Previous studies have shown a decrease in EFV concentration attributed to CYP3A4 and CYP2B6 induction by Rifapentine. One larger, longer, and newer study has shown instead a slight increase in concentration of EFV in the presence of RPT. Still these studies concluded that HIV viral suppression was maintained. Hence, concomitant use of these drugs should still be effective.
Efavirenz pharmacokinetics and pharmacodynamics in HIV-infected persons receiving rifapentine and isoniazid for tuberculosis prevention.
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Study Design
Open-label study in 12 HIV-positive, TB-negative subjects with CD4 > 350 cells/mm3 and unquantifiable viral load who were receving ATRIPLA (fixed dose combination of efavirenz [EFV] 600 mg, emtricitabine [FTC] 200 mg, and tenofovir disoproxil fumarate [TDF] 300 mg). Rifapentine (RPT) was administered at 900 mg once weekly for 3 doses. Blood samples were collected over 24 hours before RPT administration, following the 1st RPT dose and 38 hours after the 3rd RPT dose.
Study Results
Modest decreases in EFV Cmin and AUC0-24 were seen with repeated RPT dosing. Geometric mean ratios and 90%CI (with/without repeated RPT doses) for the PK parameters were Cmax: 0.92 (0.82-1.03), Cmin: 0.85 (0.79-0.93) and AUC0-24: 0.86 (0.79-0.93). Co-administration of ATRIPLA with RPT was well-tolerated and no clinically significant changes in CD4 counts or viral loads were observed.
Study Conclusions
This study suggests that EFV exposure was not significantly affected by RPT co-administration.
However, the DHHS guidelines currently states that RPT is expected to decrease EFV concentrations as it is a CYP3A4 and CYP2B6 inducer, and co-administration is not recommended.
References
Podany AT, Bao Y, Swindells S, Chaisson RE, Anderson JW, Mwelase T, Kim P. Efavirenz pharmacokinetics and pharmacodynamics in hiv-infected persons receiving rifapentine and isoniazid for tuberculosis prevention. Clinical Infectious Diseases. 2015; 8: 1322-1327.
Efavirenz versus Rifapentine
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Study Design
This substudy included participants already suppressed on at least two months of efavirenz (EFV)-containing (600mg) ART, and randomized to one of two regimens containing daily Rifapentine (RPT1200mg), isoniazid (H), pyrazinamide, and either ethambutol or moxifloxacin. Mid interval EFV concentrations were measured in plasma samples collected at weeks 0 (pre-RPT/H), 4, and 8 during concomitant RPT/H. EFV apparent oral clearance (CL/F) was modeled using Bayesian estimation. Week 4 and 8 EFV concentrations were combined to estimate EFV CL/F during RPT/H therapy.
Study Results
All participants had HIV-1 RNA <200 copies/mL at randomization, 16/16 (100%) had HIV-1 RNA <200 copies/mL at week 8; the median baseline CD4+ count was 401 cells/mm3 (118-998). The GMR for EFV CL/F was 0.88 (0.75-0.96). The number of participants with EFV concentrations ≥ 1 mg/L at both week 4 and 8, was 21 (91%). Median (IQR) RPT concentrations were 14.7 mg/L (12.2-19.25 mg/L). Baseline IQR EFV concentration was 2.54 mg/L (1.81-3.96 mg/L) while at week 8 on RPT therapy, EFV concentration was 2.63 (2.09-7.23).
Study Conclusions
The CL/F of EFV decreased slightly with RPT/H. However, the proportion of participants with EFV concentrations ≥1mg/L did not cross below the pre-specified threshold of 80%. Plasma HIV-RNA levels during RPT/H indicated maintenance of viral suppression. These data provide preliminary support for co-administration of high-dose RPT/H with EFV-containing ART.
References
Podany, A, Sizemore, E, Chen, M. Efavirenz pharmacokinetics in hiv/tb coinfected persons receiving rifapentine. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
Efavirenz versus Rifapentine
^
Study Design
This substudy included participants already suppressed on at least two months of efavirenz (EFV)-containing (600mg) ART, and randomized to one of two regimens containing daily Rifapentine (RPT1200mg), isoniazid (H), pyrazinamide, and either ethambutol or moxifloxacin. Mid interval EFV concentrations were measured in plasma samples collected at weeks 0 (pre-RPT/H), 4, and 8 during concomitant RPT/H. EFV apparent oral clearance (CL/F) was modeled using Bayesian estimation. Week 4 and 8 EFV concentrations were combined to estimate EFV CL/F during RPT/H therapy.
Study Results
All participants had HIV-1 RNA <200 copies/mL at randomization, 16/16 (100%) had HIV-1 RNA <200 copies/mL at week 8; the median baseline CD4+ count was 401 cells/mm3 (118-998). The GMR for EFV CL/F was 0.88 (0.75-0.96). The number of participants with EFV concentrations ≥ 1 mg/L at both week 4 and 8, was 21 (91%). Median (IQR) RPT concentrations were 14.7 mg/L (12.2-19.25 mg/L). Baseline IQR EFV concentration was 2.54 mg/L (1.81-3.96 mg/L) while at week 8 on RPT therapy, EFV concentration was 2.63 (2.09-7.23).
Study Conclusions
The CL/F of EFV decreased slightly with RPT/H. However, the proportion of participants with EFV concentrations ≥1mg/L did not cross below the pre-specified threshold of 80%. Plasma HIV-RNA levels during RPT/H indicated maintenance of viral suppression. These data provide preliminary support for co-administration of high-dose RPT/H with EFV-containing ART.
References
Podany, A, Sizemore, E, Chen, M. Efavirenz pharmacokinetics in hiv/tb coinfected persons receiving rifapentine. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
Efavirenz pharmacokinetics and pharmacodynamics in HIV-infected persons receiving rifapentine and isoniazid for tuberculosis prevention.
^
Study Design
Open-label study in 12 HIV-positive, TB-negative subjects with CD4 > 350 cells/mm3 and unquantifiable viral load who were receving ATRIPLA (fixed dose combination of efavirenz [EFV] 600 mg, emtricitabine [FTC] 200 mg, and tenofovir disoproxil fumarate [TDF] 300 mg). Rifapentine (RPT) was administered at 900 mg once weekly for 3 doses. Blood samples were collected over 24 hours before RPT administration, following the 1st RPT dose and 38 hours after the 3rd RPT dose.
Study Results
Modest decreases in EFV Cmin and AUC0-24 were seen with repeated RPT dosing. Geometric mean ratios and 90%CI (with/without repeated RPT doses) for the PK parameters were Cmax: 0.92 (0.82-1.03), Cmin: 0.85 (0.79-0.93) and AUC0-24: 0.86 (0.79-0.93). Co-administration of ATRIPLA with RPT was well-tolerated and no clinically significant changes in CD4 counts or viral loads were observed.
Study Conclusions
This study suggests that EFV exposure was not significantly affected by RPT co-administration.
However, the DHHS guidelines currently states that RPT is expected to decrease EFV concentrations as it is a CYP3A4 and CYP2B6 inducer, and co-administration is not recommended.
References
Podany, A, Sizemore, E, Chen, M. Efavirenz pharmacokinetics in hiv/tb coinfected persons receiving rifapentine. Conference On Retroviruses And Opportunistic Infections. Boston. 2018; March 2018.
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