Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

Adam de Beaumais Tiphaine; Lisa Lynqsie Hjalgrim; Jacob Nersting; Joerg Breitkreutz; Brigitte Nelken; Martin Schrappe; Martin Stanulla; Caroline Thomas; Yves Bertrand; Guy Leverger; André Baruchel; K. Schmiegelow; Evelyne Jacqz-Aigrain

doi:10.1016/j.ejps.2015.12.002

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

Adam de Beaumais Tiphaine, Lisa Lynqsie Hjalgrim, Jacob Nersting, Joerg Breitkreutz, Brigitte Nelken, Martin Schrappe, Martin Stanulla, Caroline Thomas, Yves Bertrand, Guy Leverger, André Baruchel, K. Schmiegelow, Evelyne Jacqz-Aigrain

Department of Clinical Medicine

6 Citations (Scopus)

Abstract

BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.

METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.

RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.

CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	83
Pages (from-to)	1-7
Number of pages	7
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2015.12.002
Publication status	Published - 15 Feb 2016

Keywords

Journal Article
Research Support, Non-U.S. Gov't

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10.1016/j.ejps.2015.12.002

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Tiphaine, A. D. B., Hjalgrim, L. L., Nersting, J., Breitkreutz, J., Nelken, B., Schrappe, M., Stanulla, M., Thomas, C., Bertrand, Y., Leverger, G., Baruchel, A., Schmiegelow, K., & Jacqz-Aigrain, E. (2016). Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children. European Journal of Pharmaceutical Sciences, 83, 1-7. https://doi.org/10.1016/j.ejps.2015.12.002

Tiphaine, ADB, Hjalgrim, LL, Nersting, J, Breitkreutz, J, Nelken, B, Schrappe, M, Stanulla, M, Thomas, C, Bertrand, Y, Leverger, G, Baruchel, A, Schmiegelow, K & Jacqz-Aigrain, E 2016, 'Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children', European Journal of Pharmaceutical Sciences, vol. 83, pp. 1-7. https://doi.org/10.1016/j.ejps.2015.12.002

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abstract = "BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.",

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author = "Tiphaine, {Adam de Beaumais} and Hjalgrim, {Lisa Lynqsie} and Jacob Nersting and Joerg Breitkreutz and Brigitte Nelken and Martin Schrappe and Martin Stanulla and Caroline Thomas and Yves Bertrand and Guy Leverger and Andr{\'e} Baruchel and K. Schmiegelow and Evelyne Jacqz-Aigrain",

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T1 - Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

AU - Tiphaine, Adam de Beaumais

AU - Hjalgrim, Lisa Lynqsie

AU - Nersting, Jacob

AU - Breitkreutz, Joerg

AU - Nelken, Brigitte

AU - Schrappe, Martin

AU - Stanulla, Martin

AU - Thomas, Caroline

AU - Bertrand, Yves

AU - Leverger, Guy

AU - Baruchel, André

AU - Schmiegelow, K.

AU - Jacqz-Aigrain, Evelyne

PY - 2016/2/15

Y1 - 2016/2/15

N2 - BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.

AB - BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization.METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination.RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75 mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred.CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.ejps.2015.12.002

DO - 10.1016/j.ejps.2015.12.002

M3 - Journal article

C2 - 26657824

SN - 0928-0987

VL - 83

SP - 1

EP - 7

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

ER -

Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children

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