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Development of Physiologically Based Pharmacokinetic Model and Assessment of the Impact of Renal Underdevelopment in Preterm Infants on the Pharmacokinetics of Aminophylline #354
https://journals.sagepub.com/doi/full/10.1177/0976500X221080209
Journal of Pharmacology and Pharmacotherapeutics, DOI: 10.1177/0976500X2210802
Hari Prabhath Tummala, Rachana Balusu, Sahithi Thotakura, Achyuth Kumar Pasnoor, Arun Prasath Raju, Shivakumar Mahadeva Lal, Leslie Edwards Lewis, and Surulivelrajan Mallayasamy
AbstractBackground: Apnea of prematurity is a serious issue in infants delivered before 37 weeks of gestation. Along with premature
birth, renal underdevelopment is another complication in these neonates leading to poor clearance of administered drugs.
Hence, dosage adjustment is required in these cases. The present work focuses on the development of a physiologically
based pharmacokinetic (PBPK) model to help in the individualization of the dosing regimen considering the physiological
requirements of these preterm neonates.
Methods: The study comprised preterm newborns with fewer than 34 weeks of gestation and six apneic episodes in 24 h.
A PBPK model was created using PK-SIM (version 9, update 1, GitHub, San Francisco, CA, USA). A PBPK model is built using
a typical loading dosage of 5 mg/kg and a maintenance dose of 1.5 mg/kg. Based on the verified base model, a PBPK model
representing renal underdevelopment based on nRIFLE/pRIFLE categorization was developed.
Results: The PK parameters of Aminophylline were computed using the PBPK model. As per the model prediction, T1/2 and
area under the curve reduced as postnatal age increased, and in the event of renal underdevelopment, even while Cmax for patients
under R (RISK), I (injury) was within the therapeutic range; it was greater compared to preterm without any renal complications.
Mean Cmax (mol/L) was 59.53 and for R, I, and F (FAILURE) categories the values were 83.04, 99.69, and 126.98, respectively.
Conclusion: The model was created using appropriate drug, study subject, and dosage protocol inputs. The established
PBPK model could help in individualizing aminophylline dose in preterm babies.
https://journals.sagepub.com/doi/full/10.1177/0976500X221080209 Journal of Pharmacology and Pharmacotherapeutics, DOI: 10.1177/0976500X2210802 Hari Prabhath Tummala, Rachana Balusu, Sahithi Thotakura, Achyuth Kumar Pasnoor, Arun Prasath Raju, Shivakumar Mahadeva Lal, Leslie Edwards Lewis, and Surulivelrajan Mallayasamy
Abstract Background: Apnea of prematurity is a serious issue in infants delivered before 37 weeks of gestation. Along with premature birth, renal underdevelopment is another complication in these neonates leading to poor clearance of administered drugs. Hence, dosage adjustment is required in these cases. The present work focuses on the development of a physiologically based pharmacokinetic (PBPK) model to help in the individualization of the dosing regimen considering the physiological requirements of these preterm neonates. Methods: The study comprised preterm newborns with fewer than 34 weeks of gestation and six apneic episodes in 24 h. A PBPK model was created using PK-SIM (version 9, update 1, GitHub, San Francisco, CA, USA). A PBPK model is built using a typical loading dosage of 5 mg/kg and a maintenance dose of 1.5 mg/kg. Based on the verified base model, a PBPK model representing renal underdevelopment based on nRIFLE/pRIFLE categorization was developed. Results: The PK parameters of Aminophylline were computed using the PBPK model. As per the model prediction, T1/2 and area under the curve reduced as postnatal age increased, and in the event of renal underdevelopment, even while Cmax for patients under R (RISK), I (injury) was within the therapeutic range; it was greater compared to preterm without any renal complications. Mean Cmax (mol/L) was 59.53 and for R, I, and F (FAILURE) categories the values were 83.04, 99.69, and 126.98, respectively. Conclusion: The model was created using appropriate drug, study subject, and dosage protocol inputs. The established PBPK model could help in individualizing aminophylline dose in preterm babies.
Keywords Apnea of prematurity, Methylxanthines, PBPK Model, Preterm infants, dose optimization, Renal insufficiency