Piqray Drug Interactions

The elimination of alpelisib is majorly driven by non-hepatic hydrolysis (45%), mediated by multiple enzymes (esterases, amidases, choline esterase) and excretion by hepatobiliary export and intestinal secretion (40%). The overall contribution of CYP3A4 to the overall metabolism and clearance of alpelisib was shown to be low in humans (≤15%) and therefore PIQRAY can be administered without any dose adjustments with drugs that are CYP3A4 inhibitors or inducers.
Medicinal products that may increase alpelisib plasma concentrations: BCRP inhibitors: Alpelisib is a sensitive substrate for BCRP in vitro, predominantly expressed in the liver, intestine, and at blood-brain barrier. Absorption of alpelisib will not be affected by BCRP inhibition due to saturation of the transporter in the intestine. However, due to the involvement of BCRP in the hepatobiliary export and intestinal secretion of alpelisib, caution is advised when co-administering PIQRAY with a BCRP inhibitor (e.g. eltrombopag, lapatinib, pantoprazole), as inhibition of BCRP in the liver and in the intestine after absorption may lead to an increase in systemic exposure of PIQRAY.
Medicinal products whose plasma concentrations may be altered by alpelisib: CYP3A4 substrates: In vitro, alpelisib is a time-dependent inhibitor and an inducer of CYP3A4. No dose adjustment is required when co-administering PIQRAY with CYP3A4 substrates (e.g. everolimus, midazolam).
Caution is recommended when PIQRAY is used in combination with CYP3A4 substrates that also possess an additional time-dependent inhibition and induction potential on CYP3A4 that affects their own metabolism (e.g. rifampicin, ribociclib, encorafenib). Systemic exposures of such CYP3A4 auto-inhibitors and auto-inducers may be decreased and increased, respectively, when PIQRAY is co-administered, based on PBPK simulations.
CYP2C9 substrates with narrow therapeutic index: In vitro, alpelisib is an inducer of CYP2C9. The pharmacological activity may be reduced by the CYP2C9 induction effects of alpelisib. Based on PBPK modeling data with sensitive CYP2C9 substrate warfarin, after co-administration of alpelisib (300 mg once daily for 20 days), AUC and Cmax ratios of warfarin were estimated to be 0.91 and 0.99, respectively, indicating no or weak induction potential of alpelisib on CYP2C9. No dose adjustment is required when PIQRAY is co-administered with CYP2C9 substrates with narrow therapeutic index (e.g. warfarin). However, in the absence of clinical data, caution is recommended.
CYP2B6 sensitive substrates with narrow therapeutic index: Alpelisib is an inducer of CYP2B6 in vitro. Static mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a reduction of exposure by up to 3-fold can be expected when co-administered with alpelisib based on in vitro assessment, no clinical study was performed. Sensitive CYP2B6 substrates (e.g. bupropion) or CYP2B6 substrates with a narrow therapeutic window should be used with caution in combination with PIQRAY, as PIQRAY may reduce the clinical activity of such drugs.
Drug-food interactions: In healthy subjects, co-administration of alpelisib with food resulted in an increased AUC of alpelisib by 77% (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions). Therefore, PIQRAY should be taken immediately after food, at approximately same time each day (see Dosage & Administration).
Hormonal contraceptives: It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.
Metabolic interaction: Based on the results of metabolic in vitro induction and inhibition studies, alpelisib may induce the metabolic clearance of co-medications metabolized by CYP2B6, CYP2C9 and CYP3A4 and may inhibit the metabolic clearance of co-medications metabolized CYP3A4 (time-dependent inhibition) if sufficiently high concentrations are achieved in vivo.
In a drug-drug interaction study, co-administration of alpelisib with everolimus, a sensitive CYP3A4 substrate, confirmed that there are no clinically significant pharmacokinetic interactions (increase in AUC by 11.2%) between alpelisib and CYP3A4 substrates. No change in everolimus exposure was observed at alpelisib doses ranging from 250 to 300 mg, also confirmed by PBPK modeling with everolimus and midazolam (≤15% increase in AUC). Due to the concurrent induction and time-dependent inhibition by alpelisib, PBPK simulations with substrates of CYP3A4 that also possess an additional time-dependent inhibition and induction potential on CYP3A4 that affects their own metabolism predict changes in exposure (decrease or increase) less than 2-fold, depending on the substrate.
CYP2C9 substrates: In lieu of a clinical study, PBPK modeling showed that AUC and Cmax ratios of warfarin (10 mg single dose) were estimated to be 0.91 and 0.99, respectively, after repeated co-administration of alpelisib (300 mg), indicating no or weak induction potential of alpelisib on CYP2C9.
Transporter-based interaction: Alpelisib showed weak in vitro inhibition towards the efflux transporters P-gp, BCRP, and BSEP, solute carrier transporters at the liver inlet (OATP1B1, OATP1B3, and OCT1) and solute carrier transporters in the kidney ( OCT2, MATE1, and MATE2K). As unbound systemic steady state concentrations at the therapeutic dose are significantly lower than the experimentally determined unbound inhibition constants or IC₅₀, the inhibition will not translate into clinical significance. However, given the relatively high intestinal and hepatic inlet concentrations of alpelisib, clinically relevant inhibition of oral absorption of P-gp substrates and hepatic uptake of OCT1, OATP1B1 and OAT1B3 substrates may occur. Both alpelisib and the major metabolite, BZG791 inhibited the renal uptake transporter OAT3 (Ki 29.4 and 1.38 μM, respectively) in vitro, and thus alpelisib might increase plasma concentrations of drugs that are predominantly excreted by this transporter. As an in vitro inhibitor of OATP1B1 (IC50 20.9 μM) alpelisib might also increase plasma concentrations of drugs that are OATP1B1 substrates and predominantly cleared by hepatic metabolism.
Fulvestrant: Data from a clinical study in patients with breast cancer indicated no effect of fulvestrant on alpelisib exposure (and vice versa) following co-administration of the drugs.