title: Lack of pharmacokinetic interaction between rilpivirine and integrase inhibitors dolutegravir and GSK1265744.
abstract: Dolutegravir (DTG) and GSK1265744 are HIV integrase inhibitors (INIs) in clinical development. The oral formulation of rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor (NNRTI), has been approved for treatment-naive HIV infection. Long-acting depot injections of GSK1265744 and RPV are also being developed. This study evaluated the potential for drug interactions between RPV and these INIs. This phase 1, open-label, two-cohort, three-period, single-sequence crossover study evaluated oral coadministration of RPV with DTG or GSK1265744. Healthy subjects received DTG (50 mg every 24 h for 5 days) or GSK1265744 (30 mg every 24 h for 12 days) in period 1 followed by a washout, RPV (25 mg every 24 h for 11 or 12 days) in period 2, immediately followed by RPV (25 mg every 24 h) plus DTG (50 mg every 24 h) for 5 days or GSK1265744 (30 mg every 24 h) for 12 days in period 3. Steady-state pharmacokinetic (PK) parameters were estimated using noncompartmental analysis of data collected on the last day of each period. The combinations of RPV and DTG (n = 16) and of RPV and GSK1265744 (n = 11) were well tolerated; no grade 3 or 4 adverse events (AEs) or AE-related discontinuations were observed. The 90% confidence intervals for the area under the curve from time zero until the end of the dosage interval [AUC0-τ] and maximum concentration of drug in serum (Cmax) geometric mean ratios were within 0.8 to 1.25. Following administration of DTG + RPV, DTG and RPV Cτ increased by 22% and 21%, respectively. Following administration of GSK1265744 + RPV, RPV Cτ decreased 8%. DTG and GSK1265744 can be administered with RPV without dosage adjustment for either agent. These results support coadministration of RPV with DTG or GSK1265744 as either oral or long-acting depot injection regimens. (This study has been registered at ClinicalTrials.gov under registration no. NCT01467531.).
authors: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors: Susan L
authors: SL
authors: Ford
authors: Elizabeth
authors: E
authors: Gould
authors: Shuguang
authors: S
authors: Chen
authors: David
authors: D
authors: Margolis
authors: William
authors: W
authors: Spreen
authors: Herta
authors: H
authors: Crauwels
authors: Stephen
authors: S
authors: Piscitelli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D019428:HIV Integrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006575:Heterocyclic Compounds, 3-Ring / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics*; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000068696:Rilpivirine; D000099226:Dolutegravir; D054659:Diketopiperazines
chemical_list: D004338:Drug Combinations; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D009570:Nitriles; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine; D000099226:Dolutegravir; C584914:cabotegravir; D054659:Diketopiperazines
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