Eliglustat tartrate, trade named Cerdelga, was developed by Genzyme Company (a secondary of the Sanofi Company)1,2,3. Eliglustat tartrate is a small molecule drug that was developed for the treatment of Gaucher’s disease1,2,3. Gaucher’s disease is an uncommon autosomal recessive lysosomal storage condition where there is an accumulation of lipid glucosylceramide in the Gaucher cells in the spleen, liver and bone marrow1,2,3. This accumulation of lipid glucosylceramide occurs due to the limited production of glucosylceramidase and leads to an enlarged spleen, enlarged liver, skeletal issues, anaemia, and thrombocytopenia1,2,3. To reduce the accumulation of lipid glucosylceramide in the Gaucher cells, eliglustat tartrate inhibits glucosylceramide synthase, therefore, reducing the enzyme producing glucosylceramide1,2,3. Eliglustat tartrate is taken orally and then metabolized in the liver by the cytochrome P450 system, specifically CYP2D6 and CYP3A4; however, CYP3A4 is less involved in the metabolism than CYP2D61,2,3. It was determined that the pharmacokinetics of eliglustat tartrate is contingent on the phenotype of CYP2D63. Patients with extensive or intermediate metabolizers have a greater than dose proportional, time-dependent, non-linear pharmacokinetic profile3. Those that have poor metabolizers were time-independent and had a linear pharmacokinetic profile3.
The U.S. Food and Drug Administration approved eliglustat tartrate for the treatment of Gaucher’s disease in August 20141,2,3. There were three phase 1 clinical trials performed for eliglustat tartrate, an escalating single-dose trial, a multiple dose trial and a trial looking at fed versus fasted states1,2,3. In the escalating single-dose trial, there were 99 healthy men were enrolled that were between the ages of 18 and 442. The inclusion criteria also required that the men weight between 50 to 100 kg and be within 20 percent of ideal body weight; that the men have regular physical examinations, electrocardiograms, vital signs and clinical laboratory assessments2. The exclusion criteria required that the 99 participants not ingest any associated medications within seven days before enrolling in the trial while also not receiving any immunizations, donating any blood or receiving an investigational drug 30 days prior to enrollment in the trial2. A history of drug allergies, active eczema or psoriasis at screening, positive tests for HIV, hepatitis C or hepatitis B antibodies along with any positive drug screen or urine tests were included in the exclusion criteria as well2. This study was a double-blind, placebo-controlled, randomized, parallel-group study that the 99 participants were broken out into cohorts1,2. There were eight in each cohort, six with the active drug and two with placebo2. All of the participants in the group were required to check into the clinic the night before the trial to sign the informed consent and have all the inclusion/ exclusion criteria re-checked2. The participants were not randomized into active drug versus placebo until after all the inclusion/ exclusion criteria re-checked and fasted until four hours after dosing2. The single dose study had a 21-day screening period with a 72-hour evaluation period, and a safety follow up of 9-11 days later1,2. The dose of eliglustat tartrate was given based on the weight of the participant with the initial dose being 0.01 mg/kg2. When studying dose escalation, the new cohort of participants were not able to start their study until the previous group had completed their 9-11 day safety follow up and the dose given was deemed safe and tolerable2. Finally, the single dose was given orally, the morning after an overnight fast, with blood samples taken before dosing and after dosing at 5, 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 8, 10, 12, 18, 24, and 48 hours2. Urine samples were also taken between 0-4 hours and 4-8 hours after dosing2.
Regarding the study design for the escalating single-dose clinical trial, I thought that the study was set up quite well. The study made sure that there was informed consent of the participants, they checked all the inclusion and exclusion criteria before every dosing to make sure the participants met each one before being administered the drug. I also thought it was very beneficial to the study that before starting a new cohort for dose escalation, that they completely finished the safety window for the previous cohort, ensuring that the previous dose was safe. However, there was something that I found interesting with the inclusion criteria for the escalating single-dose study, and that was that there was no mention of cytochrome P450s. Since eliglustat tartrate requires the metabolism of CYP2D6 and CYP3A4 to be active and the phenotype of the CYP2D6 plays an essential role in the pharmacokinetics of the drug, then shouldn’t there be something in the inclusion criteria for a clinical test on those specific P450s? This question must have been one that was asked by others in the study as well because, in addition to the inclusion criteria for the single-dose study, the multi-dose study performed clinical tests on the phenotype of CYP2D6 before the participants were enrolled into the trail2.