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Prediction of Clearance, Volume of distribution, and Half-life of Drugs in Extremely Low to Low Birth Weight Neonates: An Allometric Approach

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Abstract

Background and Objectives

More than 20 million infants worldwide (15.5 % of all births) are born with low birth weight. Low birth weight is associated with poor growth in childhood and a higher incidence of adult diseases, such as type 2 diabetes, hypertension and cardiovascular disease. The objective of this study was to evaluate the predictive performance of allometric models to predict clearance, volume of distribution, and half-life in extremely low to low birth weight neonates (<1 to 2.5 kg body weight).

Methods

Several allometric models were used to predict clearance (4 models), volume of distribution (2 models), and half-life (2 models) in extremely low to low birth weight neonates. From the literature, clearance, volume of distribution, and half-life values for 16 drugs for these neonates were obtained. The predictive performance of these allometric models was evaluated by comparing the predicted values of the aforementioned pharmacokinetic parameters with the observed pharmacokinetic parameters in an individual neonate. For the evaluation of the predictive performance of these allometric models, there were 16 drugs with 36 (n = 279), 34 (n = 261), and 31 (n = 197) weight groups for clearance, volume of distribution, and half-life, respectively.

Results

The prediction error of ≤50 % for mean clearance, volume of distribution, and half-life values were 69, 79, and 58 %, respectively, by proposed allometric models. The prediction error of ≤50 % for mean clearance, volume of distribution, and half-life values by theoretical allometric exponents were 0 % (exponent = 0.75), 71 % (exponent = 1.0), and 0 % (exponent = 0.25), respectively. In this analysis, out of 16 drugs, there were three drugs (ibuprofen, zidovudine, and buprenorphine) which are metabolized by glucuronidation and one drug (furosemide) is renally secreted. The predicted clearances of these four drugs were substantially higher by the proposed allometric methods. It seems that drugs of these physiological characteristics may require different method(s) to improve the prediction of clearance in the neonates.

Conclusions

Overall, the proposed allometric methods can predict mean pharmacokinetic parameters of drugs in extremely low to low birth weight neonates with reasonable accuracy and are of practical value during neonatal drug development.

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Authors and Affiliations

  1. Division of Hematology Clinical Review, Office of Blood Review and Research (OBRR), Center for Biologic Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Iftekhar Mahmood

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Correspondence to Iftekhar Mahmood.

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The views expressed in this article are those of the author and do not reflect the official policy of the US FDA. No official support or endorsement by the FDA is intended or should be inferred.

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Mahmood, I. Prediction of Clearance, Volume of distribution, and Half-life of Drugs in Extremely Low to Low Birth Weight Neonates: An Allometric Approach. Eur J Drug Metab Pharmacokinet 42, 601–610 (2017). https://doi.org/10.1007/s13318-016-0372-z

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