Dose Individualization of CYP3A Substrates in Children: Characterization of Maturation of Intestinal and Hepatic CYP3A Activity in Children to Predict First-pass and Systemic CYP3A-mediated Metabolism
Janneke M. Brussee (1), Huixin Yu (1,2), Elke H.J. Krekels (1), Semra Palic (1,3),Margreke J.E. Brill (4), Jeffrey S. Barrett (5,6), Amin Rostami-Hodjegan (7,8), Saskia N. de Wildt (9,10), Catherijne A.J. Knibbe (1,11)
(1) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands, (2) Current affiliation: Novartis, Basel, Switzerland, (3) Current affiliation: Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands, (4) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (5) Translational Informatics, Sanofi, Bridgewater, NJ, USA, (6) Department of Pediatrics, Division of Clinical Pharmacology & Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA, (7) Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK, (8) Simcyp Limited (A Certara Company), Sheffield, UK, (9) Intensive Care and Department of Pediatric Surgery, Erasmus MC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (10) Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, the Netherlands, (11) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: Our aim is to characterize the intestinal and hepatic metabolism of midazolam in children in order to predict first-pass and systemic metabolism and fraction escaping gut wall (Fg) and hepatic (Fh) metabolism as well as total bioavailability (Ftotal). The characterization of the maturation processes in gut wall and liver is essential for development of dose individualization of CYP3A substrates in children, where the relative contribution of Fg and Fh to total bioavailability varies between drugs. For this purpose, a previously developed physiological population pharmacokinetic modelling approach [1] was applied in which accepted PBPK principles and parameter values from literature are combined with the estimation of intrinsic clearance parameters based on population PK data. In this work, the estimated intrinsic clearance of midazolam is used as a surrogate marker for CYP3A activity.
Methods: Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam was available from 266 post-operative children aged 1-18 years who received orally administered midazolam [2]. The physiological population PK model [1] used to analyze these data, includes physiological compartments representing the gut wall, the portal vein and the liver, and empirical central and peripheral distribution compartments for midazolam and 1-OH-midazolam. Age-specific hematocrit values and formulas for calculation of the age-specific physiological parameter values for tissue volumes, organ blood flows, intestinal surface area, and abundance of plasma proteins were obtained from literature (e.g. for liver volumes [3]). Central and peripheral volumes were linearly scaled from adults. The fraction midazolam metabolized into 1-OH-midazolam was assumed 100%. Intrinsic intestinal and hepatic clearance values were estimated based on the PK data and from these parameters, gut wall, hepatic, and total bioavailability (Fg, Fh and Ftotal) as well as systemic plasma clearance were derived. The model was evaluated using goodness-of-fit plots, bootstrap and NPDE analysis. To evaluate the assumptions made by using the physiological parameters, a sensitivity analysis was performed.
Results: The intrinsic clearance of midazolam in the gut wall and liver were found to increase with body weight throughout the pediatric age-range, but they did not mature in parallel. The exponents in the body-weight based covariate relationships were 0.98 (RSE 9%) and 0.38 (RSE 18%) for intestinal and hepatic intrinsic clearance, respectively. The intestinal intrinsic clearance proved lower than hepatic intrinsic clearance through the entire range with a 219 times lower intestinal clearance compared to hepatic clearance in children < 2 years of age, while this factor difference was 60 in children ≥ 16 years-of-age. Based on the estimated intrinsic clearance, the fraction unbound, hepatic blood flow and blood: plasma ratio, it can be derived that the systemic plasma clearance also increases with age from 9.3 L/h in infants to 24.2 L/h in adolescents. The fractions escaping gut wall (Fg) and hepatic metabolism (Fh) were derived from the estimated intrinsic clearance, the organ blood flows and the unbound drug fraction. In all children, the Fg was found to be lower (median Fg 0.36, range 0.02-0.88) than the Fh (median Fh 0.65, range 0.32-0.93). The Fh showed an increase with age, ranging from 54% in children < 2 years of age, to 70% in adolescents of 12-18 years of age, while Fg showed an inverse, but smaller, age-related trend. The resulting total bioavailability was found to be age-independent with a median of 21.6% in children (95%CI: 3.9-51.1%). The sensitivity analysis indicated that changes in assumed values for hepatic or the intestinal blood flow would not impact the derived values for plasma clearance and bioavailability.
Conclusions: The intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance throughout the pediatric age-range. Using intrinsic clearance of midazolam as surrogate marker for intestinal and hepatic CYP3A activity, gut wall CYP3A activity is less mature in young children, but matures faster than hepatic CYP3A activity. This, together with disproportional changes in blood flow, results in decreasing intestinal and increasing hepatic bioavailability with age, which together lead to little or no changes in total oral bioavailability of midazolam in children with increasing age and body weight.
References:
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