the AUC rose by some 501% with ketoconazole and 425% with saquinavir. Effects on Tmax or t1/2 were not significantly altered.

A fourth poster looked at the CYP-based drug-drug interaction possibilities of UK-427. UK-427 seems to be a weak inhibitor of CYP activity and is unlikely to inhibit the metabolism of co-administered CYP substrates. But because UK-427 is a substrate for 3A4, its pharmacokinetics probably will be altered in the presence of agents that do modulate 3A4: the protease inhibitors.

HIV+ Thymidine Kinase

Levels of the nucleoside activator thymidine kinase (TK) are significantly higher and vary more widely in people with HIV infection than in HIV-negative individuals. TK levels were measured in PBMCs from 46 antiretroviral-naive HIV-positive and 10 HIV-negative volunteers. AZT and 3TC were used as a substrate for the enzyme. TK activity ranged widely in people with HIV infection and much less so in the HIV-negative controls. Deoxycytidine kinase activity varied more widely in the HIV+ people than in the controls, but mean activity was not significantly higher in the HIV group.

Viral or cellular factors may contribute to these differences in people with HIV and the effects of such factors on response to antiretroviral therapy is being investigated.

Back to the TAGline June 2004 contents page.

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