Mitapivat

Mitapivat is a pyruvate kinase activator and acts by directly binding to the pyruvate kinase tetramer. The red blood cell (RBC) form of pyruvate kinase (PKR) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP) levels, shortened RBC lifespan and chronic haemolysis. Mitapivat improves RBC energy homeostasis by increasing PKR activity.

In healthy volunteers, decreases in 2,3 diphosphoglycerate and increases of ATP concentrations were observed after dosing mitapivat to steady state. Changes to these pharmacodynamic markers are not considered significant for the assessment of activity in subjects with PK deficiency that should rely on clinical parameters only.

The pharmacokinetics of mitapivat have been characterised in healthy adults and patients with PK deficiency. Mitapivat is readily absorbed, extensively distributed and exhibits low clearance following oral administration.

Autoinduction of mitapivat clearance was evident upon repeat dosing.

The pharmacokinetics of mitapivat showed low to moderate variability in healthy adult subjects.

Absorption

Mitapivat was readily absorbed after single and multiple doses both in healthy subjects and in patients with PK deficiency. Median T_max values at steady state were 0.5 to 1 hour post dose across the dose range studied (5 mg to 700 mg twice daily).

The absolute bioavailability after a single dose was approximately 73%.

Mitapivat exhibits pH-dependent solubility. High solubility is observed up to pH 5.5, with decreasing solubility at higher pH which may decrease mitapivat absorption.

Effect of food

Following administration of a single dose in healthy subjects, and a high-fat meal (approximately 900 to 1000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate and 150 calories from protein) there was no change in AUC_inf while mitapivat C_max decreased by 42%. Administration of mitapivat with a high-fat meal had no clinically meaningful effect on mitapivat pharmacokinetics.

Distribution

Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution. The mean volume of distribution (Vz) was 135 L.

Biotransformation

In vitro studies showed that mitapivat is primarily metabolised by CYP3A4. Following a single oral dose of 120 mg of radiolabelled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.

In vitro drug interaction studies

Metabolic pathways

Mitapivat induces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and UGT1A1. Mitapivat may inhibit CYP3A4.

Drug transporter systems

Mitapivat is a substrate for P-gp and may induce and inhibit P-gp.

Elimination

Mitapivat has a mean t_1/2 ranging from 16.2 to 79.3 hours following single oral dose administrations (5 to 2 500 mg) under fasted conditions to healthy subjects. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7 and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.

After a single oral administration of radiolabelled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.1%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the faeces (less than 1% unchanged).

Linearity / non-linearity

The AUC and C_max of mitapivat increased in a dose-proportional manner over the clinically relevant dose range of 5 to 50 mg twice daily in healthy subjects and in patients with PK deficiency.

Special populations

No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race or body weight.

Elderly

There were 5 patients 65 years of age or older who received mitapivat in the clinical studies ACTIVATE and ACTIVATE-T. No differences in the pharmacokinetics were observed in these patients compared to younger patients.

Hepatic impairment

The pharmacokinetics of mitapivat in patients with mild, moderate or severe hepatic impairment have not been studied.

Renal impairment

The effects of renal impairment on mitapivat pharmacokinetics were assessed as part of the population pharmacokinetic analyses. There were 24 patients with mild (estimated glomerular filtration rate [eGFR] ≥60 to ˂90 mL/min/1.73 m²) and 4 with moderate (eGFR ≥30 to ˂60 mL/min/1.73 m²) renal impairment. Steady-state AUC was similar between patients with normal renal function and mild renal impairment. Geometric mean for steady-state AUC from the small number of patients with moderate renal impairment was higher than that for patients with normal renal function but within the range of steady-state AUCs observed for patients with normal renal function. There are no data available in patients with severe renal impairment.

Paediatric population

The pharmacokinetics of mitapivat in children and adolescent patients less than 18 years old have not been studied.

Mitapivat was not carcinogenic in transgenic rasH2 mice when administered twice daily for a minimum of 26 weeks up to the highest total daily dose of 500 mg/kg/day in male mice (6.4-fold difference in human exposure) and 250 mg/kg/day in female mice (2.6-fold difference in human exposure).

In the 2-year rat carcinogenicity study, proliferative and neoplastic lesions were observed in the liver, thyroid, ovaries and pancreas. Findings in the liver and thyroid were attributed to CYP enzyme induction and were considered rodent-specific. In the ovaries, an increased incidence and/or severity of granulosa and/or luteal/granulosa cell hyperplasia was noted at mitapivat AUC_0-12hr values >100-fold above the range observed in humans at the maximum recommended human dose (MRHD) of 50 mg twice daily. Benign acinar hyperplasia and adenoma in the exocrine pancreas were observed at an increased incidence and/or severity in males from all dose groups (30, 100 and 300 mg/kg/day): a no-effect level was not determined. The incidence of the pancreatic findings was only outside the range observed historically in the test strain at 300 mg/kg/day (47-fold the human AUC_0-12hr at the MRHD). The relevance of the pancreatic findings for humans is unknown.

Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay nor in an in vivo rat bone marrow micronucleus assay.

In embryo-foetal development studies, foetal adverse events were observed at AUC_0-12 values 63-fold (rats) and 3.1-fold (rabbits) above the human AUC_0-12hr value at the MRHD.

In a rat embryo-foetal toxicity study, oral administration of mitapivat was associated with foetal adverse events, including a decrease in the mean number and litter proportion of viable foetuses, lower mean foetal weights, and test article-related external, soft tissue and skeletal malformations. The maternal and foetal no-observed adverse effect level (NOAEL) occurred at a dose of 50 mg/kg/day (13-fold the human AUC 0-12hr at the MRHD).

In a rabbit embryo-foetal toxicity study, oral administration of mitapivat resulted in lower mean foetal body weights. No effects on foetal morphology were observed. The maternal and foetal NOAEL occurred at a dose of 60 mg/kg/day (1.5-fold the human AUC_0-12hr at the MRHD).

In rats, mitapivat was shown to induce perinatal mortality in relation to drug-induced dystocia/prolonged parturition in both the pre-and post-natal development and juvenile toxicity studies at doses ≥ 50 mg/kg/day (≥ 20-fold the human AUC_0-12hr at the MRHD).

In a fertility and early embryonic development study, oral administration of mitapivat twice daily at doses up to 300 mg/kg/day in male rats and 200 mg/kg/day in female rats prior to and during mating, and continuing in females through organogenesis, resulted in no adverse events on fertility in male or female animals. Reversible findings related to the reproductive organs of males and females were observed, which were considered related to aromatase inhibition. In males, reversible microscopic findings (degeneration of the seminiferous tubules, spermatid retention, atypical residual bodies in the testes, and increased incidence of cellular debris in the epididymides) correlating with abnormal sperm evaluation findings (decreased sperm motility and density, increased numbers of abnormal sperm) were observed at AUC_0-12hr values ≥ 23-fold above the human exposure at the MRHD. In females, decreased number of oestrus stages before cohabitation was observed at AUC_0-12hr values 49-fold above the human exposure at the MRHD, and this change resolved upon cessation of dosing.

In repeat dose toxicity studies in male and female rats, reproductive organ changes were observed and were attributable to aromatase inhibition. In males, lower accessory sex gland weights and higher testis weights, as well as microscopic findings in the testis and accessory sex glands were seen at AUC_0-12hr values ≥ 4.7 fold the human exposure at the MRHD. In females, higher ovarian weights and lower uterus weights, and microscopic findings in the ovary and vagina occurred at AUC_0-12hr values 3.0-fold the human exposure. All findings were reversible.

In a juvenile toxicology study initiated in rats aged 7 days and treated up to sexual maturity, most treatment-related findings were considered related to aromatase inhibition. In males, microscopic findings in the testis were observed from the low-dose level of 30 mg/kg/day (1.5-fold the human AUC_0-12hr at the MRHD) and delayed sexual maturity, abnormal sperm evaluation findings, and mating and fertility changes were observed at ≥150 mg/kg/day (≥22-fold the human AUC_0-12hr at the MRHD). In females, oestrous cycle changes were observed at the high-dose level of 200 mg/kg/day (60-fold the human AUC_0-12hr at the MRHD). All evaluable reproductive changes were reversible or partially reversible. Treatment-related decrease and increase in body weights were observed in males and females, respectively, at ≥20-fold the human AUC_0-12hr at the MRHD and were not reversed in females. Bone changes, including lower bone density and mass, were observed at ≥1.5- and ≥20-fold the human exposure in males and females, respectively. These changes were fully reversible in females; in males, they were fully reversible at 1.5-fold the human exposure and partially reversible at higher exposure levels.