Lack of meaningful effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model prediction and clinical confirmation.
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.
Clinical PK/PD, Merck & Co., Inc., Whitehouse Station, NJ, USA.
Mark
M
Stroh
Jennifer
J
Talaty
Punam
P
Sandhu
Jacqueline
J
McCrea
Amita
A
Patnaik
Anthony
A
Tolcher
John
J
Palcza
Keith
K
Orford
Sheila
S
Breidinger
Narayana
N
Narasimhan
Deborah
D
Panebianco
Richard
R
Lush
Kyriakos P
KP
Papadopoulos
John A
JA
Wagner
Michele
M
Trucksis
Nancy
N
Agrawal
D000368:Aged; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; C515074:ridaforolimus; D008874:Midazolam; D020123:Sirolimus
midazolam; pharmacokinetics; ridaforolimus