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  18th International Workshop on
Clinical Pharmacology of Antiviral Therapy
June 14-17, 2017
Chicago, Ill.C
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Dolutegravir Plus Rilpivirine Levels High Enough After Switch From NNRTI
  18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago
Mark Mascolini
Concentrations of dolutegravir and rilpivirine in a two-drug regimen proved high enough to maintain virologic control in pooled analysis of the SWORD 1 and 2 trials [1]. All dolutegravir and rilpivirine levels lay above the 90% inhibitory concentration (IC90) in an intensive substudy of patients switching from the nonnucleoside (NNRTI) efavirenz or nevirapine.
The integrase inhibitor dolutegravir depends on UGT1A1 and CYP3A4 for its metabolism, while the nonnucleoside rilpivirine depends primarily on CYP3A4. Because the nonnucleosides efavirenz and nevirapine induce both UGT1A1 and CYP3A4, they can cut concentrations of dolutegravir and rilpivirine. People switched from efavirenz or nevirapine to another regimen have detectable levels of the nonnucleoside for some time after stopping it. If persisting efavirenz or nevirapine lower levels of dolutegravir and rilpivirine, it could lead to virologic failure and emergent resistance. To explore these issues, ViiV Healthcare researchers and colleagues analyzed pharmacokinetic findings in SWORD-1 and SWORD-2.
SWORD-1 and 2 randomized adults with a viral load below 50 copies while taking a nonnucleoside, a protease inhibitor, or an integrase inhibitor to maintain their current regimen or switch to dolutegravir/rilpivirine (50/25 mg once daily) [2]. Everyone gave blood samples 4, 24, and 48 weeks after switching, while people switching from efavirenz or nevirapine gave additional samples at weeks 2 and 8.
In the overall population of 481 participants, 95% in both the dolutegravir/rilpivirine arm and the maintenance arm had a viral load below 50 copies at week 48, a result establishing the noninferiority of switching to once-daily dolutegravir/rilpivirine. At study weeks 4, 24, and 48, geometric mean dolutegravir concentrations just before dosing (C0) were 1.26 ug/mL (coefficient of variation [CV%] 78%), 1.36 ug/mL (72%), and 1.34 (72%) ug/mL. Respective geometric means (CV%) for rilpivirine C0 were 71.8 ng/mL (57%), 79.8 ng/mL (50%), and 82.9 ng/mL (53%).
In 54 participants in the nonnucleoside subset, at weeks 2, 4, 8, 24, and 48, geometric mean dolutegravir C0s (and CV%) were 0.685 ug/mL (67%), 0.919 ug/mL (71%), 1.24 ug/mL (80%), 1.31 ug/mL (89%), and 1.03 ug/mL (81%) ug/mL. Respective C0 values for rilpivirine were 53.9 ng/mL (55%), 66.8 ng/mL (47%), 69.3 ng/mL (59%), 76.2 ng/mL (49%), and 75.6 ng/mL (56%). Dolutegravir and rilpivirine C0 levels at week 4 were comparable to those of the entire SWORD study population. Dolutegravir and rilpivirine concentrations always lay above the protein-adjusted IC90 for each antiretroviral.
Median efavirenz C0 dropped from 82.6 to 7.95 ng/mL from week 2 to week 4. Over the same period, median nevirapine levels fell from 2.92 ng/mL to a nonquantifiable level.
SWORD investigators presented 48 week virologic and safety results at the 2017 CROI [2]. ViiV has submitted data for approval of a single-tablet dolutegravir/rilpivirine regimen in Europe and the United States.
CROI: SWORD 1 & 2: Switch to DTG + RPV Maintains Virologic Suppression Through 48 Weeks, a Phase III Study - (02/16/17)

1. Adkison K, Kahl L, Blair E, et al. Pharmacokinetics of dolutegravir and rilpivirine after switching to the two-drug regimen from an efavirenz- or nevirapine-based antiretroviral regimen: SWORD-1/2 pooled PK analysis. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy, June 14-17, 2017, Chicago. Abstract O_10.
2. Llibre JM, Hung CC, Brinson C, et al. Phase III SWORD 1&2: switch to DTG+RPV maintains virologic suppression through 48 wks. CROI. February 13-16, 2017, Seattle. Abstract 44LB. http://www.croiconference.org/sessions/phase-iii-sword-12-switch-dtgrpv-maintains-virologic-suppression-through-48-wks