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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBritish Journal of Clinical Pharmacology
DOIs
StateAccepted/In press - Jan 1 2019

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Ritonavir
Coinfection
Hepacivirus
HIV-1
Acquired Immunodeficiency Syndrome
Pharmacokinetics
Clinical Trials
HIV
Confidence Intervals
Area Under Curve
Therapeutics
ABT-267
ABT-450
Raltegravir Potassium
ABT-333
Ribavirin
Weights and Measures

Keywords

  • antiretrovirals
  • drug interactions
  • hepatitis
  • HIV/AIDS
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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. / 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.

In: British Journal of Clinical Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

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title = "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.",
keywords = "antiretrovirals, drug interactions, hepatitis, HIV/AIDS, pharmacokinetics",
author = "Venuto, {Charles S.} and Cramer, {Yoninah S.} and Rosenkranz, {Susan L.} and Mark Sulkowski and Wyles, {David L.} and Cohen, {Daniel E.} and Jeffrey Schmidt and Alston-Smith, {Beverly L.} and Morse, {Gene D.}",
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T1 - Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus-1 and hepatitis C virus coinfection

T2 - AIDS Clinical Trials Group sub-study A5334s

AU - Venuto, Charles S.

AU - Cramer, Yoninah S.

AU - Rosenkranz, Susan L.

AU - Sulkowski, Mark

AU - Wyles, David L.

AU - Cohen, Daniel E.

AU - Schmidt, Jeffrey

AU - Alston-Smith, Beverly L.

AU - Morse, Gene D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - HIV/AIDS

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