Reduction of saquinavir exposure by coadministration of loperamide: a two-way pharmacokinetic interaction.
OBJECTIVE
To assess any pharmacokinetic interactions between loperamide and saquinavir.


METHODS
Double-blind, double-dummy, randomised, placebo-controlled, three-way crossover trial.


METHODS
Twelve healthy male and female volunteers, aged 24-46 years.


METHODS
Saquinavir and loperamide pharmacokinetics were determined over a 72-hour period after single dose administration of saquinavir 600mg and/or loperamide 16mg. Plasma and urine concentrations of loperamide, its metabolites, and saquinavir were analysed using a single liquid chromatography/tandem mass spectrometry method for all compounds.


RESULTS
Saquinavir exposure was reduced by 54% when given with loperamide (median area under the concentration-time curve from zero to infinity [range], 1189 [243-2113] vs 550 [234-1468] pmol . h/mL; p = 0.016) with unchanged renal clearance. In contrast, loperamide concentrations increased and desmethylloperamide concentrations decreased during saquinavir coadministration, resulting in a reduced metabolic clearance of loperamide (median [range], 544 [224-1393] vs 443 [238-692] mL/min; p = 0.016).


CONCLUSIONS
Whereas the effect of saquinavir on loperamide disposition is unlikely to be of clinical relevance, the reduced drug exposure of saquinavir when loperamide is coadministered is worrisome because a relationship between protease inhibitor drug exposure and antiviral response has been reported. Patients receiving saquinavir monotherapy should be advised not to combine these drugs, especially for prolonged periods of time because a reduction in therapeutic efficacy may result.
Mikus
Gerd
G
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. gerd_mikus@med.uni-heidelberg.de
Schmidt
Laila
L
Burhenne
Jürgen
J
Ding
Reinhard
R
Riedel
Klaus-Dieter
KD
Tayrouz
Yorki
Y
Weiss
Johanna
J
Haefeli
Walter Emil
WE
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008139:Loperamide / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019258:Saquinavir / Q000494:pharmacology*
D008139:Loperamide; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D019258:Saquinavir