Reduction of saquinavir exposure by coadministration of loperamide: a two-way pharmacokinetic interaction.

Objective: To assess any pharmacokinetic interactions between loperamide and saquinavir.

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

Participants: 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.