Greta Staubly 

 (L0X0-305) is a highly selective inhibitor used to treat patients with chronic lymphocytic leukemia (CLL).

 Although there are various other drugs in the same class of Bruton’s tyrosine kinase (BTK) inhibitors, each possesses different characteristics and pharmacological properties.

Of particular interest, pirtobrutinib is the first to offer the characteristic of non-covalent, reversible binding. This will allow higher BTK inhibition and a higher selectivity, reducing any off-target adverse effects.

There is growing concern for the development of resistance to covalent BTK inhibitors, leading to treatment discontinuation in a large majority of patients. Researchers are recognizing pirtobrutinib for its ability to treat recurrent or relapsing CLL.

B-cell malignancies often develop due to signaling during the B-cell receptor pathway. BTK is a protein found early in this pathway. Inhibitors target it for therapeutic intervention to downregulate signaling and cell growth.

Ibrutinib is one of numerous BTK inhibitors discovered that treat a range of B-cell lymphomas. However, patients with B-cell malignancies often acquire resistance to BTK inhibitors during therapy. Mutations at the Cys-481 residue cause resistance against first and second generation BTK inhibitors.

As a third generation BTK inhibitor, pirtobrutinib does not rely on binding to Cys-481 in the active site, therefore resistance does not occur. As the body synthesizes new amounts of BTK, pirtobrutinib will remain in the body and cause constant inhibition. This is unlike other BTK inhibitors, which do not have long half-lives and cause gaps in inhibition.

Currently, pirtobrutinib is under investigation in clinical trials in patients with CLL/small lymphocytic lymphoma, mantle cell lymphoma, and non-Hodgkin lymphoma. The BRUIN phase 1/2 trial has shown that patients tolerate pirtobrutinib well. Of 252 patients with CLL/SLL in the trial, the overall response rate was a promising 68%.

Researchers have not yet determined a maximum tolerated dose. Phase 2 of the BRUIN trial aims to determine the therapeutic range. Only 1% of patients permanently discontinued pirtobrutinib because of treatment-related AEs.

The most common AEs included diarrhea, fatigue, and neutropenia, with hemorrhage and hypertension occurring in rare cases.

Multiple studies throughout the world are evaluating pirtobrutinib’s safety and efficacy. Researchers at Loxo Oncology at Lilly are currently enrolling participants in phases 2 and 3 of the BRUIN trial.

Pirtobrutinib shows promise for treating recurrent and relapsing CLL.

Greta Staubly is a 2024 PharmD candidate at the University of Connecticut.

BTK Inhibitor Molecule Overview | Loxo Oncology. Lillyloxooncologypipeline.com. https://www.lillyloxooncologypipeline.com/molecule/btk-inhibitor?gclid=CjwKCAjwv-GUBhAzEiwASUMm4rr69kaDRjX_VR-HBgVo6TGVW2OwrVw3S1Nvuh9EXFoB6Jjd87XUnhoCh5QQAvD_BwE. Published 2022. Accessed June 1, 2022.

Shirley M. Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features [published correction appears in Target Oncol. 2021 Dec 24;:]. 

. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8

Mato A. Rapid Readout: Pirtobrutinib, A Highly Selective, Noncovalent (Reversible) BTK Inhibitor In Previously Treated CLL/SLL: Updated Results From The Phase 1/2 BRUIN Study. OncLive. https://www.onclive.com/view/pirtobrutinib-a-highly-selective-non-covalent-reversible-btk-inhibitor-in-previously-treated-cll-sll-updated-results-from-the-phase-1-2-bruin-study. Published 2022. Accessed June 1, 2022.

Expanded Access Program for Pirtobrutinib for Participants With B-Cell Cancer - Full Text View - ClinicalTrials.gov. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT05172700. Published 2022. Accessed June 1, 2022.

Articles

Pirtobrutinib is under investigation in clinical trials in patients with CLL/small lymphocytic lymphoma, mantle cell lymphoma, and non-Hodgkin lymphoma.

Oncology Overview: Pirtobrutinib—A New BTK Inhibitor

Organ system toxicities from methotrexate can lead to acute 

, myelosuppression, mucositis, and further nephrotoxicity. 

 (Voraxaze) is for adult and pediatric patients with delayed methotrexate clearance due to impaired renal function.

Glucarpidase reduces toxic plasma methotrexate concentrations. Patients who demonstrate the expected clearance and plasma methotrexate concentration should not take glucarpidase. The FDA approved the use of glucarpidase in 2012.

Methotrexate is an immunosuppressive agent used to treat cancer, dermatology-, and rheumatology-related issues.

 In some cases, patients with impaired renal function may have reduced methotrexate clearance. This causes a methotrexate buildup that leads to toxicity.

Symptoms include diarrhea, nausea, vomiting, acute renal failure, and other adverse effects (AEs). This toxicity can eventually be fatal, which is why it is important to use glucarpidase when needed.

Clinical trials studying the efficacy of glucarpidase examined patients who had significantly delayed methotrexate clearance due to impaired renal function. After a significant study, researchers concluded that glucarpidase caused a clinically important 99% or greater sustained reduction of serum methotrexate levels.

It also provided noninvasive rescue from methotrexate toxicity in renally impaired patients.

If providers administer glucarpidase upon discovery of toxicity, morbidity risk is significantly lowered. Additionally, patients may experience reductions in plasma methotrexate concentrations within as early as 15 minutes

In some cases, intrathecal administration of glucarpidase was successful in lowering toxicity after clinicians accidentally administering methotrexate intrathecally.

This is only for emergency situations and glucarpidase is not FDA-approved for intrathecal use.

Glucarpidase is a carboxypeptidase enzyme that rapidly metabolizes circulating methotrexate into glutamate and 2,4-diamino-

Also known as carboxypeptidase-G2 (CPDG2), glucarpidase is a modified form of 

Glucarpidase is a zinc peptidase, so it hydrolyzes the amide linkage on circulating (not intracellular) methotrexate to form glutamate and DAMPA. The liver then metabolizes these metabolites.

Glucarpidase is an intravenous injection. The recommended dosage is 50 units per kilogram as a single injection. Providers should administer it over 5 minutes. It is available as 1000 units of a white lyophilized powder in a single dose vial for reconstitution.

Health care providers should reconstitute the contents of the vial with 1 mL of 0.9% sodium chloride injection, USP. After reconstitution, providers should roll and tilt the vial gently to mix but should not shake it.

Health care providers should administer glucarpidase immediately once reconstituted, or store under refrigeration for up to 4 hours if not used immediately. Patients with renal impairment do not need dose adjustments.

Pharmacists should counsel patients regarding the importance of continuous monitoring of plasma methotrexate concentration and renal functions throughout therapy.

Pediatric patients can safely and effectively use glucarpidase. Clinical trials studied the use of glucarpidase in patients 5 years of age and older. There are also additional safety data in patients 1-17 years of age and older.

There are no contraindications for glucarpidase. If patients are to receive glucarpidase concomitantly with leucovorin, providers should administer leucovorin at least 2 hours before or 2 hours after the glucarpidase dose. Serious hypersensitivity reactions occurred in less than 1% of patients.

AEs to glucarpidase include headache, hypotension, nausea and/or vomiting, and paresthesia.

Data are not available regarding the use of glucarpidase during pregnancy, however patients would only receive glucarpidase if also receiving methotrexate, which can cause embryo-fetal harm.

Patients should consult their physician regarding the use of methotrexate or glucarpidase during pregnancy. There is additionally no information relating to the presence of glucarpidase in human milk.

Greta Staubly is a 2024 PharmD candidate at the University of Connecticut

Highlights of Prescribing Information. Voraxaze.com. https://voraxaze.com/getmedia/21552a20-ab2d-4476-a5ac-93e920aecbed/VORAXAZE-PI_August-2019_2-column-format.pdf. Published 2012. Accessed May 16, 2022.

Bidaki R, Kian M, Owliaey H, Babaei Zarch M, Feysal M. Accidental Chronic Poisoning with Methotrexate; Report of Two Cases. 

Widemann BC, Schwartz S, Jayaprakash N, et al. Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. 

. 2014;34(5):427-439. doi:10.1002/phar.1360

Rattu MA, Shah N, Lee JM, Pham AQ, Marzella N. Glucarpidase (voraxaze), a carboxypeptidase enzyme for methotrexate toxicity. 

 Clinical Overview: Glucarpidase (Voraxaze) for Methotrexate Toxicity

Sonidegib (Odomzo) treats adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy.

 Patients may also take it if they are not candidates for surgery or radiation therapy for their BCC.

BCC is the most common form of skin cancer and among the most diagnosed forms of cancer in the United States. Until recently, visomodegib was the only targeted treatment available for locally advanced BCC where surgery and radiotherapy are inappropriate.

Sonidegib has beneficial lipophilicity in comparison to vismodegib, making it preferable for tissue penetration.

Sonidegib is a biphenyl carboxamide that blocks the signaling in the hedgehog (Hh) pathway.

 It binds to and inhibits Smoothened, a transmembrane protein involved in Hh signal transduction.

 This Hh signaling pathway is one of the pathways involved in cancer development.

The clinical trial BOLT evaluated the safety and efficacy of sonidegib. Researchers randomized patients (2:1) to receive either sonidegib 800 mg or 200 mg.

Of the 66 patients receiving 200 mg, 37 patients had either partial or complete responses after 30 months. The study defined a complete response as disappearance of all lesions.

In patients taking 800 mg, there was no evidence of better antitumor patients.

 Currently, the FDA only approves sonidegib to treat locally advanced BCC and metastatic BCC, however, researchers are investigating it for use in treatment of other cancer types.

These types include renal cell carcinoma, lung cancer, myeloid leukemia, pancreatic cancer, and lymphoma.

Sonidegib comes in 200 mg capsules taken by mouth once daily. Patients should take sonidegib on an empty stomach, at least 1 hour before or 2 hours after a meal. Providers should obtain serum creatinine kinase (CK) levels and renal function tests prior to administration in all patients.

Patients taking sonidegib may experience abdominal pain, alopecia, diarrhea, decreased weight or appetite, fatigue, nausea, or pruritis. Musculoskeletal AEs occurred in 68% of patients treated with sonidegib 200 mg in the BOLT study.

These reactions include muscle spasms, musculoskeletal pain, and myalgia. If a patient experiences musculoskeletal symptoms, providers should consider a temporary dose interruption or discontinuation based on severity. Pharmacists should counsel patients to watch for all possible AEs and report to providers as soon as possible.

Patients taking sonidegib must avoid strong CYP3A4 inhibitors. This is because CYP3A is the primary metabolizer of sonidegib. In trials, pediatric patients exposed to sonidegib reported premature fusion of the epiphyses which is why pediatric patients should not use this drug.

Pregnant patients must avoid taking sonidegib due to the severe birth defects it can cause. Sonidegib is embryotoxic, fetotoxic, and teratogenic.

Female patients of reproductive potential should use effective contraception during and at least 20 months after treatment with sonidegib. There is a risk of exposure to sonidegib through semen.

Males taking sonidegib should use condoms with a pregnant partner or a female partner or reproductive potential. Patients should not donate blood or blood products while taking sonidegib and for at least 20 months after their last dose because their blood products may be given to a female of reproductive potential.

There are no data regarding the presence of sonidegib in breast milk. However, due to the potential for serious AEs in breastfed infants, women should not breastfeed during treatment with sonidegib and for at least 20 months after the last dose.

. [online] Available at: <https://www.odomzo.com/themes/custom/odomzo/global/pdfs/pi.pdf> [Accessed 24 May 2022].

Dummer R, Ascierto PA, Basset-Seguin N, et al. Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion. 

. 2020;34(9):1944-1956. doi:10.1111/jdv.16230

Jain S, Song R, Xie J. Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. 

. 2017; 10:1645-1653. Published 2017 Mar 16. doi:10.2147/OTT.S130910

National Center for Biotechnology Information. PubChem Compound Summary for CID 24775005, Sonidegib. 

https://pubchem.ncbi.nlm.nih.gov/compound/Sonidegib

Sonidegib is a biphenyl carboxamide that blocks the signaling in the hedgehog pathway.

Oncology Overview: Sonidegib (Odomzo) for Locally Advanced Basal Cell Carcinoma

The combination medication sacubitril and valsartan (Entresto) is indicated for use in adult patients with 

 (HF) to reduce the risk of hospitalization and death related to cardiovascular complications. In pediatric patients 1 year of age or older, sacubitril/valsartan treats symptomatic HF with systolic left ventricular systolic dysfunction.

In both populations, sacubitril/valsartan reduces negative cardiovascular outcomes. The 

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI). Sacubitril prevents breakdown of natriuretic peptides by blocking neprilysin.

 Valsartan is an angiotensin receptor blocker (ARB), halting the function of the renin-angiotensin-aldosterone-system.

Neprilysin breaks down angiotensin II, which is why sacubitril is formulated with an ARB to block the buildup of excess angiotensin II.

The PARADIGM-HF trial reported that sacubitril/valsartan significantly reduced mortality and hospitalization in HF patients with a reduced ejection fraction.

 Sacubitril/valsartan therapy reduced cardiovascular hospitalization rates and mortality by 20% and prolonged survival by approximately 1-2 years in patients who had HF with reduced ejection fraction compared with enalapril.

Upon the study’s publication, the American College of Cardiology, American Heart Association, and the Heart Failure Association of America updated their guidelines. Sacubitril/valsartan further reduces morbidity and mortality in patients with the above indications.

Several ongoing trials are investigating sacubitril/valsartan in other cardiovascular and non-cardiovascular conditions. The trials are examining sacubitril/valsartan’s efficacy in advanced HF, arrhythmias, chronic kidney disease, diabetes mellitus, end-stage renal disease, and hypertension.

One study that is examining the effects on chemotherapy-induced left ventricular dysfunction will have results in September 2025.

Sacubitril/valsartan is available in 3 different strength combinations: sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, and sacubitril 97 mg/valsartan 103 mg.

The starting dose for patients on low dose angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or ARBs or not previously on ACEI or ARB is sacubitril 24 mg/valsartan 26 mg twice daily. Patients should discontinue their previous ACE inhibitor or ARB when transitioning to this drug.

For patients on moderate- to high-dose ACEIs or ARBs, the starting dose is sacubitril 49 mg/valsartan 51 mg twice daily. In both instances, patients should double their dose every 2-4 weeks as tolerated, with a maximum dose of sacubitril 97 mg/valsartan 103 mg twice daily.

For patients with moderate hepatic impairment or an eGFR less than 30 mL/minute, the starting dose should be sacubitril 24 mg/valsartan 26 mg twice daily. Patients with severe hepatic impairment should not take sacubitril/valsartan.

 for full pediatric dosing information. Pharmacists should provide oral suspensions to pediatric patients less than 40 kg or those unable to swallow tablets. Sacubitril/valsartan oral suspension 800 mg/200 mL (1.96/2.06 mg/mL) can be prepared using eight tablets of 49/51 mg tablets. See the package insert for full preparation instructions.

Adverse reactions to sacubitril/valsartan include cough, dizziness, hyperkalemia, hypotension, and renal failure.

Patients with hypersensitivity to any ingredients of sacubitril/valsartan should not use this drug. Pharmacists should counsel patients to not use sacubitril/valsartan concomitantly with ACE inhibitors or history of angioedema related to previous ARB or ACE inhibitor use.

If switching from an ACE inhibitor to sacubitril/valsartan, patients must allow 36 hours before starting sacubitril/valsartan. In patients with diabetes, concomitant use of aliskiren is contraindicated.

At each visit, pharmacists should observe patients for signs and symptoms of angioedema and hypotension. In susceptible patients, providers should monitor renal function and potassium levels while on this medication.

Sacubitril/valsartan can cause fetal harm when administered to pregnant women.

 Pregnant patients must discontinue sacubitril/valsartan as soon as possible.

Use of this medication, especially in the second and third trimesters of pregnancy, will affect the fetal renal function which can lead to renal failure, skeletal deformations, and/or death. However, if the medication is lifesaving for the mother, advise the patient of the potential risk to the fetus.

Pharmacists should counsel patients to not breastfeed during treatment with sacubitril/valsartan due to the potential presence in breast milk.

Highlights of Prescribing Information: Entresto

. Novartis United States of America. Retrieved April 29, 2022, from https://www.novartis.us/

Diala, N., Kerndt, C. C., & Reed, M. (2021, July 26). 

. National Library of Medicine. Retrieved April 30, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK507904/

Mann, D. L., Greene, S. J., Givertz, M. M., et. al. (2020). SACUBITRIL/Valsartan in advanced heart failure with reduced ejection fraction. 

https://doi.org/10.1016/j.jchf.2020.05.005

Hubers, S. A., & Brown, N. J. (2016). Combined angiotensin receptor antagonism and NEPRILYSIN inhibition. 

(11), 1115–1124. https://doi.org/10.1161/circulationaha.115.018622

Badreldin, H.A.; Aldosari, N.; Alnashwan, L.; Almutairi, T.; Yousif, N.; Alsulaiman, K.; Aljuhani, O.; Hafiz, A.; Alshaya, O. What the near Future Holds for Sacubitril/ Valsartan: A Summary of Major Ongoing Studies. 

,54. https://doi.org/ 10.3390/jcdd9020054

Sacubitril/valsartan (Entresto)reduces the risk of hospitalization and death related to cardiovascular complications in patients with heart failure.

Clinical Overview: Sacubitril/Valsartan (Entresto) for Chronic Heart Failure

The FDA has authorized the use of Evusheld for pre-exposure prophylaxis for prevention of 

 under an Emergency Use Authorization (EUA).

Tixagevimab co-packaged with cilgavimab (Evusheld) is a SARS-CoV-2 spike protein-directed attachment inhibitor. 

The EUA does not allow tixagevimab/cilgavimab to treat COVID-19 or for post-exposure prophylaxis of COVID-19.

Adults and children 12 years of age or older who weigh at least 40 kg may receive tixagevimab/cilgavimab. Individuals must not have COVID-19 or have been in contact with an individual with COVID-19. They must be moderately to severely immunocompromised with an inadequate immune response to COVID-19 vaccination or unable to complete their vaccination series due to a severe adverse reaction to a COVID-19 vaccine or any components.

Tixagevimab/cilgavimab is not a substitute for any COVID-19 vaccinations in unvaccinated individuals who are able to receive and respond appropriately to COVID-19 vaccination.

The phase 3 trial, PROVENT, supports the EUA. PROVENT is a randomized (2:1), double-blind, placebo controlled clinical trial studying tixagevimab/cilgavimab’s efficacy for pre-exposure prophylaxis of COVID-19.

All subjects selected had at least 1 elevated risk factor for COVID-19, including age (over 60 years), comorbidities, or residential or occupational status. Of the 3441 patients given 150 mg of tixagevimab plus 150 mg cilgavimab, only 8 (0.2%) developed symptomatic COVID-19. Seventeen (1.0%) of the 1731 patients administered placebo developed symptomatic COVID-19. The results show a relative risk reduction of 77%.

Detailed results from the pre-exposure prophylaxis trial showed that the treatment reduced the risk of developing symptomatic COVID-19 by 77% in the primary analysis and by 83% in the 6-month follow-up analysis, versus placebo. There were no cases of severe disease or COVID-19 related deaths in the tixagevimab/cilgavimab group through the 6-month follow-up.

Tixagevimab and cilgavimab are both human immunoglobulin G1 (IgG1k) monoclonal antibodies. The antibodies are produced in Chinese hamster ovary cells via recombinant DNA technology.

In combination, tixagevimab and cilgavimab bind to the receptor binding domain of spike protein and block its interaction with human ACE2 (the SARS-CoV-2 receptor), which prevents virus attachment to the receptor.

Tixagevimab/cilgavimab consists of 2 separate consecutive intramuscular injections of 300 mg of tixagevimab and 300 mg of cilgavimab. Currently, there are no recommendations to repeat dosages. A qualified health care provider must prepare and administer both injections, and monitor the patient for at least an hour after injections.

The provider must inspect the vials to ensure proper color and absence of particulates before withdrawal. The solutions are colorless to slightly yellow and clear to opalescent, and must not be shaken.

Tixagevimab and cilgavimab are packaged separately in 150 mg/1.5 mL (100 mg/mL) single-dose vials. The injection requires 2 vials of each drug, for a total of 3 mL (300 mg).

Providers must use a separate syringe for each drug. Both products contain no preservatives, so they require immediate administration and must be discarded if they are not administered within 4 hours.

Providers should administer tixagevimab and cilgavimab as 2 separate, consecutive intramuscular injections. The provider should give the injections in different injection sites, preferably 1 in each gluteal muscle to account for the appropriate volume of 3 mL per injection.

A health care professional must monitor the patient for at least 1 hour after the injections. Patients who have received a COVID-19 vaccination must wait at least 2 weeks before they can receive tixagevimab/cilgavimab.

Some individuals have initially received 150 mg of tixagevimab and 150 mg of cilgavimab from the previously authorized dose. Those patients should receive a second dose of 150 mg tixagevimab and 150 mg cilgavimab as soon as possible. All other individuals should receive an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab.

The most common AEs include headache, fatigue, and cough. Local injection site reactions including pain, bruising of the skin, and soreness are possible.

A health care professional should monitor the patient for at least an hour after the injections in case of serious hypersensitivity reactions. This includes anaphylaxis, which can occur with IgG1 monoclonal antibody use.

Providers should use caution when administering to patients with thrombocytopenia or other coagulation disorder. They must consider the benefit/risk ratio in patients who are at high risk for cardiovascular AEs, as clinical trials have reported a higher proportion of subjects who experienced cardiovascular AEs.

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

 Patients should only use Evusheld during pregnancy if the potential benefit outweighs the potential risk factors. It is unknown whether tixagevimab or cilgavimab are present in breastmilk.

Fact Sheet for Healthcare Providers: Emergency Use Authorization for Evusheld (tixagevimab co-packaged with cilgavimab). AstraZeneca. Accessed March 7, 2022. 

https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2_viewable_rendition__v.pdf

Prevention of SARS-CoV-2 Infection. National Institutes of Health. Accessed March 7, 2022. 

https://www.covid19treatmentguidelines.nih.gov/overview/prevention-of-sars-cov-2/

EVUSHELD™ significantly protected against symptomatic COVID-19 for at least six months in PROVENT Phase III trial in high-risk populations. AstraZeneca. April 20, 2022. 

https://finance.yahoo.com/news/evusheld-significantly-protected-against-symptomatic-221200107.html

Evusheld has been found to significantly reduce the risk of developing symptomatic COVID-19.