Exposure-QT analysis for sonidegib (LDE225), an oral inhibitor of the hedgehog signaling pathway, for measures of the QT prolongation potential in healthy subjects and in patients with advanced solid tumors.
OBJECTIVE
Sonidegib prevents activation of the Hedgehog signal transduction pathway. This PK-QT analysis has been performed to test for potential prolongation of the QT/QTc interval during extended use, and to understand the exposure-QT relationship for sonidegib in patients and in healthy volunteers (HV).


METHODS
A pooled analysis of the change in QT interval corrected for heart rate according to Fridericia's formula was conducted across four patient studies from a total of 341 patients (n = 211, 102, 21, and 7 from the phase II pivotal study A2201, study X2101, study X1101, and study B2209, respectively), and across four healthy volunteer studies from a total of 204 healthy volunteers (n = 146, 36, 16, and 6 from study A2114, study A1102, study A2108, and study A2110, respectively). A PK/ECG subgroup of 62 patients from the pivotal study A2201 was also analyzed to assess the QT prolongation risk at steady-state exposures. Sonidigib PK and ECG data were matched to determine the change from baseline in QTcF using a linear mixed-effect model.


RESULTS
Clinical data indicate sonidegib does not cause QTc prolongation. ΔQTcF at steady-state concentrations for both 200 and 800-mg doses were all below 5 ms. The highest mean ΔQTcF at steady state was -3.9 ms at week 17 pre-dose in the sonidegib 200-mg group and 2.7 ms at 2-h post-dose in the sonidegib 800-mg group. The upper one-sided 95 % confidence interval of the estimated ΔQTcF at steady-state concentrations from the linear mixed-effect models were all <10 ms. No cases of ventricular arrhythmia or torsades de pointes and no deaths associated with QT prolongation have been reported in the sonidegib clinical development program.


CONCLUSIONS
Based on these analyses, there is no evidence of QT prolongation associated with sonidegib 200 or 800 mg in solid tumor patients and HV.
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
Michelle
M
Quinlan
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
Jocelyn
J
Zhou
Novartis Institutes for BioMedical Research, Inc, Cambridge, MA, USA.|Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.
Eunju
E
Hurh
Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA. dalila.sellami@novartis.com.
Dalila
D
Sellami
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000378:metabolism*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib
Exposure-QT analysis; Prolongation; QT interval; Sonidegib
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