Impact of genetic variation on response to therapy
The SmPC for eliglustat states that the CYP2D6 predicted phenotype (metaboliser status) based on genotype is the most important factor affecting pharmacokinetic variability. CYP2D6 poor metabolisers exhibit higher eliglustat concentrations than intermediate or normal (extensive) CYP2D6 metabolisers.
After repeated oral doses of 84 mg eliglustat twice daily, eliglustat elimination half-life is approximately 9 hours in poor metabolisers compared to 4-7 hours in normal and intermediate metabolisers.
Patients who are CYP2D6 ultra-rapid metabolisers may not achieve adequate concentrations to achieve a therapeutic effect.
Testing recommendations
The SmPC for eliglustat states that before initiation of treatment, patients must be genotyped for CYP2D6 to determine the CYP2D6 metaboliser status.
Therapeutic recommendations
Treatment should be initiated and managed under the supervision of a physician experienced in the management of patients with Gaucher disease.
Consult the SmPC for detailed information on drug interactions and additional dose adjustments required in patients with hepatic or renal impairment and in patients taking CYP inhibitors.
CYP2D6 metaboliser status unknown
- Eliglustat should not be used.
CYP2D6 Ultra-rapid metabolisers: Activity score >2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1xN, *1/*2xN
- Patients who are CYP2D6 ultra-rapid metabolisers may not achieve adequate concentrations to achieve a therapeutic effect.
- Eliglustat should not be used.
CYP2D6 Normal metabolisers: Activity score ≥1.25 – ≤2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1, *1/*2, *2/*2
- Adults: 84mg twice daily.
- Paediatrics from 6 to <18 years of age weighing ≥50kg: 84mg twice daily.
- Paediatrics from 6 to <18 years of age weighing 25 to <50kg: 84mg twice daily.
- Additional dose adjustments are required in normal metabolisers with hepatic impairment and/or taking CYP3A or CYP2D6 inhibitors.
- Consult the SmPC.
CYP2D6 Intermediate metabolisers: Activity score >0 – <1.25
Some examples of CYP2D6 genotypes include (see note): *1/*4, *1/*5, *1/*4xN
- Adults: 84mg twice daily.
- Paediatrics from 6 to <18 years of age weighing ≥50kg: 84mg twice daily.
- Paediatrics from 6 to <18 years of age weighing 25 to <50kg: 84mg twice daily.
- Additional dose adjustments are required in intermediate metabolisers with hepatic impairment and/or taking CYP3A or CYP2D6 inhibitors.
- Consult the SmPC.
CYP2D6 Poor metabolisers: Activity score 0
Some examples of CYP2D6 genotypes include (see note): *4/*4, *4/*4xN, *3/*4, *5/*5
- Predictive of higher plasma exposure than normal or intermediate metabolisers.
- Adults: 84mg once daily.
- Paediatrics from 6 to <18 years of age weighing ≥50kg: 84mg once daily.
- Paediatrics 6 to <18 years of age weighing 25 to <50kg: dose not available.
- Additional dose adjustments are required in poor metabolisers with hepatic impairment and/or taking CYP3A or CYP2D6 inhibitors.
- Consult the SmPC.
Note: This is a limited list of examples of CYP2D6 genotypes. N represents the number of additional copies of the gene.
Further information
Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Concomitant administration of substances affecting CYP2D6 or CYP3A4 activity may alter eliglustat plasma concentrations. Eliglustat is an inhibitor of P-glycoprotein and CYP2D6. Dose modifications of eliglustat with concomitant use of some other medicinal products and in patients with hepatic impairment are also dependent on the CYP2D6 phenotype. Clinicians are advised to consult both the eliglustat SmPC and the SmPC of all other prescribed medicinal products for potential drug interactions with eliglustat.
References
Sanofi (2025) Cerdelga 84mg Hard Capsules SmPC. Available at: https://www.medicines.org.uk/emc/product/2615/smpc (Accessed online 23 April 2025).
Clinical Pharmacogenetics Implementation Consortium (CPIC®). Available at: www.cpicpgx.org (Accessed online 24 April 2025).
