Dordaviprone, a protease activator of the mitochondrial caseinolytic protease P (ClpP), is an antineoplastic agent.1, 2
Dordaviprone is used to treat adults and pediatric patients ≥1 year of age with diffuse midline glioma harboring an H3 K27M mutation who have experienced disease progression despite prior therapy.1, 2 This indication was approved under accelerated approval based on response rate and duration of response; continued approval may be contingent on verification of clinical benefit in confirmatory trials.1, 2 Patients should be selected for treatment based on the presence of an H3 K27M mutation; an FDA-approved test for the detection of the H3 K27M mutation is not currently available.1
Dordaviprone has been designated an orphan drug by FDA for the treatment of malignant glioma.3
The efficacy of dordaviprone was evaluated in 5 open-label, non-randomized US studies in adults and pediatric patients with H3 K27M-mutant diffuse midline glioma.1, 2 Patients included were required to have progressive, measurable disease, be ≥90 days post-radiation, an adequate washout from prior therapies, a Karnofsky Performance Status (KPS)/Lansky Performance Status (LPS) ≥60, and stable or decreasing corticosteroid use; patients with diffuse intrinsic pontine glioma, primary spinal tumors, atypical histology, or CSF dissemination were excluded.1, 2 Inclusion criteria was met in 50 patients who comprised the efficacy population and received weight-based dosing of dordaviprone until disease progression or unacceptable toxicity.1, 2 The primary endpoint was overall response rate (ORR) as assessed by a blinded independent central review using Response Assessment in Neuro-Oncology (RANO) 2.0 criteria.1, 2 The median age of patients was 31 years (range 9-70 years) and 6% were <17 years of a 46% of patients were female, 72% were treated at first recurrence and 28% had 2 or more recurrences.1 Tumors were primarily located in the thalamus (52%) or other midline regions (48%), and most patients had prior temozolomide exposure (88%) and corticosteroid use (62%) at baseline.1, 2 Overall, dordaviprone demonstrated an ORR of 22% (16% partial and 6% minor responses) with a median duration of response of 10.3 months; 73% of responders had a duration of response ≥6 months and 27% of responders had a duration of response ≥12 months.1, 2 Median time to response was 3.6 months (range 1.6-15.6 months).1 The ORR was 20% when assessed by the RANO-High-Grade Glioma (HGG) and 20% when assessed by the RANO-Low-Grade Glioma (LGG) criteria.1, 2
Diffuse midline glioma with an H3 K27M mutation is a rare, aggressive brain tumor that occurs in both pediatric patients and adults.2 These tumors arise from midline structures, cannot typically be surgically removed, and are characterized by loss of normal H3 K27 trimethylation, leading to widespread epigenetic dysregulation and tumor growth.2 These tumors are classified as WHO Grade 4 and carry a poor prognosis, with median overall survival of about 10-15 months.2 Standard treatment consists of radiation therapy, as complete surgical resection is usually not feasible and chemotherapy has not shown clear benefit.2 Before the approval of dordaviprone, no systemic therapies were available, and most patients pursued clinical trial enrollment or supportive care after radiation.2
Administer dordaviprone orally on an empty stomach, at least 1 hour before or 3 hours after food intake.1
Swallow capsules whole.1 For patients unable to swallow the capsules, open the capsules, mix the contents with 15-30 mL of liquid, and give the mixture orally within 2 hours; discard and prepare the dose again if not used within 2 hours of mixing.1
If a dose is missed by ≤2 days, take it as soon as possible; if >2 days have passed, skip the dose and resume the next scheduled dose.1
If vomiting occurs after a dose, do not take the dose; take the next dose at the regular scheduled time.1
Store the capsules at room temperature between 20-25°C; excursions are permitted between 15-30°C.1
Dordaviprone is commercially available as the hydrochloride salt; dosage is expressed in terms of dordaviprone.1
The recommended dosage of dordaviprone for the treatment of diffuse midline glioma with an H3 K27M mutation and progressive disease in adults is 625 mg orally once weekly.1
The recommended dosage for dordaviprone for the treatment of diffuse midline glioma with an H3 K27M mutation and progressive disease in pediatric patients ≥1 year of age who weigh ≥10 kg is shown in Table 1.1
Continue therapy until disease progression or unacceptable toxicity.1
Body Weight (kg) | Recommended Oral Dosage |
|---|---|
10 to <12.5 | 125 mg once weekly |
12.5 to <27.5 | 250 mg once weekly |
27.5 to <42.5 | 375 mg once weekly |
42.5 to <52.5 | 500 mg once weekly |
≥52.5 | 625 mg once weekly |
Dosage Modifications for Adverse Reactions
If an adverse reaction occurs, treatment interruption, dosage reduction, and/or discontinuation of therapy may be necessary based on severity of the adverse event.1
Manufacturer recommended dosage modifications and reductions for adverse reactions are shown in Tables 2 and 3.1
Patient Weight (kg) | First Dosage Reduction | Second Dosage Reduction |
|---|---|---|
10 to <12.5 | Permanently discontinue | Not applicable |
12.5 to <27.5 | 125 mg once weekly | Permanently discontinue |
27.5 to <42.5 | 250 mg once weekly | 125 mg once weekly |
42.5 to <52.5 | 375 mg once weekly | 250 mg once weekly |
≥52.5 | 500 mg once weekly | 375 mg once weekly |
Adverse Reactions | Severity | Dosage Modification (see Table 2) |
|---|---|---|
Hypersensitivity | Any grade | If hypersensitivity to dordaviprone is suspected, interrupt treatment until the reaction resolves. Permanently discontinue dordaviprone if serious hypersensitivity occurs. |
QTc Interval Prolongation | QTc absolute value >500 msec or an increase of >60 msec from baseline | Interrupt dordaviprone therapy until the QTc is ≤480 msec or returns to baseline, then resume at the next lower dosage. |
QTc Interval Prolongation | Torsades de pointes, polymorphic ventricular tachycardia, or any signs or symptoms of a serious or life-threatening arrhythmia | Permanently discontinue. |
Other Adverse Reactions | Grade 3 or 4 | Interrupt dordaviprone therapy until Grade ≤1 or return to baseline, then resume at next lower dosage. |
Other Adverse Reactions | Recurrent Grade 4 | Permanently discontinue. |
Dosage Modification for Cytochrome P-450 (CYP) 3A4 Inhibitors
Avoid concomitant use of dordaviprone with strong and moderate CYP3A4 inhibitors.1
If a strong CYP3A4 inhibitor must be used with dordaviprone in adults and pediatric patients weighing ≥52.5 kg, reduce the dordaviprone dosage to 375 mg once weekly.1
If a moderate CYP3A4 inhibitor must be used with dordaviprone in adults and pediatric patients weighing ≥52.5 kg, reduce the dordaviprone dosage to 500 mg once weekly.1
Dosing for pediatric patients <52.5 kg receiving strong or moderate CYP3A4 inhibitors is not established.1
After the CYP3A4 inhibitor is stopped, wait 3-5 half-lives, then increase dordaviprone to the dosage taken prior to starting the CYP3A4 inhibitor.1
The manufacturer makes no specific dosage recommendations in patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations in patients with renal impairment.1
The manufacturer makes no specific dosage recommendations in geriatric patients.1
Dordaviprone can cause severe hypersensitivity reactions.1 In the pooled safety population of 356 patients, Grade 3 hypersensitivity occurred in 0.3% of patients.1 Symptoms may include rash, hives, fever, low blood pressure, wheezing, or facial or throat swelling.1 Patients should be counseled to seek immediate medical attention if these occur.1 If significant hypersensitivity or anaphylaxis develops, interrupt the dordaviprone dosage and provide appropriate treatment; depending on severity, treatment may be temporarily held or permanently discontinued.1
Dordaviprone causes a concentration-dependent QTc prolongation, increasing the risk of ventricular arrhythmias such as torsades de pointes and sudden death.1 Among 82 patients with post-baseline ECGs, 6% had QTc increases >60 msec and 1.2% had QTc values >500 msec.1 Monitor ECGs and electrolytes before starting dordaviprone therapy and periodically as indicated thereafter.1
Avoid using dordaviprone with other QT-prolonging drugs; if unavoidable, separate administration and increase monitoring.1 More frequent monitoring is warranted in patients with congenital long QT syndrome, existing QTc prolongation, prior ventricular arrhythmias, electrolyte disturbances, heart failure, or those receiving strong or moderate CYP3A4 inhibitors.1 Interrupt or reduce dordaviprone dosage for QT prolongation, and permanently discontinue dordaviprone if life-threatening arrhythmias occur.1
Fetal/Neonatal Morbidity and Mortality
Based on animal data and its mechanism of action, dordaviprone can cause fetal harm.1 In embryo-fetal studies, dordaviprone given to pregnant rats and rabbits during organogenesis led to fetal death, impaired growth, and structural abnormalities at exposures below those used clinically.1
Patients who are pregnant or may become pregnant should be warned of this risk.1 Females of reproductive potential should use effective contraception during treatment and for 1 month after the last dose.1 Male patients with female partners of reproductive potential should also use effective contraception during treatment and for 1 month after therapy ends.1
There are no data on dordaviprone use in pregnant women.1 Based on findings from animal studies and its mechanism of action, dordaviprone can cause fetal harm if used during pregnancy.1 In embryo-fetal development studies in rats and rabbits, dordaviprone caused fetal death, impaired growth, and structural abnormalities at exposures below those expected at the highest recommended human dose.1 Pregnant women should be advised of the potential risk to the fetus.1
There are no data on the presence of dordaviprone in human milk, its effects on a breastfed child, or its impact on milk production.1 Because of the potential for serious adverse reactions in breastfed children, women should not breastfeed during treatment with dordaviprone and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Dordaviprone can cause fetal harm if used during pregnancy.1 Pregnancy status should be verified in females of reproductive potential before starting treatment.1
Females of reproductive potential and male patients with female partners of reproductive potential should use effective contraception during dordaviprone therapy and for 1 month after the final dose.1 Based on its mechanism of action, dordaviprone may also impair fertility in both males and females.1
The safety and effectiveness of dordaviprone have been established in pediatric patients ≥1 year of age with diffuse midline glioma harboring an H3 K27M mutation.1 Efficacy was evaluated in 4 patients, 9-17 years of age, and safety was assessed in 154 patients, 3-17 years of age, across 4 open-label studies, with no additional safety concerns identified in this population.1 In pediatric patients weighing ≥10 kg, dordaviprone exposure is predicted to fall within the range observed in adults at the recommended dose.1 The safety and effectiveness of dordaviprone have not been established in pediatric patients <1 year of age.1
Among 376 patients with glioma treated with dordaviprone at the recommended dose in 4 open-label studies, 3.7% were ≥65 years of age and 0.5% were ≥75 years of age.1 The number of older patients enrolled was insufficient to determine whether responses differ from those in younger patients.1
No clinically significant differences in dordaviprone pharmacokinetics were observed in patients with mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] with AST greater than the ULN, or total bilirubin >1-1.5 times ULN with any AST); however, the effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) is unknown.1
Patients with severe renal impairment (creatinine clearance <30 mL/minute) experienced a 1.5-fold increase in AUC and a slight (1.1-fold) increase in Cmax after a single 375-mg dose of dordaviprone.1
The most common (≥20%) adverse reactions are fatigue, headache, vomiting, nausea, and musculoskeletal pain.1
The most common (≥2%) Grade 3 or 4 laboratory abnormalities are decreased lymphocytes, decreased calcium, and increased alanine aminotransferase.1
Dordaviprone is primarily metabolized by cytochrome P-450 (CYP) 3A4, with minor contributions from CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5.1
Dordaviprone inhibits CYP1A2, CYP2B6, and CYP2C19, induces CYP2B6, and is a substrate for CYP3A4.1
Dordaviprone inhibits multidrug and toxin extrusion protein (MATE) 1, MATE 2-K, organic anion transporter (OAT) 1, OAT3, organic anion-transporting polypeptide 1B1 (OATP1B1), OATP1B3, and organic cation transporter 1 (OCT1).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Strong or moderate CYP3A4 inhibitors can markedly increase dordaviprone exposure, increasing the risk of adverse reactions; avoid concomitant use and if use cannot be avoided in adults and pediatric patients weighing ≥52.5 kg, reduce dordaviprone dosage as recommended.1
Strong or moderate CYP3A4 inducers should be avoided because concomitant use substantially reduces dordaviprone exposure and may decrease antitumor activity.1
Coadministration of dordaviprone with itraconazole, a strong CYP3A4 inhibitor, increased dordaviprone Cmax by 2-fold and AUC by 4-fold.1 Coadministration of dordaviprone with moderate CYP3A4 inhibitors, such as fluconazole or erythromycin, is predicted to increase dordaviprone Cmax by ~1.5-fold and AUC by 2.5-fold.1 No clinically significant pharmacokinetic changes are expected when dordaviprone is given with cimetidine, a weak CYP3A4 inhibitor.1
Coadministration of dordaviprone with rifampin, a strong CYP3A4 inducer, is predicted to decrease dordaviprone Cmax by 68% and AUC by 83%, while coadministration with efavirenz, a moderate inducer, is predicted to decrease dordaviprone Cmax by 44% and AUC by 65%.1
Drugs Known to Prolong QTc Interval
Dordaviprone causes concentration-dependent QTc prolongation; combining dordaviprone with QT-prolonging drugs increases the risk of arrhythmias and should generally be avoided.1 At 1.2 times the maximum recommended dordaviprone dosage, the estimated mean QTc(Fridericia's formula) increase was 11.8 msec.1
If concomitant use is unavoidable, separate the dosages and increase the frequency of monitoring.1
Dordaviprone is a brain-penetrant imipridone that activates mitochondrial caseinolytic protease (ClpP) and blocks the dopamine D2 receptor.1, 2 In H3 K27M-mutant glioma cells (where lysine 27 on histone H3 is replaced by methionine), dordaviprone disrupts tumor metabolism, damages mitochondria, and activates the integrated stress response, leading to apoptosis.1, 2 These metabolic changes also inhibit histone demethylases, restoring H3 K27 trimethylation, the key epigenetic defect in H3 K27M-mutant diffuse glioma.1, 2
Dordaviprone demonstrates predictable pharmacokinetics at the approved dosage, with exposure increasing proportionally across the therapeutic dosage range and no evidence of drug accumulation with once-weekly administration.1 After administration, the median time to peak concentration is 1.4 hours.1 Administration with a high-fat meal (800-1,000 calories, 50% fat) decreases dordaviprone Cmax by 40% without affecting overall exposure.1 Dordaviprone is 95-97% protein-bound, and has a blood-to-plasma ratio of 0.67 (in vitro).1 Dordaviprone is primarily metabolized by CYP3A4, with minor contributions from several other CYP enzymes (i.e., CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A5).1 The mean terminal half-life of dordaviprone is 11 hours, and most of the administered dose is recovered as metabolites in urine (70%) and feces (20%).1 In severe renal impairment (creatinine clearance [ClCr] <30 mL/minute), a single dose of 375 mg increased dordaviprone exposure by 10-50%.1 In moderate hepatic impairment (Child Pugh class B), a single dose of 125 mg increased dordaviprone exposure 20-50%.1 No clinically significant pharmacokinetic differences have been observed based on age, sex, race, or mild hepatic impairment, although the effects of severe hepatic impairment remain unknown.1 In pediatric patients weighing ≥10 kg, dordaviprone exposure is predicted to fall within the adult exposure range at the recommended dosage.1
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Dordaviprone is available through the designated specialty pharmacy, Onco360 Oncology Pharmacy. Consult the Onco360 Oncology Pharmacy website ([Web]) or the dordaviprone website ([Web]) for more information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 125 mg (of dordaviprone) | Modeyso® | Jazz Pharmaceuticals |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions May 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Jazz Pharmaceuticals, Inc. MODEYSO® (dordaviprone) ORAL prescribing information. 2025 Aug. [Web]
2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 219876Orig1s000: Multidiscipline review. [Web]
3. Food and Drug Administration. Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2025 Nov 16 [Web]