Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin.
OBJECTIVE
Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein.


METHODS
Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.125 mg once daily to day 11. On day 7, a single oral 400-mg dose of valspodar was given, followed by a regimen of 200 mg twice daily from days 8 to 11. Serial blood samples and urine collections were obtained on days 6, 7, and 11 for digoxin pharmacokinetics and on days 7 and 11 for valspodar pharmacokinetics. On these days, blood pressure, pulse rate, and electrocardiograms were recorded at multiple time points.


RESULTS
Coadministration of single-dose valspodar with steady-state digoxin on day 7 yielded an average 76% increase in digoxin AUC and a 62% decrease in digoxin renal clearance (both P = .0001). After a 5-day coadministration period, digoxin AUC increased by an average 211% and apparent total body clearance was decreased by 67% (day 11) compared with steady-state administration of digoxin alone (day 6). Contributing to the change in total body clearance were decreases in both renal clearance (73%) and apparent nonrenal clearance (58%). Both drugs were well tolerated throughout the study. There was no clinically relevant change in the effect of digoxin on vital signs or electrocardiographic parameters when administered with single- or multiple-dose valspodar compared with administration alone in volunteers with healthy cardiovascular systems.


CONCLUSIONS
Coadministration of oral valspodar and oral digoxin resulted in a twofold to threefold increase in digoxin systemic exposure. On the basis of these data in healthy volunteers, an initial digoxin dose reduction of 50% would appear to be appropriate when beginning oral valspodar treatment. Throughout the period of coadministration, patients should be carefully monitored for clinical signs of digoxin toxicity in conjunction with digoxin therapeutic drug monitoring. Together, these should serve as the basis for individualized digoxin dose titration.
Kovarik
J M
JM
Novartis Pharma AG, Basel, Switzerland.
Rigaudy
L
L
Guerret
M
M
Gerbeau
C
C
Rost
K L
KL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004077:Digoxin / Q000008:administration & dosage / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D012016:Reference Values
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D003524:Cyclosporins; D004077:Digoxin; C070272:valspodar