Higher Dosing Regimen Used of ABT-378/r--

-ABT-378/r (Kaletra) + Efavirenz: 24 week study results in multiple PI Experienced -ABT-378/r & Efavirenz Interactions

This study was discussed extensively at the Resistance Workshop this Summer in June in Sitges, Spain, where the resistance aspects were discussed in detail. You can read the NATAP report on those talks by dale Kempf and Eugene Sun from Abbott on the NATAP web site (www.natap.org) in the Conference Reports Section of the Resistance Workshop. An update was reported at Durban with additional data, which can be read in the NATAP report from the Durban Conference on our web site. At ICAAC the following report was presented on this study (M98-957) by S Becker from San Francisco, CA. This report contains the updated data for percent below 50 copies/ml, while the previous reports only contained the percents below 400 copies/ml. Also at ICAAC, Rick Bertz of Abbott reported on the interactions between ABT-378/r and efavirenz and that report is included below.

This was a study for individuals with >1,000 copies/ml on a present PI regimen and a history of sequential or concurrent treatment with at least 2 protease inhibitors for at least 3 months. This study experimented with a dose higher than the standard dose of ABT-378 used and approved by the FDA. The standard dose used is 400/100 (ABT-378/RTV), but in this study Abbott experimented with a higher dose (533/133) to see if it would have more antiviral activity in reducing viral load for individuals who have extensive PI resistance. Patients were NNRTI naÔve. Patients were randomized to one of 2 arms: 400/100 mg BID ABT-378/r + EFV + NRTIs (n=29), or ABT-378/r 400/100 +EFV+NRTIs for 2 weeks and them patients dosing was raised to 533/133 by adding one extra capsule (n=28). ABT-378/r trough levels were measured at week 2, full PK at week 5, and EFV levels were measured at weeks 2 and 5.

BASELINE. The median viral load and CD4s were 4.7 log (50,000 copies/ml) and 218 in the 400/100 arm, and 4.2 log (16,000 copies/ml) and 271 in the 533/133 arm. There were 24% women in the 400/100 arm and 18% in 533/133 arm; 7% Black and 7% Hispanic in 400/100 and 11% Black and 0% Hispanic in the 533/133 arm.

EFV-ABT-378 INTERACTION. ABT-378/r levels achieved with the 400/100 dose are reduced when co-administered with EFV: Ctrough reduced about 33%, and AUC reduced about 25%. Ctrough is the lowest drug level at the end of the dosing period and AUC is the total drug amount or concentration throughout the entire dosing period. When dosed at 533/133 twice daily, ABT-378 exposures were similar to those of 400/100 twice daily without EFV. And EFV levels were the same in either arm, so ABT-378/r did not effect EFV blood levels.

Abbott recommended that dose should be increased to 533/133 bid when co-administered with EFV in patients with extensive prior PI use.

TREATMENT EXPERIENCE

PRIOR PI USE. In the 400/100 arm, the percent of patients who had used IDV was 83%, NFV 55%, RTV 90%, SQV 69%. In the 533/133 arm, the percent of patients who used IDV was 89%, NFV 61%, RTV 64%, and SQV 75%.

PRIOR NRTI USE. In the 400/100 arm, the percent of patients who had used 3TC was 93%, d4T 83%, AZT 97%, ddI 83%, ddC 45%, and abacavir 14%. In the 533/133 the percents were--3TC 89%, d4T 100%, AZT 89%, ddI 79%, ddC 46%, and abacavir 21%.

BASELINE SENSITIVITY (Phenotypic Susceptibility) TO PROTEASE INHIBITORS

68% of patients had baseline viral isolates demonstrating cross-resistance („ fold loss of susceptibility) to „3 approved protease inhibitors.

Becker reported 4/29 (14%) of patients discontinued in the 400/100 arm and 3/28 (11%) in the 533/133 arm. There were 2 discontinuations in each of tHe arms for adverse events (CNS[2], GI/CNS, lactic acidosis), and 2 for virologic failure in the 400/100 arm and 1 for virologic failure in the 533/133 arm. Both discontinuations for AE in the 533/133 arm occurred prior to day 14 and start of the switch to 533/133.

CD4 increases were about the same in both groups: 48 cells in 400/100 and 41 in 533/133.

Week 24 Virologic Response By Baseline Genotype Mutations (Baseline Mutation Score)

There is a trend towards the more mutations a person has the less likely they are to achieve undetectable. The mutations used were from a list of 11 associated with reduced susceptibility to ABT-378 from individuals with prior PI use before receiving ABT-378 (10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90).

At the Resistance Workshop there appeared to be general agreement that by the time a person had about 6-7 or 8 mutations the antiviral activity may be due solely to efavirenz.

Week 24 Virologic Response by Baseline Phenotypic Resistance (Baseline Susceptibility)

This is based on the fold change in phenotypic resistance at baseline to ABT-378 (based on the EC50 fold change relative to the wild-type). This data also suggests a trend that the more phenotypic resistance a person has to ABT-378 before using it the less likely they are to achieve undetectable.

Again, at the Resistance Workshop there appeared to be general agreement that somewhere around 40 fold the antiviral activity or reduced viral load was due solely to efavirenz.

Becker characterized these adverse events of at least moderate severity and probably, possible, or unkown relationship to ABT-378.

Abbott reported that these individuals tended to have elevated cholesterol and triglycerides before starting ABT-378. But that isn't likely to account for all the incidence or severity of lipid elevations.

PK Interaction Between ABT-378/ritonavir and Efavirenz in Healthy Volunteers and in HIV+ Persons

Ritonavir potently inhibits the CYP3A-mediated metabolism of ABT-378, and ABT-378/r is metabolized by and is both an inducer and inhibitor of CYP3A. Efavirenz is metabolized by and is an inducer of CYP3A. EFV reduces blood concentrations of several protease inhibitors: saquinavir, indinavir, and amprenavir. This study evaluates the PK interaction between ABT-378 in healthy volunteers after multiple dosing (study M97-741). And examines the steady-state PK profile of ABT-378 at 2 different dosing regimens in conjunction with EFV in HIV+ (study M98-957, multiple PI-NNRTI naive study)

In the healthy volunteer study 9 individuals received 400/100 every 12 hours, 18 individuals received 400/100 every 12 hrs + 600 mg EFV, and an additional 18 individuals received EFV 600 mg alone once per day. ABT-378 was taken with food and ABT-378/r and EFV 24 hr dosing interval PK evaluation was done on day 9.

In the HIV+ study, 29 individuals received 400/100 bid + EFV 600mg once daily +NRTIs, and 28 received 400/100 +EFV 600mg once daily + NRTIs for 14 days and then raised dose to 533/133. ANT-378/r was taken with food. ABT-378/r Ctrough was evaluated at week 2, and 12 hour dosing interval PK at week 5. EFV C12h measured at weeks 2 and 5.

Study Entry Criteria

Females had to be non-pregnant and non-lactating. Persons were excluded if positive for HIV antibody, HBV, and HCV. Persons had to be non-nicotine user and within 15% of ideal body weight. For the study in HIV+, persons had to have no avtive OI or treatment for such within 30 days.

RESULTS

46 subjects were enrolled and 18 discontinued (15 due to rash, 1 vasodilation, 1 abnormal dreams, 1 non-compliance), leaving 30 included in the PK analysis. There were 24 men and 6 women in the healthy volunteer study. In the PI experienced study, there were 41 men and 9 women. The racial breakdown was 27 white and 3 black in the healthy volunteer study. And 43 white, 5 black, and 2 hispanic in the HIV+ study.

…        No dosage adjustment of Efavirenz is necessary when taken with ABT-378/r  

…        At 400/100 bid, AUC, and Cmin of ABT-378 were reduced by about 20-25% and 40-45%, when taken with EFV in healthy volunteers and in HIV+ persons.

…        Increasing ABT-378/r by 33% to 533/133 (4 capsules: 133/33) bid during EFV co-administration produced concentrations similar to those achieved with 400/100 bid without EFV.

…        Abbott recomends: when EFV or nevirapine are used with ABT-378/r 533/133 dose (4 capsules) should be used with food in patients where reduced susceptibility to ABT-378 is clinically suspected (by treatment history or lab evidence).