ABT-378 (Kaletra) in Multiple PI Experienced: 48 Week Update

Abbott updated to 48 week data on the ABT-378 study in multiple PI experienced indivuals. Study 957 is an ongoing phase II, open-label, randomized trial of Kaletra in combination with efavirenz in NNRTI naÔve persons. They reported PK data, 48 week efficacy & safety, and association of virologic response at week 24 with baseline virologic genotype/phenotype data.

57 patients received Kaletra 400/100 mg twice daily (bid), 3 coformulated capsules, in place of their current PI in combination with EFV (600 mg once daily) with NRTIs as determined by the investigator, for the first 13 days of the study. On day 14 of study, patients randomized to Arm B (n=28) increased their Kaletra dose to 533/133 mg (4 coformulated capsules) bid, while 29 patients in Arm A remained on the 400/100 mg bid dose. ABT-378 trough levels (the lowest drug level in blood at end of dosing period: 12 hours) were drawn at week 2; full PK was performed at week 5; EFV levels were drawn at weeks 2 & 5. Plasma HIV-RNA was quantified using Roche Amplicor HIV-1 Monitor (LLQ 400 copies/ml). All patients in Arm A began conversion to 533/133  bid dose after week 24 and completed process prior to week 48.

BASELINE

About 80% men.

• In 400/100 arm, median viral load 50,000 copies/ml, CD4 218.

• In 533/133, median viral load 15,000 copies/ml; CD4 271.

75% of patients did not receive a new NRTI in conjunction with Kaletra within the first 8 weeks of study.

68% (38/56) had baseline viral isolates showing cross resistance („4 fold increase in EC50 relative to wild-type) to at least 3 licensed protease inhibitors. 43% of baseline isolates (24/56) showed „10 fold increase in EC50 of ABT-378 relative to wild-type. Baseline phenotypic resistance to ABT-378 was 9 fold in 400/100 arm and 4 fold in 533/133 arm. All patients had 9 to 37 fold baseline resistance to RTV, IDV and NFV. To APV, 2-3 fold; to SQV, 5-6 fold.

PK DATA
ABT-378 kevels achieved with 400/100 gose are reduced when co-dosed with EFV (trough reduced by about 33%; AUC reduced about 25%). 533/133 dose with EFV provides similar ABT-378 blood levels to the 400/100 dose without Kaletra based on historical controls. EFV levels are similar for both Kaletra dose levels studied.

DISCONTINUATIONS

7 patients discontinued out of 29 in the 400/100 arm, and 4 of 28 discontinued in the 533/133 arm. Abbott reported 2 stopped due to CNS symptoms, 1 due to lactic acidosis, 1 due to CNS & triglycerides. VIROLOGIC FAILURE: 3 in 400/100, 1 in 533/133.

VIRAL LOAD RESULTS (<400 copies/ml) AT WEEK 48

<50 copies/ml at week 48 was not reported.

The responses based on genotypic and phenotypic resistance at baseline at week 24 is reported in the ICAAC report, as well as week 24 <50 copies/ml data, and here is link. 

http://www.natap.org/sept2000/ICAAC/ICAAC6higher_dosing_regimen_used_of_ab_10300.htm