The nucleotide/nucleoside reverse transcriptase inhibitor backbone combination of tenofovir (Viread) plus emtricitabine (FTC; Emtriva) is the most widely prescribed combination for initial antiretroviral therapy.

It is known that 3TC (lamivudine; Epivir) -- a drug chemically similar to emtricitabine -- does not interact with nevirapine (Viramune). However, a pharmacokinetic interaction study of the combination of tenofovir/emtricitabine and nevirapine has not previously been done.

Study 1100.1424 was an open-label, investigator-initiated trial evaluating the clinical efficacy of the combination of tenofovir, emtricitabine, and nevirapine. It enrolled 54 HIV-infected patients without previous exposure to antiretroviral therapy and with a viral load > 5000 copies/mL.

Participants were excluded if they had evidence of mutations associated with primary drug resistance to nevirapine (K103N, Y181C, Y188L, G190S), tenofovir (M41L, T69 insertion, Q151M, L210W, and K65R), and/or emtricitabine (M184V) previously documented or at the time of screening.

Patients with estimated creatinine clearance of < 60 mL/min, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limits of normal, or total bilirubin > 1.5 mg/dL were also excluded, as were those with malabsorption or severe chronic diarrhea for more than 30 days or current treatment for malignancies other than skin or cervical carcinoma.

Finally, women with a CD4 cell count > 250 cells/mm³ (and men > 400 after this warning was added to the nevirapine label) were excluded due to an increased risk of hypersensitivity reactions.

The trial included a pharmacokinetic (PK) substudy to evaluate the impact of the combination of tenofovir and emtricitabine co-administration on nevirapine drug levels, as well as a viral load decay substudy assessing the early efficacy of this combination.

Pharmacokinetic Substudy

• A PK evaluation was performed in 7 volunteers to assess the impact of tenofovir and emtricitabine on nevirapine.

• PK parameters were evaluated at the end of Week 2 during the 200 mg once-daily nevirapine lead-in period and again at Week 8 following 6 weeks of 200 mg twice-daily dosing.

• Plasma samples were obtained at baseline and at 1, 3, 6, 12, and 24 hours after nevirapine dosing

• The PK assessment was repeated at Week 8 following 6 weeks of 200 mg twice-daily nevirapine dosing, using the same sampling scheme.

• PK assessed by HPLC with MS/MS detection bioanalytical method, developed and validated by PPD (Richmond, VA).

Viral Decay Substudy

• In order to better understand the kinetics of viral decay with this regimen, a secondary analysis of virological decay in response to therapy with tenofovir/emtricitabine/nevirapine was assessed in 10 patients (who did not participate in the PK substudy).

• HIV-1 RNA levels were assessed at screen, days 3, 7, and 14, in addition to the regularly scheduled visits in the parent study. 

Results

• 7 African-American male patients completed Week 2 and Week 8 PK sampling.

• Mean age was 43 years; median baseline CD4 189 cells/mm³, and median baseline HIV RNA 99500 copies/mL.

• The mean nevirapine Cmin (minimum drug concentration) at Weeks 2 and 8 was 2876 and 4971 ng/mL, respectively. 

• The range and standard deviation of the Week 8 values were 2330-8300 ng/mL and 1985 ng/mL, respectively.

• Week8:Week 2 normalized Cmin (Cmin/dose) for the group was 0.86. 

• The median reduction in HIV RNA at Week 8 from baseline was 2.69 log₁₀ copies/mL. 

• 10 different patients were enrolled in the viral decay substudy.

• 60% were women, 90% were African American, and mean baseline HIV RNA was 4.71 log₁₀ copies/mL (range 3.72-5.88).

• 8 subjects attained viral load suppression to less than 50 copies/mL (5 patients by Week 8, 3 by Week 24).

• 2 subjects discontinued prior to viral suppression. 1 due to clinical hepatitis and 1 due to treatment non-adherence. 

Discussion

• At Week 8, steady-state nevirapine Cmins were above the historical mean (~4 mcg/mL) in 5 of 7 patients and below this level in 2 patients (3.39 and 2.33 mcg/mL respectively) 

• Normalized Cmin (Cmin/dose) Week 8:Week 2 ratio for the group was 0.86, consistent with no significant drug-drug interaction 

• The viral decay of a tenofovir/emtricitabine + nevirapine regimen through Week 8 was comparable to that seen with other, non-nevirapine-based regimens

Limitations of this analysis

• Researchers were unable to definitely determine the individual impact of tenofovir or emtricitabine on nevirapine pharmacokinetics since patients were started on all 3 drugs at the same time. 

• Week 2 nevirapine PK does not completely represent steady-state levels because the full inductive effect of CYP 2B6 can take up to 4 weeks. 

Conclusion

The study authors concluded that, “Based on a comparison with historical nevirapine PK data, the combination of tenofovir and emtricitabine has no significant impact on nevirapine PK at steady state.”

They added that, “The combination of tenofovir, emtricitabine, and nevirapine provides potent antiviral activity with rapid viral decay, including in patients with a high viral load.”

Institute of Human Virology, Baltimore, MD, University of Maryland School of Medicine, Division of Infectious Diseases, Baltimore, MD, Boehringer-Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.

11/09/07

Reference
C Davis, B Gilliam, A Amoroso, and others. Lack of Pharmacokinetic (PK) Interaction of Tenofovir (TDF) and Emtricitabine (FTC) on Nevirapine (NVP). 11th European AIDS Conference (EACS). Madrid, Spain. October 24-27, 2007.