CORRESPONDENCE: LETTER TO THE EDITOR
Long-Term Bosentan Treatment in Children With Pulmonary Arterial Hypertension
Joseph F. Standing, MPharm, MRPharmS*
* School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, United Kingdom (Email: Joseph.Standing{at}ulsop.ac.uk).
One of the core principles of scientific research is to provide full details of the experimental methods for replication in further study or clinical practice. As with many published studies (1), Rosenzweig et al. (2) failed to provide details of the drug formulation in their report. Bosentan is currently only commercially available in tablet form, and the dosing used in their study appears to be multiples of halved/quartered tablets. It is widely recognized that splitting tablets causes significant dosing inaccuracy, even when commercially available tablet cutters are used (3,4). Furthermore, many children are unable to swallow whole tablets (5), and crushing the tablets can impair drug absorption (6). Rosenzweig et al. (2) do not report how their patients took the dose (whether or not it was swallowed whole).
If the published report does not detail the drug formulation and method of administration, the reliability of any findings is questionable as the methods cannot be repeated accurately. If tablets were cut in half/quartered and crushed, both the amount of drug administered and its absorption are questionable, bringing the validity of the results into doubt.
In their report, Rosenzweig et al. (2) cite a pharmacokinetic study (7) on the dosing of bosentan in pediatric patients that also fails to give formulation and administration details and whose lowest dose is 31.25 mg as opposed to 15.6 mg in Rosenzweig et al. (2). Bosentan may well be a useful agent in the treatment of pulmonary arterial hypertension in children; surely it is now time that a pediatric liquid formulation be developed, the efficacy and dose optimization of which can be addressed in a well-conducted prospective clinical trial.
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1. Standing JF, Khaki ZF, Wong IC. Poor formulation information in published pediatric drug trials Pediatrics 2005;116:559-562.[Free Full Text]2. Rosenzweig EB, Ivy DD, Widlitz A, et al. Effects of long-term bosentan in children with pulmonary arterial hypertension J Am Coll Cardiol 2005;46:697-706.[Abstract/Free Full Text] 3. Teng J, Song CK, Williams RL, Polli JE. Lack of medication dose uniformity in commonly split tablets J Am Pharm Assoc 2002;42:195-199. 4. Breitkreutz J, Wessel T, Boos J. Dosage forms for peroral drug administration to children Paediatr Perinat Drug Ther 1999;3:25-33. 5. Czyzewski DI, Runyan RD, Lopez MA, Calles NR. Teaching and maintaining pill swallowing in HIV-infected children AIDS Reader 2000;10:88-95. 6. Notterman DA, Nardi M, Saslow JG. Effect of dose formulation on isoniazid absorption in two young children Pediatrics 1986;77:850-852.[Abstract/Free Full Text] 7. Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension Clin Pharmacol Ther 2003;73:372-382.[CrossRef][Web of Science][Medline]
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