Double NNRTIs: Nevirapine+Efavirenz
Opinions have been mixed about whether combining 2 NNRTIs can provide additive antiviral actvity. Several researchers have said they don't feel 2 NNRTIs can bind at the same time. However, that's been offered about protease inhibitors as well. If 2 NNRTIS can provide additive activity it might provide a cornerstone for a regimen for individuals with broad PI cross-resistance.
DONUT Study: The Pharmacokinetics (PK) of Once Daily Nevirapine (NVP) and Efavirenz (EFV) When Used in Combination.
To date, no data are available on the PK of the combined use of NNRTIs. Since NVP and EFV can induce and/or inhibit CYP450 iso-enzymes, a PK interaction cannot be ruled out. Veldkamp, Hoetelmans, Lange and others reported on this study which was conducted to investigate the PK of NVP and EFV when administered in combination.
HIV-1-infected individuals who already used EFV (600 mg qd) for at least two weeks were included. The PK of EFV were determined during 24 hours at baseline. Subsequently, NVP was added to the regimen: the first 2 weeks at 200 mg qd, followed by 400 mg qd. The PK of EFV and NVP were assessed on day 29. The following PK parameters were determined: area under the plasma concentration versus time curve (AUC 0-24h), maximum (C-max}), and minimum (C-min} plasma concentrations. The PK of NVP were compared with historical controls. Differences in EFV PK with and without NVP were analysed using the Wilcoxon matched pairs signed ranks test.
14 patients (of a total of 19 patients to be enrolled) were analysed thus far. Plasma HIV-1 RNA was below 400 copies/mL in 10/12 patients. No changes in HIV-1 RNA were observed during the study.
Median steady state EFV PK parameters on day 1 and day 29:
| Parameter | EFV without NVP(n=14) | EFV with NVP(n=14) | p-value |
| AUC(0-24) | 54.8(33.3-66.6) | 38.80(23.9-54.3) | 0.001 |
| Cmax(mg/L) | 3.63(2.61-5.37) | 3.36(1.93-4.24) | 0.048 |
| Cmin(mg/L) | 1.55(0.93-2.04) | 0.96(0.51-1.40) | 0.001 |
| Tmax(h) | 2.00(1.5-3.0) | 2.20(1.5-2.5) | 0.840 |
| T-1/2(h) | 35.80(18.1-50.6) | 18.90(14.8-34.0) | 0.060 |
| Cl/F(L/h) | 11.10(9.1-18.1) | 15.70(11.1-36.2) | 0.001 |
| V/F | 506.60(307.5-851.7) | 416.80(334.9-929.7) | 0.880 |
Median steady state NVP PK parameters on days 1 and 29:
| Parameter | NVP with EFV (n=14) | NVP without EFV (n=5) | p=value |
| AUC | 112.10(93.6-166.2) | 101.80(92.6-145.3) | 0.620 |
| Cmax | 6.19(5.12-8.79) | 6.69(5.95-8.64) | 0.510 |
| Cmin | 3.66(2.86-5.51) | 2.88(2.23-4.09) | 0.250 |
| Tmax | 2.00(1.5-3.4) | 1.50(1.0-2.4) | 0.380 |
| T-1/2 | 27.00(16.4-35.2) | 21.50(15.0-32.8) | 0.340 |
| Cl/F | 3.60(2.4-4.3) | 3.90(2.8-4.3) | 0.610 |
| V/F | 143.80(117.9-199.4) | 116.50(88.5-161.8) | 0.070 |
Authors concluded NVP PK are not affected by the coadministration of EFV. The exposure to EFV, however, is significantly decreased by approximately 22% (measured as AUC), and 36% (measured as C-min) when combined with NVP. It may be appropriate to increase the dose of EFV to 800 mg qd. Possibly, increasing EFV to 900 mg may be more appropriate. What about individuals whose AUC or Cmin is affected differently than the median PK effects seen above?