Author + information
- Erika Berman Rosenzweig, MD⁎ (, )
- D. Dunbar Ivy, MD,
- Allison Widlitz, MS, PA,
- Aimee Doran, RN, MS, CPNP,
- Lori R. Claussen, RN,
- Delphine Yung, MD,
- Steven H. Abman, MD and
- Robyn J. Barst, MD
- ↵⁎Division of Pediatric Cardiology, New York Presbyterian Hospital, 3959 Broadway, BHN 2-255, New York, New York 10032
We agree with Dr. Standing that a pediatric formulation of bosentan is needed. The pharmaceutical development of a pediatric formulation, in the form of an orodispersible tablet with a flexible dosage of 8 to 32 mg, is currently undergoing clinical evaluation in children in Europe and in the U.S.
However, during the course of development and validation of the pediatric formulation, the current adult formulation of bosentan was used to begin evaluation of the pharmacokinetics and safety of bosentan in children (1). We acknowledge that we do not describe in detail in our study (2) the technical aspects associated with cutting the adult tablets for the treatment of children. However, several studies have shown the adult formulation is suitable to this situation:
1. The active bosentan substance is uniformly spread throughout the bosentan tablet.
2. Seventy-five percent of the tablet weight is drug substance, thereby limiting the possibility of nonuniformity of the medication dose.
3. The weight of halved tablets, split with a commercially available tablet cutter, was within European and U.S. Pharmacopeia specifications (Actelion, personal communication, 2001). In addition, dissolution rates were measured and found to be similar for both whole and halved tablets.
Therefore, the use of split tablets was considered appropriate for conducting a pharmacokinetic study (1). Quartered tablets were not tested at that time. In our study (2), we followed the sponsor’s recommendations of using a commercially available cutter to split the tablets, with no crushing of halved/quartered tablets, and direct oral administration.
Whereas the pharmaceutical development of the pediatric formulation of bosentan was ongoing, we treated children with symptomatic pulmonary arterial hypertension (PAH) at our clinics with the adult bosentan formulation following the sponsor’s recommendation for dosing in children at that time (i.e., based on a conservative extrapolation by weight of the recommended adult dosages). Using this approach, these data demonstrated the safety and efficacy of bosentan for pediatric PAH. However, we also agree with Dr. Standing that pediatric dosing needs to be studied further. We anticipate that the current evaluation of a pediatric bosentan formulation will lead to optimal bosentan dosing regimens for children with PAH.
- American College of Cardiology Foundation