Chemical formula: C₂₄H₂₆N₄O₃S Molecular mass: 450.56 g/mol
Mitapivat interacts in the following cases:
Based on in vitro data, mitapivat may induce UGT1A1, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 and may decrease systemic exposure to substrates of these enzymes (e.g. irinotecan [UGT1A1]; bupropion [CYP2B6]; omeprazole [CYP2C19]; repaglinide [CYP2C8]; warfarin [CYP2C9]). Concomitant use of mitapivat with substrates of these enzymes was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not UGT1A1 substrates or sensitive substrates of CYP2B6 or CYP2C should be considered during treatment with mitapivat. If co-administration is unavoidable, patients should be monitored for loss of therapeutic effect of substates of these enzymes, especially for those with a narrow therapeutic index (e.g. irinotecan [UGT1A1]; cyclophosphamide [CYP2B6]; valproic acid [CYP2C19]; paclitaxel [CYP2C8]; warfarin, phenytoin [CYP2C9]).
The effect of rifampicin (a strong CYP3A4 inducer) on the pharmacokinetics of a single dose of mitapivat was evaluated in a Phase 1 study. Rifampicin decreased mitapivat AUC0-t, AUC∞ and Cmax by 91%, 91% and 77%, respectively. Decreased mitapivat plasma exposures may reduce the efficacy of mitapivat. The concomitant use of CYP3A4 inducers with mitapivat should be avoided. If concomitant use of a CYP3A4 inducer is unavoidable, patients should be monitored for reduced efficacy of mitapivat.
The effect of itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of a single dose of mitapivat was evaluated in a Phase 1 study. Itraconazole increased mitapivat AUC0-t, AUC∞ and Cmax by 4.7-fold, 4.9-fold and 1.7-fold, respectively. Increased mitapivat plasma exposures may increase the risk of insomnia. The concomitant use of CYP3A4 inhibitors with mitapivat should be avoided. If concomitant use of a CYP3A4 inhibitor is unavoidable, patients should be monitored for increased risk of insomnia.
Mitapivat induces and may inhibit CYP3A4 and co-administration with sensitive CYP3A4 substrates (e.g. midazolam) may alter systemic exposure of these medicinal products. Concomitant use of Pyrukynd with substrates of this enzyme was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not sensitive substrates of CYP3A4 should be considered during treatment with mitapivat. If co-administration of mitapivat with sensitive CYP3A4 substrates is unavoidable, patients should be carefully monitored especially for those substrates with a narrow therapeutic index (e.g. alfentanil, carbamazepine, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).
Based on in vitro data, mitapivat may induce and inhibit P-gp and may alter systemic exposure of substrates (e.g. dabigatran etexilate) of this transporter. Concomitant use of mitapivat with substrates of P-gp was not evaluated in a clinical drug-drug interaction study. Alternative therapies that are not P-gp substrates should be considered during treatment with mitapivat. If co-administration of mitapivat with P-gp substrates is unavoidable, patients should be carefully monitored especially for those substrates with a narrow therapeutic index (e.g. colchicine, digoxin).
Mitapivat exhibits pH-dependent solubility and coadministration with gastric acid-reducing agents (e.g. famotidine) may decrease mitapivat absorption. Concomitant use of mitapivat with medicinal products that elevate gastric pH was not evaluated in a clinical drug-drug interaction study. If concomitant use of gastric acid-reducing agents is unavoidable, patients should be monitored for reduced efficacy of mitapivat.
Mitapivat may decrease the systemic exposure of hormonal contraceptives that are sensitive substrates of cytochrome P450 3A4 (CYP3A4) (e.g. ethinylestradiol). Women of childbearing potential should be counselled regarding the use of additional or alternative contraception methods.
There are no human data on the effect of mitapivat on fertility. Animal studies have shown reversible effects on reproductive organs of males and females. While taking mitapivat, there may be an impact on the ability of a woman and a man to conceive.
There are no or limited amount of data from the use of mitapivat in pregnant women. Studies in animals have shown reproductive toxicity.
Mitapivat is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether mitapivat and/or its metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to abstain from mitapivat therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Women of childbearing potential should avoid becoming pregnant while receiving mitapivat.
Women of childbearing potential should use contraception during treatment with mitapivat and for at least 1 month after the last dose. Mitapivat may decrease the systemic exposure of hormonal contraceptives that are sensitive substrates of CYP3A4. Additional or alternative methods of contraception should be considered.
There are no human data on the effect of mitapivat on fertility. Animal studies have shown reversible effects on reproductive organs of males and females. While taking mitapivat, there may be an impact on the ability of a woman and a man to conceive.
Mitapivat has a minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience insomnia during treatment with mitapivat.
The safety evaluation of mitapivat is based on experience from a randomised, double-blind, placebocontrolled clinical study of adult patients with PK deficiency who were not regularly transfused (ACTIVATE) and a single-arm clinical study of adult patients with PK deficiency who were regularly transfused (ACTIVATE-T).
The most common adverse reaction across both studies was insomnia (19.4%) and the most common laboratory abnormalities observed were oestrone decreased (males) (43.5%) and oestradiol decreased (males) (8.7%).
The adverse reactions associated with mitapivat as identified in clinical studies of patients with PK deficiency are tabulated below.
Adverse reactions are listed by MedDRA system organ class and frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
| System organ class | Very common | Common |
|---|---|---|
| Psychiatric disorders | Insomnia | |
| Gastrointestinal disorders | Nausea | |
| General disorders and administration site conditions | Hot flush | |
| Investigations | Oestrone decreased (males) | Blood testosterone increased (males), Oestradiol decreased (males) |
Abrupt interruption or discontinuation of mitapivat can lead to acute haemolysis.
In a Phase 2 study, 2 of 52 patients (3.8%) experienced haemolysis upon sudden withdrawal of mitapivat, including 1 serious adverse event of acute haemolysis. In both patients who received an initial mitapivat dose of 300 mg twice daily, a rapid and large Hb increase was observed during the first 3 weeks of treatment. This was followed by a sudden discontinuation of mitapivat without taper, which resulted in acute haemolysis with anaemia. Patients who missed a few doses of mitapivat later in their treatment course, or for whom the dose was tapered, did not experience events of acute haemolysis.
Mitapivat is a weak aromatase inhibitor in vitro. In ACTIVATE, 1 of 16 (6.3%) males experienced increases in testosterone to above normal levels and 2 of 16 (12.5%) and 9 of 16 (56.3%) males experienced decreases in oestradiol and oestrone below the lower limit of normal, respectively. In ACTIVATE-T, 1 of 7 males (14.3%) experienced oestrone decrease below the lower limit of normal. These changes in hormone levels were maintained throughout the study period. In patients who discontinued mitapivat at the end of the core period, the hormone changes were reversible. Sex hormone analysis in female patients was limited due to physiological variations in hormone levels expected throughout the normal menstrual cycle and the various types of hormonal contraceptives used by patients.
In ACTIVATE, insomnia was reported with a similar incidence between patients who received mitapivat and patients who received placebo and was reported in 6 of 27 (22.2%) patients in ACTIVATE-T. In a Phase 2 study, 5 of 27 (18.5%) patients treated at 50 mg twice daily and 16 of 25 (64%) patients treated at 300 mg twice daily experienced insomnia during the core period.
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