Abstract
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 (Clrenal) when administered simultaneously or staggered but significantly increased DIG area under the curve from time zero to 24 h (AUC0–24 h) only when administered simultaneously. RIF decreased DIG AUC0–24 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 Clrenal was decreased. An unexpected and potentially clinically significant DDI was observed between DIG and the CYP2B6 probe, bupropion, which decreased DIG AUC0–24 h 1.6-fold and increased Clrenal 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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM032165]; the National Institutes of Health National Institute on Drug Abuse [Grants K24-DA00417, R01-DA14211]; and the National Institutes of Health National Center for Research Resources [Grant M01-RR00037]. A portion of this work was conducted through the Clinical Research Center Facility at the University of Washington. B.J.K. was supported in part by an ARCS fellowship, a National Institutes of Health National Institute of General Medical Sciences Pharmacological Sciences training grant [Grant GM07550], and a Simcyp-sponsored fellowship.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- PI
- protease inhibitor
- DDI
- drug-drug interaction
- P450
- cytochrome P450
- P-gp
- P-glycoprotein
- RTV
- ritonavir
- RIF
- rifampin
- NFV
- nelfinavir
- DIG
- digoxin
- BUP
- bupropion
- Cmax
- maximal observed plasma concentration
- Tmax
- time of maximal observed plasma concentration
- Clrenal
- renal clearance
- OATP
- organic anion-transporting polypeptide
- AUC0-t
- area under the plasma concentration-time curve
- AUC0–24 h
- area under the curve from time zero to 24 h
- AUC0–4 h
- area under the curve from time zero to 4 h
- AUC0–3 h
- area under the curve from time zero to 3 h
- AUC0–72 h
- area under the curve from time zero to 72 h
- AUC
- area under the plasma concentration-time curve
- BUP/Met
- bupropion and/or its metabolites.
- Received September 10, 2011.
- Accepted December 5, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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