Computer modeling confirms Daybue dosing regimen
Back-to-back studies confirm weight-based strategy
Computer modeling confirms the weight-based dosing strategy for Daybue (trofinetide) to treat people with Rett syndrome, ages 2 and older.
That’s according to two, back-to-back studies published separately in Advances in Therapy.
Daybue, from Acadia Pharmaceuticals, is the first therapy approved in the U.S. for people with Rett syndrome. Taken daily by mouth or feeding tube, the liquid solution contains an analog of glypromate, a naturally occurring protein fragment found in the brain. It’s thought this molecule will address inflammation and impaired growth of nerve cell connections that contribute to abnormalities seen in Rett patients.
Two clinical trials demonstrated the therapy’s benefits: the Phase 3 LAVENDER trial (NCT04181723), which enrolled girls and women with Rett ages 5-20, and the Phase 2/3 DAFFODIL study (NCT04988867), with Rett girls, ages 2-4.
Dosing in both trials was based on participants’ body weight. In LAVENDER, participants received one of four twice-daily doses of Daybue, ranging from 6 grams to 12 grams for those weighing 12 kg to 50 kg or more (26-110 pounds). Participants in DAFFODIL received one of two twice-daily doses of 5 grams or 6 grams for weights from 9 kg to 20 kg (20-44 pounds).
Doses chosen for pharmacokinetics
Daybue doses for the trials were selected according to early modeling of population pharmacokinetics, or popPK, the study of how a medicine moves into, through, and out of the body, at the population level. It’s commonly used to guide drug development by assessing the variability in drug concentrations within a patient population receiving different doses of a medication.
Scientists at Acadia and their collaborators conducted popPK modeling analyses for each trial using updated data to confirm whether the weight-based dosing regimen resulted in Daybue blood levels within the effective range.
For the LAVENDER analysis, “Population Pharmacokinetic Modeling to Support Trofinetide Dosing for the Treatment of Rett Syndrome,” the team collected data on 5,595 Daybue blood concentrations in 442 healthy volunteers and Rett patients who participated in 13 clinical trials, including LAVENDER.
The researchers built the popPK model based on these data and ran simulations to predict blood levels over time for each of the four weight-based dosing groups.
According to computer simulations, the blood levels of Daybue for each weight-based dosing group fell within the effective range over a 12-hour period. Factors such as age, body weight, disease status, kidney function, and the occurrence of diarrhea did not appear to affect the findings.
“These results show that the approved weight-banded dosing regimen that was used in the LAVENDER study is adequate for girls and women aged 5-20 years with Rett syndrome,” the team wrote.
Likewise, in the DAFFODIL analysis, “Population Pharmacokinetics of Trofinetide in a Pediatric Population Aged 2–4 Years with Rett Syndrome,” researchers built a popPK model based on 5,709 Daybue blood concentrations in 455 participants enrolled in 14 clinical studies, including samples obtained from 13 participants in the DAFFODIL study.
Modeling showed that the amount of Daybue in the blood over 12 hours following a single dose of 5 or 6 grams achieved the same blood level known to be effective in people with Rett. Model-predicted Daybue exposures in DAFFODIL were similar to those found in the LAVENDER study analysis, the team noted.
“This study supports the approved dosing recommendations for trofinetide in individuals aged 2-4 years with Rett syndrome,” the scientists wrote.
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