Age Related Changes in Fractional Elimination Pathways for Drugs: Assessing the Impact of Variable Ontogeny on Metabolic Drug-Drug Interactions

Salem, Farzaneh; Johnson, Trevor N.; Barter, Zoe; Leeder, J. Steven; Rostami‐Hodjegan, Amin

doi:10.1002/jcph.100

Cited by 54 publications

(45 citation statements)

References 24 publications

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“…The current study does illustrate the potential usefulness of the p-PBPK modeling approach as a research tool in pediatric subjects where performing direct clinical studies to assess the ontogeny of biliary excretion would not be feasible because of logistical and ethical reasons. Previously we have shown the utility of this methodology for other scenarios, where it was challenging to perform studies that assessed metabolic drug-drug interactions in children of different ages (Salem et al, 2013). The latter approach has been taken up in regulatory guidance on drug-drug interaction assessment in special populations, including pediatric subjects, by both the Food and Drug Administration and European Medicines Agency.…”

Section: Discussionmentioning

confidence: 99%

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Johnson

Jamei

Rowland‐Yeo

2016

Drug Metabolism and Disposition

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Information on the developmental changes in biliary excretion (BE) of drugs is sparse. The aims of this study were to collate literature data on the pharmacokinetics of biliary excretion of drugs used in pediatrics and to apply a physiologically based pharmacokinetic (PBPK) model to predict their systemic clearance (CL) with a view to elucidating age-related changes in biliary excretion. Drug parameters for azithromycin, ceftriaxone, and digoxin administered intravenously and buprenorphine (intravenous and sublingual) were collated from the literature and used in the Simcyp Simulator to predict adult CL values, which were then validated against observed data. The change in CL with age was simulated in the pediatric model and compared with observed data; where necessary, the ontogeny function associated with BE was applied to recover the age-related CL. For azithromycin a fraction of adult BE activity of 15% was necessary to predict the CL in neonates (26 weeks gestational age) and 100% activity was apparent by 7 months. For ceftriaxone and digoxin full BE activity appeared to be present at term birth; for digoxin, an adult BE activity of 10% was needed to predict the CL in premature neonates (30 weeks gestational age). The CL of buprenorphine with age was described by the ontogeny of the major elimination pathways (CYP3A4 and UGT1A1) with no ontogeny assumed for the biliary component. Thus, the ontogeny of BE for all four drugs appears to be rapid and they attain adult levels at birth or within the first few months of postnatal age.

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Section: Discussionmentioning

confidence: 99%

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Johnson

Jamei

Rowland‐Yeo

2016

Drug Metabolism and Disposition

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“…This is because all of these pediatric patients were above 1 month of age and the two major cyp-enzymes for carvedilol metabolism (i.e., CYP2D6 and CYP2C9) have a fast ontogeny profile, as they achieve more than ;50% of adult activity by the age of 0.1 year (Salem et al, 2013). Nevertheless, in the developed model, about 20% of the total assigned metabolism of S-carvedilol is due to cyp-enzymes with slow enzyme ontogeny and a later maturation time point, that is, CYP1A2, 10%; CYP2E1, 5%; and CYP3A4, 5%.…”

Section: Discussionmentioning

confidence: 99%

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Rasool

Khalil

Läer

2016

Drug Metabolism and Disposition

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Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.

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“…The mechanistic prediction of the formation clearance to ODT and NDT in pediatrics has to take into account (i) the ontogenic profiles of the CYP isoforms 2D6, 3A4, and 2B6 (16), as well as changes in (ii) the amount of microsomal proteins per gram of liver, (iii) liver size, (iv) liver blood flow, and (v) plasma protein binding (17,18). Third, on the one hand, CYP maturation functions for CYP2D6 (17) and CYP3A4 (18) were compared to experimentally determined human liver microsomal (HLM) activities of tramadol (together with the activity of CYP-specific probe substrates dextromethorphan (DEX for CYP2D6) and midazolam (MDZ for CYP3A4)) in two pediatric batches of 1 and 3 months of age. On the other hand, the pediatric PBPK in vivo clearance predictions were compared to popPKderived maturation functions (19,20).…”

Section: Introductionmentioning

confidence: 99%

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

T’jollyn

Snoeys

Vermeulen

et al. 2015

AAPS J

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Abstract. This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life. In two in vitro pediatric human liver microsomal (HLM) batches (1 and 3 months), O-desmethyltramadol and N-desmethyltramadol formation rates were compared with CYP2D6 and CYP3A4 activity, respectively. O-desmethyltramadol formation was mediated only by CYP2D6, while N-desmethyltramadol was mediated in part by CYP3A4. Additionally, the clearance maturation of the PBPK model predictions was compared to two in vivo maturation models (Hill and exponential) based on plasma concentration data, and to clearance estimations from a WinNonlin® fit of plasma concentration and urinary excretion data. Maturation of renal and CYP2D6 clearance is captured well in the PBPK model predictions, but total tramadol clearance is underpredicted. The most pronounced underprediction of total and CYP2D6-mediated clearance was observed in the age range of 2-13 years. In conclusion, the PBPK technique showed to be a powerful mechanistic tool capable of predicting maturation of CYP2D6 and renal tramadol clearance in early infancy, although some underprediction occurs between 2 and 13 years for total and CYP2D6-mediated tramadol clearance.

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Age Related Changes in Fractional Elimination Pathways for Drugs: Assessing the Impact of Variable Ontogeny on Metabolic Drug-Drug Interactions

Cited by 54 publications

References 24 publications

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation

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