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TMC-114: new protease inhibitor for PI-resistance
Reported by Jules Levin
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"First Clinical Results on Antiretroviral Activity, Pharmacokinetics and Safety of TMC-114, an HIV-1 Protease Inhibitor, in Multiple PI-experienced Patients"
TMC-114 has demonstrated in vitro (in the test tube) anti-HIV activity against multi-PI resistant viruses. Patient viruses with extensive PI-resistance were fully sensitive to TMC-114. These were viruses with 20 to 100 to 300 fold resistance to currently available protease inhibitors.
This study was conducted in Europe and evaluated changes in HIV viral load changes over a 14 day study for patients receiving treatment with TMC-114 at 3 different doses. Safety, tolerability, genotypic/phenotypic patterns, and pharmacokinetics were also evaluated.
Patients had to have been treated with 2-4 protease inhibitors and failing a current PI-containing regimen to qualify for the study. And they had no NNRTI in their baseline regimen.
This study evaluated TMC-114 in twice daily and once daily regimens. Study patients were randomized for 14 days to continue their current regimen or to receive one of three TMC-114 doses: 300 mg TMC-114 plus 100 mg of ritonavir twice daily; 600 mg TMC-114 plus 100 mg of ritonavir, twice daily; 900 mg TMC-114 plus 100 mg of ritonavir, once daily. Patients remained on their accompanying nukes for the 2 weeks. After the 14 days patients were given the best available regimens. The 100 mg dose of ritonavir is used to boost the levels of TMC-114.
The study randomized 50 patients, mostly male and caucasian. Baseline median viral load was 20,000 copies/ml, which is relatively low, and CD4 was 305. On average patients had HIV for 10 years.
Study patients had taken an array of protease inhibitors and appeared to have quite a bit of resistance to protease inhibitors. 54% of the patients had taken Kaletra; 14% had taken indinavir boosted by ritonavir; 6% had taken nelfinavir; and 26% had taken others. So 86% had taken PI boosted protease inhibitors. Patients had a median of 6 protease inhibitor mutations. On average each patient had 3 primary protease muations (D30N, M46I/L, G48V, I50V/L, V82A/F/S/T, I84V, L90M. Using the Virco Antivirogram resistance test over 70% of the patients had resistance to Kaletra, ritonavir, nelfinavir, indinavir, saquinavir, and 57% of patients had resistance to amprenavir. Baseline testing showed that patients on average should be sensitive to TMC-114 and sensitivity perhaps to amprenavir. 46% of patients had phenotypic resistance to all approved protease inhibitors. 27% were sensitive to 1 PI. 3% were sensitive to 2 protease inhibitors. And 24% were sensitive to 2 or more protease inhibitors. Phenotypic sensitivity to TMC-114 at baseline was 1.7 fold on average.
RESULTS
Blood Levels of TMC-114
Over the course of 12 hours patients had higher peak levels and higher blood levels of TMC-114 with the once daily dose compared to the two twice daily regimens. At 24 hours the plasma concentration of the once daily regimen was about 200 ng/ml. Although at the 12 hour point the blood level of the 600/100 twice daily regimen was the same as the 900/100 once daily regimen. The 300/100 regimen had lower blood levels throughout the 12 hour period compared to both other regimens. All regimens had levels well above the EC50.
Viral Load Changes
The 12 patients receiving the 600/100 dose regimen had median -1.50 log reduction in viral load. Patients (n=13) receiving 900/100 once daily regimen had median -1.13 viral load reduction. Patients (n=13) receiving 300/100 had -1.24 reduction in viral load. The 12 patients who did not change their regimen, stayed on current PI, had no change in viral load. 69% to 92% of all study patients had decrease of >1 log in viral load. 92% to 100% of patients had decrease of >0.5 log in viral load. 31% of the patients receiving 900/100 achieved <400 copies/ml; 42% of patients receiving 600/100 had <400 copies/ml; and 46% of patients receiving 300/100 had <400 copies/ml.
Clinical Adverse Events
Most commonly reported adverse events were GI and CNS related:
--diarrhea 32%
--flatluence 18%
--headache 16%
--dizziness 11%
Study authors described these as primarily mild/moderate in severity, and no there was no dose relationship.
There were 2 patient discontinuations: 1 person experienced grade 2/3 GI and CNS related events; 1 person developed HIV-related esophageal candidiasis.
Five patients developed a grade 3 or 4 adverse event: primarily GI and CNS events; 1 grade 4 rash.
There was 1 serious adverse event: hepatotoxicity in the 600/100 dose. Lab abnormalities retuned to normal within 6 weeks.
Lab Abnormalities
12 patients experienced grade 2 or more cholesterol. 8 patients experienced grad2 or greater triglycerides. In both cases less patients continuing on current PI experienced this. Otherwise few patients experienced other grade 2 lab abnormalities.
The study authors concluded that there was no correlation between baseline PI resistance and virologic outcome. The next step is to conduct dose finding study with solid formulation.
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