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Jaypirca ® (pirtobrutinib) tablets
50 mg,100 mg
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling. See Prescribing Information above, if applicable.
Are there any drug-drug interactions with Jaypirca® (pirtobrutinib)?
Jaypirca (pirtobrutinib) is a CYP3A substrate as well as a P-gp inhibitor, a moderate CYP2C8 and BCRP inhibitor, and a weak CYP2C19 and CYP3A inhibitor.
Metabolism of Pirtobrutinib
Pirtobrutinib is primarily metabolized by cytochrome (CYP) 3A4 and direct glucuronidation by uridine diphosphate glucoronosyl transferases UGT1A8 and UGT1A9, in vitro.1
Cytochrome P450 Enzymes
Effect of Strong CYP3A Inhibitors on Pirtobrutinib
Pirtobrutinib is a CYP3A substrate. Concomitant use of pirtobrutinib with a strong CYP3A inhibitor increased pirtobrutinib systemic exposure, which may increase the risk of pirtobrutinib adverse reactions.1
Avoid concomitant use of strong CYP3A inhibitors with pirtobrutinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the pirtobrutinib dose by 50 mg. If the current dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of strong CYP3A inhibitor use. After discontinuation of a strong CYP3A inhibitor for 5 half-lives, resume the pirtobrutinib dose that was taken prior to initiating the strong CYP3A inhibitor.1
Effect of Strong or Moderate CYP3A Inducers on Pirtobrutinib
Concomitant use of pirtobrutinib with a strong or moderate CYP3A inducer decreased pirtobrutinib systemic exposure, which may reduce pirtobrutinib efficacy.1
Avoid concomitant use of strong or moderate CYP3A inducers with pirtobrutinib. If moderate CYP3A inducers is unavoidable and the current dosage of pirtobrutinib is 200 mg once daily, increase the dose to 300 mg. If the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg.1
Effect of Pirtobrutinib on Sensitive CYP2C8, CYP2C19, and CYP3A Substrates
Pirtobrutinib is a moderate CYP2C8 inhibitor and a weak CYP2C19 and CYP3A inhibitor.1
Concomitant use of pirtobrutinib with sensitive CYP2C8, CYP2C19, or CYP3A substrates increased their plasma concentrations, which may increase the risk of adverse reactions related to these substrates for drugs which are sensitive to minimal concentration changes. Follow recommendations for sensitive CYP2C8, CYP2C19, and CYP3A substrates provided in their approved product labeling.1
Drug Interaction Studies
Clinical Studies and Model Informed Approaches
CYP Inhibitors |
Effect of CYP Inhibitor on Pirtobrutinib |
Itraconazole (strong CYP3A4 inhibitor) |
|
Verapamil (moderate CYP3A inhibitor) |
|
Diltiazem (moderate CYP3A inhibitor) |
|
CYP Inducers |
Effect of CYP Inducer on Pirtobrutinib |
Rifampin (strong CYP3A inducer) |
|
Bosentan (moderate CYP3A inducer) |
|
Efavirenz (moderate CYP3A inducer) |
|
CYP Substrates |
Effect of Pirtobrutinib on CYP Substrate |
Midazolama (sensitive CYP3A substrate) |
|
Repaglinide (CYP2C8 substrate) |
|
Caffeine (CYP1A2 substrate) |
|
S-warfarin (CYP2C9 substrate) |
|
Omeprazole (CYP2C19 substrate) |
|
Abbreviations: AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; CYP = cytochrome P450 enzyme.
aOrally administered. Pirtobrutinib did not have a clinically meaningful effect on the exposure of intravenously administered midazolam.
In Vitro Studies
In in vitro studies pirtobrutinib
- inhibited CYP2C8, CYP2C9, CYP3A, CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and
- induced CYP3A4, CYP3A5, CYP2B6, and CYP2C19.1
Transporter Systems
Effect of Pirtobrutinib on Sensitive P-gp and BCRP Substrates
Pirtobrutinib is a P-glycoprotein (P-gp) inhibitor and moderate breast cancer resistance protein (BCRP) inhibitor.1
Concomitant use of pirtobrutinib with sensitive P-gp or BCRP substrates increased their plasma concentrations, which may increase the risk of adverse reactions related to these substrates for drugs which are sensitive to minimal concentration changes. Follow recommendations for sensitive P-gp, or BCRP substrates provided in their approved product labeling.1
Drug Interaction Studies
Clinical Studies and Model Informed Approaches
Potential Interactions Between Pirtobrutinib and Substrates or Modulators of Transporter Systems Observed in Clinical Studies and Model-Informed Approaches summarizes the results of clinical studies and modeling approaches investigating the effects of transporter systems on pirtobrutinib activity as well as the effect of pirtobrutinib on transporter systems.
Transporter Inhibitor or Substrate |
Effect of Coadministration of Pirtobrutinib |
Itraconazole (P-gp inhibitor) |
|
Digoxin (P-gp substrate) |
|
Rosuvastatin (BCRP substrate) |
|
Abbreviations: AUC = area under the plasma concentration-time curve; BCRP = breast cancer reactive protein; Cmax = maximum plasma concentration; P-gp = P-glycoprotein.
In Vitro Studies
Pirtobrutinib was shown to be both a substrate and inhibitor of P-gp and BCRP.1
Acid-Reducing Agents
No clinically significant differences in pirtobrutinib pharmacokinetics were observed when coadministered with omeprazole, a proton pump inhibitor. In a clinical study with healthy subjects (N=10), coadministration of omeprazole with pirtobrutinib showed
Use in Clinical Trials
In clinical studies, pirtobrutinib was allowed to be taken with or without agents that modify gastric pH such as proton pump inhibitors (acid reducing agents) and histamine H2-receptor antagonists.2
Interaction With Venetoclax
The phase 1b portion of the BRUIN phase study is evaluating the safety, efficacy, and pharmacokinetics of pirtobrutinib in combination with venetoclax (n=15) and rituximab plus venetoclax (n=10).3,4 Patients are treated on a 28 day cycle with either
- pirtobrutinib at 200 mg daily starting cycle 1, day 1; venetoclax starting cycle 2, day 1 with a standard 5-week dose ramp to 400 mg daily (Arm A) or
- rituximab at 375 mg/m2 on cycle 1, day 1, then 500 mg/m2 on day 1 of cycles 2-6; pirtobrutinib at 200 mg daily starting cycle 1, day 3; and venetoclax starting cycle 2, day 1 with a standard 5-week dose ramp to 400 mg daily (Arm B).4,5
Pirtobrutinib and venetoclax were given in combination in a fixed duration for a total of 24 cycles and each cycle was 28 days. Patients received treatment for 25 cycles or until disease progression, unacceptable toxicity, or withdrawal.4
The study collated venetoclax pharmacokinetic data for both Arm A and Arm B patients. Pirtobrutinib and venetoclax pharmacokinetics were similar in both combination regimens (Pharmacokinetic Analysis for Pirtobrutinib and Venetoclax Treatment). There was no apparent drug-drug interaction between pirtobrutinib and venetoclax. Both combination therapies had pharmacokinetic exposures comparable to pirtobrutinib and venetoclax monotherapies.4
Parameters |
Pirtobrutinib PK |
Venetoclax PK |
||
Arm A |
Arm B |
Arm A |
Arm B |
|
Cycle 3 Day 8 of treatment |
||||
N |
13 |
9 |
12 |
9 |
Cmax (ng/mL), mean CV% |
5490 (26.3) |
5460 (31.3) |
3730 (37.3) |
1600 (49.7) |
Tmax (h), median (range) |
2.18 (0.133–7.50) |
1.95 (0.933–7.73) |
7.74 (6.97–8.00) |
7.57 (4.07–8.00) |
AUC0-tlast (hr*ng/mL), mean CV% |
34800 (23.8) |
32400 (28.8) |
17200 (52.4) |
8220 (31.4) |
Cycle 4 Day 1 of treatment |
||||
N |
13 |
10 |
12 |
10 |
Cmax (ng/mL), mean CV% |
3790 (114) |
5570 (38.7) |
2540 (66.3) |
1780 (89.9) |
Tmax (h), median (range) |
1.97 (0.00–4.15) |
2.93 (0.833–7.53) |
7.56 (1.90–7.78) |
7.52 (1.75–8.00) |
AUC0-tlast (hr*ng/mL), mean CV% |
29600 (33.7) |
32500 (41.9) |
12700 (68.2) |
10500 (84.6) |
Abbreviations: AUC = area under the curve; Cmax = maximum concentration; CV = coefficient of variation; Tmax = time to peak drug concentration.
Use With Grapefruit Juice or Orange Drinks
No specific recommendations are available against taking pirtobrutinib with drinks containing grapefruits or oranges
BRUIN Phase 1/2 Trial Criteria
Relevant Inclusion/Exclusion Criteria Related to Concomitant Medications
In the BRUIN phase 1/2 trial, subjects who tested positive for the human immunodeficiency virus (HIV) were excluded due to potential drug-drug interactions between antiretroviral medications and pirtobrutinib as well as the risk of opportunistic infections with both HIV and irreversible Bruton's tyrosine kinase inhibitors. The subjects with unknown HIV status had to undergone HIV testing at screening.6
The phase 1/2 portion of the study also excluded subjects from enrollment if they were currently being treated with certain strong CYP3A4 modulators (List of Strong and Moderate CYP3A4 Modulators) and/or strong P-gp inhibitors. The study allowed subjects to take moderate inhibitors or inducers of CYP3A4 and mild inhibitors of P-gp with caution.6
Permitted concomitant medications included ongoing medications and all medications that were administered within 14 days prior to the planned start of study drug (that is, from screening) through the safety follow-up visit, which was at least 28 days (+7 days) after the last dose of study treatment.6
Inducers |
Inhibitors |
|
Stronga |
Avasimibe, carbamazepine, enzalutamide, phenytoin, rifampin, and St John’s wort |
Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, star fruit, grapefruit/product, and Seville oranges/product |
Moderateb |
Bosentan, efavirenz, etravirine, modafinil, and nafcillin |
Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, and verapamil |
Abbreviations: AUC = area under the plasma concentration-time curve; CYP3A4 = cytochrome P450 3A4 enzyme.
Note: The above list is not exhaustive. Please also refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.
aDefined as inducers that decrease the AUC of the substrate by ≥ 80% and inhibitors that increase the AUC of the substrate by ≥ 5-fold.
bDefined as inducers that decrease the AUC of the substrate by 50-80% and inhibitors that increase the AUC of the substrate by 2-to 5-fold.
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Jaypirca [package insert]. Indianapolis, IN: Eli Lilly and Company; 2024.
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3A study of oral LOXO-305 in patients with previously treated CLL/SLL or NHL. ClinicalTrials.gov identifier: NCT03740529. Updated October 2, 2024. Accessed October 16, 2024. https://www.clinicaltrials.gov/ct2/show/NCT03740529
4Roeker LE, Woyach JA, Cheah CY, et al. Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: phase 1b BRUIN trial. Blood. Published online June 11, 2024. https://doi.org/10.1182/blood.2024024510
5Roeker LE, Woyach J, Cheah CY, et al. Fixed-duration pirtobrutinib combined with venetoclax ± rituximab in relapsed/refractory chronic lymphocytic leukemia: updated results, including MRD data, from the BRUIN Phase 1b study. Poster presented at: 65th Annual Meeting of the American Society of Hematology (ASH); December 9-12, 2023; San Diego, California. Accessed December 11, 2023.
6Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. https://doi.org/10.1016/S0140-6736(21)00224-5
Date of Last Review: December 19, 2022