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Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion.

Publication ,  Journal Article
Kirby, BJ; Collier, AC; Kharasch, ED; Whittington, D; Thummel, KE; Unadkat, JD
Published in: Drug Metab Dispos
March 2012

As part of a larger clinical drug-drug interaction (DDI) study aimed at in vitro to in vivo prediction of HIV protease inhibitor metabolic and transporter-based DDIs, we measured the inductive (staggered administration) and inductive plus inhibitory (simultaneously administered) effect of multiple dose ritonavir (RTV), nelfinavir (NFV), or rifampin (RIF) on the pharmacokinetics of the P-glycoprotein probe, digoxin (DIG), when administered simultaneously or staggered with the protease inhibitors or RIF. In both cases, NFV did not significantly affect DIG disposition. RTV decreased DIG renal clearance (Cl(renal)) when administered simultaneously or staggered but significantly increased DIG area under the curve from time zero to 24 h (AUC(0-24 h)) only when administered simultaneously. RIF decreased DIG AUC(0-24 h) only when RIF and DIG administration was staggered. When RIF and DIG were administered simultaneously, DIG maximal observed plasma concentration and area under the curve from time zero to 4 h were significantly increased, and DIG Cl(renal) was decreased. An unexpected and potentially clinically significant DDI was observed between DIG and the CYP2B6 probe, bupropion, which decreased DIG AUC(0-24 h) 1.6-fold and increased Cl(renal) 1.8-fold. Because this was an unexpected DDI and our studies were not specifically designed to quantify this interaction, further studies are required to confirm the interaction and understand the mechanistic basis of the DDI. In summary, RTV or NFV do not induce P-glycoprotein activity measured with DIG, and RIF does so only under staggered administration.

Duke Scholars

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

March 2012

Volume

40

Issue

3

Start / End Page

610 / 616

Location

United States

Related Subject Headings

  • Ritonavir
  • Rifampin
  • Pharmacology & Pharmacy
  • Nelfinavir
  • Male
  • Humans
  • HIV Protease Inhibitors
  • Female
  • Drug Interactions
  • Drug Administration Schedule
 

Citation

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Kirby, B. J., Collier, A. C., Kharasch, E. D., Whittington, D., Thummel, K. E., & Unadkat, J. D. (2012). Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab Dispos, 40(3), 610–616. https://doi.org/10.1124/dmd.111.042705
Kirby, Brian J., Ann C. Collier, Evan D. Kharasch, Dale Whittington, Kenneth E. Thummel, and Jashvant D. Unadkat. “Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion.Drug Metab Dispos 40, no. 3 (March 2012): 610–16. https://doi.org/10.1124/dmd.111.042705.
Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab Dispos. 2012 Mar;40(3):610–6.
Kirby, Brian J., et al. “Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion.Drug Metab Dispos, vol. 40, no. 3, Mar. 2012, pp. 610–16. Pubmed, doi:10.1124/dmd.111.042705.
Kirby BJ, Collier AC, Kharasch ED, Whittington D, Thummel KE, Unadkat JD. Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion. Drug Metab Dispos. 2012 Mar;40(3):610–616.
Journal cover image

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

March 2012

Volume

40

Issue

3

Start / End Page

610 / 616

Location

United States

Related Subject Headings

  • Ritonavir
  • Rifampin
  • Pharmacology & Pharmacy
  • Nelfinavir
  • Male
  • Humans
  • HIV Protease Inhibitors
  • Female
  • Drug Interactions
  • Drug Administration Schedule