Sin Yin Lim1, Cynthia B May2, Peter N Johnson3, Jamie L Miller3. 1. Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA. Sinyin.lim@wisc.edu. 2. Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA. 3. Department of Pharmacy, Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA.
Abstract
BACKGROUND: The optimal caffeine dosing in extremely premature neonates remains elusive. This study aimed to evaluate the impact of birth weight on caffeine pharmacokinetics and various dosing regimens. METHODS: In this pharmacokinetic simulation study, we generated the body weights (0-49 days of postnatal age [PNA]) of neonates <28 weeks gestational age with different birth weights (550, 750, and 1050 g). Their pharmacokinetic parameters were determined based on published pharmacokinetic models. Then, we simulated and compared the caffeine base concentration-time profiles of standard versus off-label caffeine citrate dose regimens. RESULTS: The half-life decreased and the weight-adjusted clearance increased more significantly in neonates with lower birth weights, resulting in lower caffeine plasma concentrations. The neonate with the lowest birth weight did not achieve a threshold trough concentration of 15 mg/L after receiving the standard dose (5 mg/kg/day), while the higher-birth-weights (≥750 g) had trough concentrations below the threshold around the second week of life. Higher caffeine doses (10 mg/kg/day) resulted in peak concentrations of <36 mg/L by 10-14 days of PNA while maintaining trough concentrations above 15 mg/L throughout the 49 days PNA. CONCLUSION: Higher-than-standard caffeine dosing may be needed for extremely premature neonates, especially for those with lower birth weights. IMPACT: Extremely premature neonates with a lower birth weight may require a higher weight-based caffeine dosing due to their higher weight-adjusted clearance and shorter half-lives. Not only do these extremely premature neonates have a higher risk of developing bronchopulmonary dysplasia due to their structurally underdeveloped lungs, but the low birth weight-related underdosing may further contribute to the reduced caffeine effectiveness. Higher-than-standard caffeine citrate dosing (e.g., 10 mg/kg/day maintenance dose) may be needed to further prevent bronchopulmonary dysplasia.
BACKGROUND: The optimal caffeine dosing in extremely premature neonates remains elusive. This study aimed to evaluate the impact of birth weight on caffeine pharmacokinetics and various dosing regimens. METHODS: In this pharmacokinetic simulation study, we generated the body weights (0-49 days of postnatal age [PNA]) of neonates <28 weeks gestational age with different birth weights (550, 750, and 1050 g). Their pharmacokinetic parameters were determined based on published pharmacokinetic models. Then, we simulated and compared the caffeine base concentration-time profiles of standard versus off-label caffeine citrate dose regimens. RESULTS: The half-life decreased and the weight-adjusted clearance increased more significantly in neonates with lower birth weights, resulting in lower caffeine plasma concentrations. The neonate with the lowest birth weight did not achieve a threshold trough concentration of 15 mg/L after receiving the standard dose (5 mg/kg/day), while the higher-birth-weights (≥750 g) had trough concentrations below the threshold around the second week of life. Higher caffeine doses (10 mg/kg/day) resulted in peak concentrations of <36 mg/L by 10-14 days of PNA while maintaining trough concentrations above 15 mg/L throughout the 49 days PNA. CONCLUSION: Higher-than-standard caffeine dosing may be needed for extremely premature neonates, especially for those with lower birth weights. IMPACT: Extremely premature neonates with a lower birth weight may require a higher weight-based caffeine dosing due to their higher weight-adjusted clearance and shorter half-lives. Not only do these extremely premature neonates have a higher risk of developing bronchopulmonary dysplasia due to their structurally underdeveloped lungs, but the low birth weight-related underdosing may further contribute to the reduced caffeine effectiveness. Higher-than-standard caffeine citrate dosing (e.g., 10 mg/kg/day maintenance dose) may be needed to further prevent bronchopulmonary dysplasia.