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.

Abstract

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.

• Authors: Charles S Venuto, Yoninah S Cramer, Susan L Rosenkranz, Mark Sulkowski, David L Wyles, Daniel E Cohen, Jeffrey Schmidt, Beverly L Alston-Smith, Gene D Morse
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 86 Issue 1 Pg. 132-142 (01 2020) ISSN: 1365-2125 [Electronic] England
• PMID: 31656054 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2019 The British Pharmacological Society.

Chemical References

• Anilides
• Antiviral Agents
• Cyclopropanes
• Lactams, Macrocyclic
• Macrocyclic Compounds
• Sulfonamides
• ombitasvir
• Raltegravir Potassium
• Uracil
• Proline
• 2-Naphthylamine
• dasabuvir
• Valine
• Ritonavir
• paritaprevir

Topics

• 2-Naphthylamine
• Acquired Immunodeficiency Syndrome (drug therapy)
• Adult
• Anilides
• Antiviral Agents (therapeutic use)
• Coinfection (drug therapy)
• Cyclopropanes
• Drug Therapy, Combination
• HIV-1
• Hepacivirus
• Hepatitis C (complications, drug therapy)
• Hepatitis C, Chronic (drug therapy)
• Humans
• Lactams, Macrocyclic
• Macrocyclic Compounds (therapeutic use)
• Proline (analogs & derivatives)
• Raltegravir Potassium (therapeutic use)
• Ritonavir
• Sulfonamides
• Uracil (analogs & derivatives)
• Valine