Effect of voriconazole on the pharmacokinetics of reduced doses of sirolimus

Abstract number: P1251

Damle B., Fang A., LaBadie R., Jen F., Swanson R., Glue P., Antin J.H.

Objectives: Sirolimus (SIR) is metabolised by CYP3A4/5, while voriconazole (VORI) inhibits CYP3A4-mediated drug clearance. Systemic exposure of SIR (with standard 2 mg dose) is significantly increased by VORI coadministration. Hence, concomitant use of VORI and SIR is contraindicated. Our aim was to determine SIR dose adjustments, when coadministered with VORI, which result in exposures similar to monotherapy.

Methods: This was an open-label, nonrandomised, parallel-group, multiple-dose, fixed-sequence, 2-period study in 30 healthy males. The effect of steady state oral VORI on the multiple-dose pharmacokinetics (PK) of 3 reduced doses of SIR (oral solution; 0.25, 0.15 and 0.10 mg/d; n = 30/group) was investigated relative to the standard dose alone in the same subjects. Serial blood samples were collected at predose and over a 24-h interval on the final day of each study period; SIR and VORI concentrations were determined by LC/MS/MS. PK were determined by noncompartmental methods. A modelling approach was used to estimate the effect of staggered VORI dosing on steady state SIR levels.

Results: The changes in PK parameters when reduced doses of SIR were coadministered with VORI are shown in the table.

A decrease in SIR AUC24 of 16% (90% CI: 8%-24%), relative to standard-dose SIR was observed for 0.10 mg SIR with concomitant VORI, resulting in suboptimal exposure to SIR. Conversely, AUC24 was increased by 23% (90% CI: 11%-36%) and 36% (90% CI: 21%-54%) with SIR doses of 0.15 and 0.25 mg, respectively, resulting in slightly higher exposure to SIR than with standard-dose monotherapy. Across all 3 study groups, SIR C_max values were lower by 19%-59%, Cmin values were higher by 9%-64% and t½ values were higher by 70%-77% compared with standard-dose monotherapy. SIR had no effects on VORI PK. Modelling indicated that staggering dosing of VORI and SIR is likely to decrease the magnitude of interaction.

Conclusion: It is possible to coadminister reduced doses of SIR with VORI to achieve systemic exposures similar to standard-dose SIR monotherapy. While not specifically tested in this study, our results suggest that a 90% reduction in SIR dose would maintain SIR therapeutic levels when coadministered with VORI. Our results are applicable only when both drugs are administered simultaneously orally. Further studies assessing the PK, safety and efficacy of coadministration of reduced SIR doses and VORI in transplant patients are necessary.