Lack of meaningful effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: Model prediction and clinical confirmation

Abstract

Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC(0- ∞)) of between 1.13- and 1.25-fold in the presence of therapeutic concentrations of ridaforolimus. The pharmacokinetic interaction between multiple oral doses of ridaforolimus and a single oral dose of midazolam was evaluated in an open-label, fixed-sequence study, in which cancer patients received a single oral dose of 2 mg midazolam followed by 5 consecutive daily single oral doses of 40 mg ridaforolimus with a single dose of 2 mg midazolam with the fifth ridaforolimus dose. Changes in midazolam exposure were minimal [geometric mean ratios and 90% confidence intervals: 1.23 (1.07, 1.40) for AUC(0-∞) and 0.92 (0.82, 1.03) for maximum concentrations (C(max)), respectively]. Consistent with model predictions, ridaforolimus had no clinically important effect on midazolam pharmacokinetics and is not anticipated to be a perpetrator of drug-drug interactions (DDIs) when coadministered with CYP3A substrates. Model-based approaches can provide reasonable estimates of DDI liability, potentially obviating the need to conduct dedicated DDI studies especially in challenging populations like cancer patients.

In vitro and clinical investigations to determine the drug-drug interaction potential of entrectinib, a small molecule inhibitor of neurotrophic tyrosine receptor kinase (NTRK)

“…Given the potential for entrectinib to inhibit and/or induce CYP3A4, a clinical study was conducted to determine the effect of entrectinib on midazolam, which is a sensitive index CYP3A4 substrate recommended for such assessments [ 11 ]. Baseline (Day 1) midazolam and 1’-hydroxymidazolam plasma concentrations and PK parameters were generally consistent with literature reports [ 12 , 13 ]. Coadministration of midazolam with a single dose of entrectinib did not have a significant effect on midazolam total exposure (AUC inf ) although peak plasma concentrations were reduced by approximately 35%.…”

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors

“…This study shares similar methodology with other cancer studies examining the impact of study drugs on midazolam pharmacokinetics. The effects of ridaforolimus, an mTOR inhibitor that exhibits anticancer activity, on midazolam activity were tested in an open-label, fixed-sequence study in 16 cancer patients [30]. Ridaforolimus was determined to have a minimal inhibitory impact on CYP3A, with no clinically significant implications [30].…”

“…The effects of ridaforolimus, an mTOR inhibitor that exhibits anticancer activity, on midazolam activity were tested in an open-label, fixed-sequence study in 16 cancer patients [30]. Ridaforolimus was determined to have a minimal inhibitory impact on CYP3A, with no clinically significant implications [30]. Carfilzomib is an irreversible proteasome inhibitor that has demonstrated antitumor activity and its pharmacokinetic profile on midazolam was assessed in 18 patients with solid tumors, using a before/ after study design over a 28-day cycle.…”

A Phase 1 Drug‐Drug Interaction Study Between Brigatinib and the CYP3A Substrate Midazolam in Patients With ALK‐Positive or ROS1‐Positive Solid Tumors

“…The sample size calculation was based on the expected 2‐sided 90%CI for the difference in the paired, log‐transformed AUC ∞ means of midazolam in the absence and in the presence of brigatinib. The within‐patient percentage coefficient of variation (%CV) for midazolam AUC ∞ was estimated to be 28% based on a pooled analysis of data from 5 previously reported DDI studies with midazolam conducted in patients with cancer 18–22 . Assuming that the AUC ∞ ratio for midazolam in the presence versus absence of brigatinib was 1, with a sample size of 15, the 90%CI for the AUC ∞ ratio was expected to be 0.84‐1.19 on the basis of the variance assumptions.…”