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.
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:
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.
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.
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.
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 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.
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.
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.
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