QT time prolongation
Adverse drug events
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Explanations of the substances for patients
We have no additional warnings for the combination of glasdegib and abarelix. Please also consult the relevant specialist information.
The reported changes in exposure correspond to the changes in the plasma concentration-time curve [ AUC ]. We do not expect any change in exposure for glasdegib, when combined with abarelix (100%). We do not expect any change in exposure for abarelix, when combined with glasdegib (100%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Glasdegib has a mean oral bioavailability [ F ] of 77%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is 14 hours and constant plasma levels [ Css ] are reached after approximately 56 hours. The protein binding [ Pb ] is moderately strong at 91% and the volume of distribution [ Vd ] is very large at 200 liters, Since the substance has a low hepatic extraction rate of 0.07, displacement from protein binding [Pb] in the context of an interaction can lead to increased exposure. The metabolism takes place via CYP2C8 and CYP3A4, among others and the active transport takes place partly via PGP and UGT1A9.
The bioavailability of abarelix is unknown. The terminal half-life [ t12 ] is rather long at 316.8 hours and constant plasma levels [ Css ] are only reached after more than 1267.2 hours. The protein binding [ Pb ] is 97.5% strong. The metabolism via cytochromes is currently still being worked on.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither glasdegib nor abarelix increase serotonergic activity.
|Kiesel & Durán b||0||Ø||Ø|
Rating: According to our knowledge, neither glasdegib nor abarelix increase anticholinergic activity.
QT time prolongation
Rating: In combination, glasdegib and abarelix can potentially trigger ventricular arrhythmias of the torsades de pointes type.
General adverse effects
|Side effects||∑ frequency||gla||aba|
|Peripheral edema||30.0 %||30.0||n.a.|
|Loss of appetite||21.0 %||21.0||n.a.|
|Taste sense altered||21.0 %||21.0||n.a.|
Constipation (20%): glasdegib
Pneumonia (19%): glasdegib
Based on your answers and scientific information, we assess the individual risk of undesirable side effects. These recommendations are intended to advise professionals and are not a substitute for consultation with a doctor. In the restricted test version (alpha), the risk of all substances has not yet been conclusively assessed.
Abstract: 1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 μCi [C]glasdegib to six healthy male volunteers (NCT02110342). 2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUCwere 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0-120 hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites. 4. Elimination of [C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.
Abstract: Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg. Following ≥6-day washout, subjects received the treatment that they did not receive in the first period. Blood samples were collected for up to 96 hours after dosing. Drug plasma concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Glasdegib pharmacokinetic parameters were calculated using noncompartmental analysis. The mean terminal half-life was 14.3 hours for oral tablet treatment vs 13.8 hours for glasdegib IV treatment. The absolute oral bioavailability measured as the ratios (oral/IV) of adjusted geometric mean (90% confidence interval) of dose normalized area under the plasma concentration-time curve was 77.12% (71.83%-82.81%). Two adverse events (1 mild and 1 moderate in severity) were reported by 2 subjects following oral tablet administration; these were fully resolved by the end of the study.