Once-daily Efavirenz 600 mg Has No Clinically Relevant Effect on the Pharmacokinetics of Tipranavir or Ritonavir in Healthy Volunteers

Tipranavir (Aptivus) is an FDA-approved protease inhibitor (PI) with potent activity against multiple protease inhibitor-resistant HIV-1. To achieve effective plasma tipranavir concentrations and a twice-daily dosing regimen in treatment experienced patients, co-administration of tipranavir with 200 mg of ritonavir (tipranavir/ritonavir) is essential [1].

Previously, it has been shown that tipranavir/ritonavir does not affect efavirenz concentrations [2]. The objective of the current study, presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago (September 17-20, 2007), was to determine the effects of steady-state efavirenz on the steady-state pharmacokinetics (PK) of tipranavir co-administered with ritonavir (Norvir) [3]. The primary endpoints were AUC, Cmax and Cmin for tipranavir and ritonavir. The secondary endpoints were Tmax, T1/2, Cl/F, and Vz/F, as well as clinical laboratory tests and adverse events (AEs).

Study Design

This was an open-label study that enrolled 34 healthy male and female volunteers to investigate the effect of steady-state efavirenz (Sustiva) on the pharmacokinetics of steady-state tipranavir and ritonavir. Subject demographics are described in Table 2.

Previously it has been shown that tipranavir/ritonavir does not affect efavirenz concentrations. This study addresses whether efavirenz affects tipranavir exposure when tipraavir is co-administered with ritonavir.

This was a single center, open-label, multiple dose study in healthy males and females. Tipranavir/ritonavir 500/200 mg BID was given with food for 24 days. Starting in the evening of day 10, efavirenz 600 mg once daily was added to the regimen. PK sampling up to 12 hours after tipranavir dosing was done at days 10 and 24 of the study.

Bioanalysis was done with LC-MS/MS and non-compartmental methods were used for PK calculations. Adverse event data were collected.

PK parameters including AUC, Cmax, Tmax, Cmin, t1/2, CL/F and Vz/F were calculated with WinNonlin using non-compartmental techniques. Based on logtransformed data GMR and 90% CI were calculated and compared to the bioequivalence ranges of 0.80-1.25. Comparisons were made within subjects.

Results

• 23 subjects entered the study: 16 completed with 5 discontinuations due to adverse events, 1 for non-compliance to the protocol, and 1 withdrew consent.

• The geometric mean ratio (GMR) and 90% confidence intervals for tipranavir AUC, Cmax and Cmin comparing tipranavir/ritonavir alone and in combination with efavirenz were: 0.97 (0.87-1.09), 0.92 (0.81-1.03) and 1.19 (0.93-1.54).

• For ritonavir, the ratios were 1.03 (0.78-1.38), 0.92 (0.65-1.30)and 1.04 (0.72-1.48). At Day 24, efavirenz exposure was1.5 ± 0.63 mg/L at 22 hours after administration.

• Study medication was well tolerated.

• The most frequent observed AEs were diarrhea (79%), headache (44%), dizziness (41%), abnormal dreams (15%), and skin disorders (18%).

Safety

Safety data including biochemistry, vital signs, physical exams, and AEs were collected throughout the study. All data were captured in an electronic online case report form. All subjects treated with at least one dose of the study drugs were included in the analysis of safety (Table 4).

Discussion

Plasma efavirenz concentrations measured in this healthy volunteer population after the final dose of efavirenz confirm adequate exposure of the subjects to efavirenz.
Co-administration of steady-state efavirenz 600 mg once daily with steady-state tipranavir/ritonavir 500/200 mg twice daily had no effect on the steady-state pharmacokinetics of tipranavir or ritonavir in healthy volunteer subjects, with the notable exception of a 19.2% increase in tipranavir Cmin, which is not a clinically relevant effect.

The most frequently observed AEs were gastrointestinal disorders (88%), nervous system disorders (73%), psychiatric disorders (26%), and skin disorders (18%).

Nervous system and psychiatric disorders occurred more frequently in the second treatment phase of the study after efavirenz was added to tipranavir/ritonavir. Consistent with other tipranavir trials, an increase in liver enzymes (ALT, AST) and in cholesterol was observed, however all laboratory abnormalities returned to baseline after the study drug was discontinued.

In general, both treatment combinations tipranavir/ritonavir and tipranavir/ritonavir + efavirenz were well tolerated, with the majority of AEs being mild in intensity.

Conclusions

• Efavirenz 600 mg once daily had no effect on the steady-state PK of tipranavir or ritonavir in healthy volunteer subjects, with the exception of a 19% increase in tipranavir Cmin, which is not clinically important.

• Efavirenz exposure was comparable to historic controls.

• Efavirenz and tipranavir/ritonavir can be safely co-administered without the need for dose adjustment.

University of Ottawa at The Ottawa Hospital and the Ottawa Health Research Institute, Ottawa, ON, Canada; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA; Boehringer Ingelheim Canada Ltd., Burlington, ON, Canada.

09/25/09

Source

CJL la Porte, JP Sabo, L Béïque, and others. Lack of effect of efavirenz (EFV) 600 mg QD on the pharmacokinetics of tipranavir/ritonavir 500/200 mg BID (TPV/r) in healthy volunteers. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2007. Chicago, IL. Abstract (poster) A-1421.

References

1. TR MacGregor, JP Sabo, SH Norris, and others. Pharmacokinetic Characterization of Different Dose Combinations of Coadministered Tipranavir and Ritonavir in Healthy Volunteers. HIV Clinical Trials 5(6): 371-382. 2004.

2. PJ Roszko, K Curry, B Brazina, and others. Standard doses of efavirenz (EFV), zidovudine (ZDV), tenofovir (TDF), and didanosine (ddI) may be given with tipranavir/ritonavir (TPV/r). Antiviral Therapy 8 (Suppl.1): abstract no. 865. 2003.