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Predose concentrations of DTG and RPV
steady through 100 weeks in SWORD trials
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20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands
Mark Mascolini
Average predose concentrations (C0avg) of coadministered dolutegravir (DTG) and rilpivirine (RPV) held steady through 100 weeks in the phase 3 SWORD-1 and SWORD-2 trials [1]. DTG or RPV C0avg did not predict virologic response or safety, and age did not affect concentrations of either drug.
More than 35 countries have licensed the once-daily, single-pill, two-drug combination DTG/RPV (50/25 mg daily) to replace an ongoing suppressive regimen in people with HIV. Two phase 3 trials, SWORD-1 and SWORD-2, established the virologic noninferiority of DTG/RPV to continued suppressive therapy through 48 weeks [2]. This analysis pooled data from the two SWORD trials to explore DTG and RPV pharmacokinetics and to see whether levels of the two antiretrovirals differed by age or affected virologic efficacy or safety.
The SWORD trials randomized 1028 people to continue their suppressive antiretroviral regimen or to switch to DTG/RPV (early-switch group). Participants who maintained an undetectable viral load with their initial regimen could switch to DTG/RPV at week 48 (late-switch group). The analysis focused on DTG and RPV C0 throughout the study and C0avg at week 100 in the early-switch and late-switch groups, in a subset switching to DTG/RPV from the drug-metabolizing enzyme inducers efavirenz or nevirapine (NNRTI subset), and in people younger than 50 versus 50 or older.
DTG and RPV C0 remained relatively steady through week 100 in both the early-switch and late-switch groups and in the NNRTI subset. C0avg did not differ between older and younger participants in a clinically meaningful way throughout follow-up. RPV C0avg was modestly lower in people under 50 versus older in the early-switch group (79.1 versus 92.9 ng/mL) and in the late-switch group (77.9 versus 88.0 ng/mL).
Only 3% of the early-switch group and 2% of the late-switch group had virologic failure in a week-100 snapshot analysis. DTG or RPV C0avg did not predict virologic failure in either the early-switch group or the late-switch group. The researchers saw no clinically meaningful associations between log-transformed DTG or RPV C0avg and change from baseline to week 100 lab values, including creatinine, glomerular filtration rate, urine albumin/creatinine ratio, alanine aminotransferase, bilirubin, and low- or high-density lipoprotein cholesterol.
Logistic regression analysis discerned no link between log-transformed DTG or RPV C0avg for four of the five most common adverse events--diarrhea, headache, upper respiratory tract infection, and viral upper respiratory tract infection. There was an association between RPV C0avg and back pain in the late-switch group, but the researchers did not rate that finding as clinically meaningful because C0avg did not predict back pain in the early-switch group and back pain has never been tied to RPV use.
GlaxoSmithKline researchers concluded that DTG and RPV C0avg in the SWORD trials proved comparable to predose concentrations seen in previous studies and lay above their protein-adjusted 90% inhibitory concentration in the overall study group and the NNRTI subset.
References
1. Lagishetty C, Mehta R, Angelis K, et al. Pharmacokinetic and pharmacokinetic/pharmacodynamic characterization of the two-drug antiretroviral regimen dolutegravir/rilpivirine following switch from current anti-retroviral therapy in the SWORD-1 and SWORD-2 phase 3 studies. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 29.
2. Llibre JM, Hung C, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomized, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391:839-849.
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