Pharmacokinetics of two 6‐mercaptopurine liquid formulations in children with acute lymphoblastic leukemia

Tolbert, Jaszianne; Bai, Shasha; Abdel‐Rahman, Susan M.; August, Keith J.; Weir, Scott J.; Kearns, Gregory L.; Neville, Kathleen

doi:10.1002/pbc.26465

Cited by 5 publications

(8 citation statements)

References 20 publications

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“…The intrinsic poor solubility of certain drugs can increase risks of non-linear PK due to incomplete dissolution within the GI tract ( 35 , 49 , 52 , 63 ), especially for children whose GI volume is less compared to adults ( 93 ).…”

Section: Resultsmentioning

confidence: 99%

“…From the relative BA studies identified, 12 studies showed drug product effects on BA ( 32 , 34 – 41 , 43 , 45 , 63 ). The magnitude of drug product effects may be amplified in pediatric populations where differences in absorption relate to factors such as GI motility where small formulation changes can result in large PK differences as shown with controlled release formulations ( 33 , 38 , 40 , 44 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Three studies reported DRBA due to excipient effects ( 32 , 34 , 63 ). For extemporaneously prepared 6-mercaptopurine (6-MP) liquid formulations, differences in formulation constituents (excipients) and viscosity, and potentially 6-MP could have contributed to the observed variability in systemic drug availability from liquid formulations ( 63 ). Lactose, which is an excipient widely used as a filler or filler-binder in the manufacture of tablet and capsules, could aid in moistening of the phenytoin particles in tablet formulation and this enhanced the dissolution rate followed by increase in absorption and plasma exposure ( 34 ).…”

Section: Resultsmentioning

confidence: 99%

“…A total of 18 studies linked DRBA to population effects from participants in the study. These population effects include: high inter-individual variability within the study population ( 33 , 36 – 39 , 41 , 45 – 48 , 54 , 55 , 58 , 61 , 63 , 65 , 66 ), high intra-individual variability ( 45 , 50 , 63 ), or genetic polymorphism associated with metabolism of drugs ( 47 , 58 , 65 ). The consequences of these population effects may increase in the developing pediatric population.…”

Section: Resultsmentioning

confidence: 99%

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Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Pawar

Zhao

et al. 2021

AAPS J

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Generally, bioequivalence (BE) studies of drug products for pediatric patients are conducted in adults due to ethical reasons. Given the lack of direct BE assessment in pediatric populations, the aim of this work is to develop a database of BE and relative bioavailability (relative BA) studies conducted in pediatric populations and to enable the identification of risk factors associated with certain drug substances or products that may lead to failed BE or different pharmacokinetic (PK) parameters in relative BA studies in pediatrics. A literature search from 1965 to 2020 was conducted in PubMed, Cochrane Library, and Google Scholar to identify BE studies conducted in pediatric populations and relative BA studies conducted in pediatric populations. Overall, 79 studies covering 37 active pharmaceutical ingredients (APIs) were included in the database: 4 bioequivalence studies with data that passed BE evaluations; 2 studies showed bioinequivalence results; 34 relative BA studies showing comparable PK parameters, and 39 relative BA studies showing differences in PK parameters between test and reference products. Based on the above studies, common putative risk factors associated with differences in relative bioavailability (DRBA) in pediatric populations include age-related absorption effects, high inter-individual variability, and poor study design. A database containing 79 clinical studies on BE or relative BA in pediatrics has been developed. Putative risk factors associated with DRBA in pediatric populations are summarized.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Pawar

Zhao

et al. 2021

AAPS J

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Bioequivalence study followed by model‐informed dose optimization of a powder for oral suspension of 6‐mercaptopurine

Arun,

Joshi,

Kakkar

et al. 2023

Pediatric Blood & Cancer

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Background6‐Mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukemia (ALL) and is conventionally available as 50 mg tablets. A new 6MP powder for oral suspension (PFOS 10 mg/mL) was developed recently by IDRS Labs, India, intended for pediatric use. A comparative pharmacokinetics of PFOS with T. mercaptopurine was conducted to determine the dose equivalence.MethodsAn open‐label, randomized, two‐treatment, two‐period, two‐sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy adult subjects. Post hoc, a population pharmacokinetic (PopPK) model was developed using the healthy volunteer data to perform simulations with various PFOS doses and select a bioequivalent dose. Further, to confirm the safety of PFOS in pediatrics, a simulation of 6MP and 6‐thioguanine exposures was performed by incorporating the formulation‐specific parameters derived from the healthy volunteer study into the PopPK model in childhood ALL available in literature.ResultsThe 6MP PFOS had 47% higher oral bioavailability compared to the reference product. Simulations using a two‐compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to 50 mg tablets. The simulated 6‐thioguanine nucleotide concentrations in children using the dose adjusted for PFOS were between 114 and 703.6 pmol/8 × 108 RBC, which was within the range reported in pediatric ALL studies.Conclusion6MP PFOS 10 mg/mL should be administered at a 20% lower dose than the tablet to achieve comparable exposure. 6MP PFOS addresses an unmet medical need for a liquid formulation of 6MP in the Indian subcontinent.

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Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia

Larsen

Hjalgrim

Grell

et al. 2020

Cancer Chemother Pharmacol

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Pharmacokinetics of two 6‐mercaptopurine liquid formulations in children with acute lymphoblastic leukemia

Abstract: Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

Cited by 5 publications

References 20 publications

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Bioequivalence study followed by model‐informed dose optimization of a powder for oral suspension of 6‐mercaptopurine

Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia

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