Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus‐1 and hepatitis C virus coinfection: AIDS Clinical Trials Group sub‐study A5334s

• Published in: British journal of clinical pharmacology Vol. 86; no. 1; pp. 132 - 142
• Main Authors: Venuto, Charles S., Cramer, Yoninah S., Rosenkranz, Susan L., Sulkowski, Mark, Wyles, David L., Cohen, Daniel E., Schmidt, Jeffrey, Alston‐Smith, Beverly L., Morse, Gene D.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.01.2020
• Subjects: 2-Naphthylamine; Acquired Immunodeficiency Syndrome - drug therapy; Adult; Anilides; antiretrovirals; Antiviral Agents - therapeutic use; Coinfection - drug therapy; Cyclopropanes; drug interactions; Drug Therapy, Combination; Hepacivirus; hepatitis; Hepatitis C - complications; Hepatitis C - drug therapy; Hepatitis C, Chronic - drug therapy; HIV-1; HIV/AIDS; Humans; Lactams, Macrocyclic; Macrocyclic Compounds - therapeutic use; Original; pharmacokinetics; Proline - analogs & derivatives; Raltegravir Potassium - therapeutic use; Ritonavir; Sulfonamides; Uracil - analogs & derivatives; Valine; HIV/AIDS; pharmacokinetics; drug interactions; antiretrovirals; hepatitis
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.14148

Aims AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight‐based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized. Methods Adults living with HIV/HCV coinfection receiving steady‐state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV. Results Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration–time curve of raltegravir with vs without HCV therapy were 0.68 (0.38–1.19) and 0.82 (0.58–1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration–time curve values by 41–82% and 4–73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV. Conclusions The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.