AL Sumpter

Amin Rostami-Hodjegan

AR Polepally

Brian J. Anderson

C Wang

Catherijne A. J. Knibbe

Dagan O. Lonsdale

E Germovsek

EA Calvier

Joseph F. Standing

JS McCune

N Holford

NH Holford

Nick H. Holford

S Hennig

SC Dijkman van

Stefanie Hennig

Trevor N. Johnston

Standing, J.F.

Anderson, B.J.

Hennig, S.

Holford, N.H.

Johnston, T.N.

Knibbe, C.A.J.

Lonsdale, D.O.

Rostami-Hodjegan, A.

NARCIS 

Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials"

Standing, Joseph F

Anderson, Brian J

Hennig, Stefanie

Holford, Nick H

Johnston, Trevor N

Knibbe, Catherijne A J

Lonsdale, Dagan O

Rostami-Hodjegan, Amin

The University of Manchester - Institutional Repository

Standing, JF

Anderson, BJ

Hennig, S

Holford, NH

Johnston, TN

Knibbe, CAJ

Lonsdale, DO

Rostami-Hodjegan, A

St George's Online Research Archive

Clinical Pharmacokinetics COMMENT ON: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigineand Potential Implications for Dose Optimisation in Epilepsy Patients--Manuscript Draft-- Manuscript Number: CPKA-D-18-00106Full Title: COMMENT ON: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigineand Potential Implications for Dose Optimisation in Epilepsy PatientsArticle Type: Letter to the EditorFunding Information:Corresponding Author: Joseph F. Standing, Ph.D.University College LondonLondon, UNITED KINGDOMCorresponding Author SecondaryInformation:Corresponding Author's Institution: University College LondonCorresponding Author's SecondaryInstitution:First Author: Joseph F. Standing, Ph.D.First Author Secondary Information:Order of Authors: Joseph F. Standing, Ph.D.Brian AndersonStefanie HennigNick HolfordTrevor JohnsonCatherijne KnibbeDagan LonsdaleAmin RostamiOrder of Authors Secondary Information:Author Comments: Letter to the editorSuggested Reviewers:Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationCOMMENT ON: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential 1 Implications for Dose Optimisation in Epilepsy Patients 2 Joseph F Standing, 1, Brian J Anderson, 2, Stefanie Hennig, 3, Nick H Holford, 4, Trevor Johnston, 3 5, Catherijne AJ Knibbe, 6, Dagan O Lonsdale, 7, Amin Rostami-Hodjegan 8 4 1 Great Ormond Street Institute of Child Health, University College London, London, UK 5 2 Department of Anaesthesia, University of Auckland, New Zealand 6 3 School of Pharmacy, The University of Queensland, Australia 7 4 Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand 8 5 Certara UK, Sheffield, UK 9 6 Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug 10 Research, University of Leiden, Netherlands 11 7 Department of Clinical Pharmacology, Institute for Infection and Immunity, St George’s University 12 of London, UK 13 8 Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, UK 14 Address for correspondence: Dr Joseph Standing Room 661, UCL Great Ormond Street Institute 15 for Child Health, London WC1N 1EH Email: j.standing@ucl.ac.uk Tel: 0207 905 2370 Fax: 0207 16 905 2882 17 Number of tables: 0 Number of figures: 1 18 Keywords: lamotrigine; pharmacokinetics; NONMEM; paediatrics 19 Dear Editor, 20 We read with interest the recent paper detailing the pharmacokinetics of lamotrigine by van 21 Dijkman et al1 and would like to congratulate the authors for compiling such a comprehensive 22 Manuscript Click here to download Manuscriptvandijkman_letter_180514.docxClick here to view linked References 1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 dataset, which they have used to evaluate apparent clearance (CL/F) changes from young infants 23 to elderly adults. In particular these results are important in patients aged younger than 2 years for 24 whom the drug is currently unlicensed. We note that an extensive erratum2 has attempted to 25 correct the interpretation of the proposed dosing guidelines, although recommendations for 26 patients with different co-medications would have been useful. Before considering dose guidelines 27 derived from the model however, we feel there is a more fundamental question on the underlying 28 assumptions in model that warrants further discussion; namely the proposed function to describe 29 changes in CL/F with age. 30 In Figure 1 we have plotted the change in predicted values of CL/F with post natal age (PNA) as 31 reported by the authors, using a continuous function to predict typical weight for age3. Here it can 32 be seen that CL/F peaks at a post-menstrual age (PMA) of approximately 110 weeks (PNA of 1.3 33 years), then declines, and does not reach the same rate again until approximately 280 weeks PMA 34 (PNA of 4.6 years). Between us we have extensive experience of modelling pharmacokinetic 35 studies over large age ranges4–8, analysed how clearance in general changes for thousands of 36 hypothetical drugs (e.g. see Calvier et al9 in this journal), and systematically reviewed clearance 37 maturation functions in children10,11. The authors describe an extremely rare (possibly the first) 38 case of decreasing CL/F with increasing age in infants and young children. Since CL/F determines 39 steady-state concentration, and in this case maintenance dose, it is important that this change in 40 CL/F with age is further explored. There are several possible explanations: 41 Firstly, the arbitrary step function used to describe decreasing CL/F with age above 65 years may 42 be causing an under-estimation of the true young adult value, and hence the dematuration function 43 the authors report is merely a result of this under-estimate exacerbated by limited data in children 44 aged 4-12 years. A more granular breakdown of goodness-of-fit to age groups of less than 1, 1-2, 45 3-4 year olds and 12-30 year olds would show whether model fit was consistent amongst each age 46 group. 47 A second possibility is that bioavailability (F) is for some reason lower in infants taking the 48 immediate release formulation, consequently making CL/F seem high. This does seem unlikely 49  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 since immediate and extended release formulations have been reported to be bioequivalent12, and 50 lamotrigine is generally well absorbed, but changes in bioavailability with age cannot be ruled out. 51 A third possibility, and one we think most likely, is that drug-drug interactions are causing 52 confounding given that different age groups had different co-medication frequencies. Re-fitting the 53 model to data only in patients not taking carbamazepine, phenytoin or valproic acid and re-54 evaluating maturation parameters would determine this. Such an analysis would give confidence 55 that the relative contribution of maturation and drug-drug interactions are correctly captured by the 56 model. Further insight may also be achieved through PBPK analysis which may predict how CL/F 57 could change with both age and in the presence of drug-drug interactions. 58 This finding of decreasing CL/F with increasing age in infants and young children is a novel 59 unexpected result, and further exploration to confirm whether it is a real phenomenon, and if so 60 why it happens with lamotrigine, is required. 61 Figure Legend 62 Figure 1: Plot of lamotrigine CL/F versus age estimated by van Dijkman et al1 63 References 64 1. Dijkman, S. C. van, Jager, N. C. B. de, Rauwe, W. M., Danhof, M. & Della Pasqua, O. Effect of 65 Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for 66 Maintenance Dose Optimisation in Future Clinical Trials. Clin Pharmacokinet (2018). 67 2. Dijkman, S. C. van, Jager, N. C. B. de, Rauwe, W. M., Danhof, M. & Della Pasqua, O. 68 Correction to: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential 69 Implications for Maintenance Dose Optimisation in Future Clinical Trials. Clin Pharmacokinet 70 (2018). 71 3. Sumpter, A. L. & Holford, N. H. Predicting weight using postmenstrual age–neonates to adults. 72 Paediatr Anaesth 21, 309–315 (2011). 73  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4. Wang, C. et al. A bodyweight-dependent allometric exponent for scaling clearance across the 74 human life-span. Pharm. Res. 29, 1570–1581 (2012). 75 5. Lonsdale, D. O. et al. Standard beta–lactam doses fail to achieve PK/PD targets in critically ill 76 patients of all ages, with children particularly at risk: results from the ABDose study. 28th ECCMID 77 meeting, Madrid, Spain O0808, (2018). 78 6. Hennig, S., Standing, J. F., Staatz, C. E. & Thomson, A. H. Population pharmacokinetics of 79 tobramycin in patients with and without cystic fibrosis. Clin Pharmacokinet 52, 289–301 (2013). 80 7. McCune, J. S. et al. Busulfan in infant to adult hematopoietic cell transplant recipients: a 81 population pharmacokinetic model for initial and Bayesian dose personalization. Clin. Cancer Res. 82 20, 754–763 (2014). 83 8. Holford, N. H., Ma, S. C. & Anderson, B. J. Prediction of morphine dose in humans. Paediatr 84 Anaesth 22, 209–222 (2012). 85 9. Calvier, E. A. et al. Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic 86 of 0.75 Fade? Clin Pharmacokinet 56, 273–285 (2017). 87 10. Holford, N., Heo, Y. A. & Anderson, B. A pharmacokinetic standard for babies and adults. J 88 Pharm Sci 102, 2941–2952 (2013). 89 11. Germovsek, E., Barker, C. I., Sharland, M. & Standing, J. F. Scaling clearance in paediatric 90 pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol 83, 777–790 91 (2017). 92 12. Polepally, A. R. et al. Steady-state pharmacokinetics and bioavailability of immediate-release 93 and extended-release formulations of lamotrigine in elderly epilepsy patients: Use of stable isotope 94 methodology. J Clin Pharmacol 55, 1101–1108 (2015). 95  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Post natal age (y)CL/F (L/h)0.40.50.60.70.80.90 1 2 3 4 5 6Figure Click here to download Figure Figure1 

Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials".

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Comment on “Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials”

Leiden University Scholary Publications

Comment on "Effect of Age-Related Factors on the Pharmacokineticsof Lamotrigine and Potential Implications for Maintenance DoseOptimisation in Future Clinical Trials"Standing, J.F.; Anderson, B.J.; Hennig, S.; Holford, N.H.; Johnston, T.N.; Knibbe, C.A.J.; ... ;Rostami-Hodjegan, A.CitationStanding, J. F., Anderson, B. J., Hennig, S., Holford, N. H., Johnston, T. N., Knibbe, C. A. J.,… Rostami-Hodjegan, A. (2018). Comment on "Effect of Age-Related Factors on thePharmacokinetics of Lamotrigine and Potential Implications for Maintenance DoseOptimisation in Future Clinical Trials". Clinical Pharmacokinetics, 57(11), 1471-1472.doi:10.1007/s40262-018-0697-7 Version: Accepted ManuscriptLicense: Leiden University Non-exclusive licenseDownloaded from: https://hdl.handle.net/1887/87421 Note: To cite this publication please use the final published version (if applicable).COMMENT ON: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential 1 Implications for Dose Optimisation in Epilepsy Patients 2 Joseph F Standing, 1, Brian J Anderson, 2, Stefanie Hennig, 3, Nick H Holford, 4, Trevor Johnston, 3 5, Catherijne AJ Knibbe, 6, Dagan O Lonsdale, 7, Amin Rostami-Hodjegan 8 4 1 Great Ormond Street Institute of Child Health, University College London, London, UK 5 2 Department of Anaesthesia, University of Auckland, New Zealand 6 3 School of Pharmacy, The University of Queensland, Australia 7 4 Department of Pharmacology and Clinical Pharmacology, University of Auckland, New Zealand 8 5 Certara UK, Sheffield, UK 9 6 Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug 10 Research, University of Leiden, Netherlands 11 7 Department of Clinical Pharmacology, Institute for Infection and Immunity, St George’s University 12 of London, UK 13 8 Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, UK 14 Address for correspondence: Dr Joseph Standing Room 661, UCL Great Ormond Street Institute 15 for Child Health, London WC1N 1EH Email: j.standing@ucl.ac.uk Tel: 0207 905 2370 Fax: 0207 16 905 2882 17 Number of tables: 0 Number of figures: 1 18 Keywords: lamotrigine; pharmacokinetics; NONMEM; paediatrics 19 Dear Editor, 20 We read with interest the recent paper detailing the pharmacokinetics of lamotrigine by van 21 Dijkman et al1 and would like to congratulate the authors for compiling such a comprehensive 22 Manuscript Click here to download Manuscriptvandijkman_letter_180514.docxClick here to view linked References 1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 dataset, which they have used to evaluate apparent clearance (CL/F) changes from young infants 23 to elderly adults. In particular these results are important in patients aged younger than 2 years for 24 whom the drug is currently unlicensed. We note that an extensive erratum2 has attempted to 25 correct the interpretation of the proposed dosing guidelines, although recommendations for 26 patients with different co-medications would have been useful. Before considering dose guidelines 27 derived from the model however, we feel there is a more fundamental question on the underlying 28 assumptions in model that warrants further discussion; namely the proposed function to describe 29 changes in CL/F with age. 30 In Figure 1 we have plotted the change in predicted values of CL/F with post natal age (PNA) as 31 reported by the authors, using a continuous function to predict typical weight for age3. Here it can 32 be seen that CL/F peaks at a post-menstrual age (PMA) of approximately 110 weeks (PNA of 1.3 33 years), then declines, and does not reach the same rate again until approximately 280 weeks PMA 34 (PNA of 4.6 years). Between us we have extensive experience of modelling pharmacokinetic 35 studies over large age ranges4–8, analysed how clearance in general changes for thousands of 36 hypothetical drugs (e.g. see Calvier et al9 in this journal), and systematically reviewed clearance 37 maturation functions in children10,11. The authors describe an extremely rare (possibly the first) 38 case of decreasing CL/F with increasing age in infants and young children. Since CL/F determines 39 steady-state concentration, and in this case maintenance dose, it is important that this change in 40 CL/F with age is further explored. There are several possible explanations: 41 Firstly, the arbitrary step function used to describe decreasing CL/F with age above 65 years may 42 be causing an under-estimation of the true young adult value, and hence the dematuration function 43 the authors report is merely a result of this under-estimate exacerbated by limited data in children 44 aged 4-12 years. A more granular breakdown of goodness-of-fit to age groups of less than 1, 1-2, 45 3-4 year olds and 12-30 year olds would show whether model fit was consistent amongst each age 46 group. 47 A second possibility is that bioavailability (F) is for some reason lower in infants taking the 48 immediate release formulation, consequently making CL/F seem high. This does seem unlikely 49  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 since immediate and extended release formulations have been reported to be bioequivalent12, and 50 lamotrigine is generally well absorbed, but changes in bioavailability with age cannot be ruled out. 51 A third possibility, and one we think most likely, is that drug-drug interactions are causing 52 confounding given that different age groups had different co-medication frequencies. Re-fitting the 53 model to data only in patients not taking carbamazepine, phenytoin or valproic acid and re-54 evaluating maturation parameters would determine this. Such an analysis would give confidence 55 that the relative contribution of maturation and drug-drug interactions are correctly captured by the 56 model. Further insight may also be achieved through PBPK analysis which may predict how CL/F 57 could change with both age and in the presence of drug-drug interactions. 58 This finding of decreasing CL/F with increasing age in infants and young children is a novel 59 unexpected result, and further exploration to confirm whether it is a real phenomenon, and if so 60 why it happens with lamotrigine, is required. 61 Figure Legend 62 Figure 1: Plot of lamotrigine CL/F versus age estimated by van Dijkman et al1 63 References 64 1. Dijkman, S. C. van, Jager, N. C. B. de, Rauwe, W. M., Danhof, M. & Della Pasqua, O. Effect of 65 Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for 66 Maintenance Dose Optimisation in Future Clinical Trials. Clin Pharmacokinet (2018). 67 2. Dijkman, S. C. van, Jager, N. C. B. de, Rauwe, W. M., Danhof, M. & Della Pasqua, O. 68 Correction to: Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential 69 Implications for Maintenance Dose Optimisation in Future Clinical Trials. Clin Pharmacokinet 70 (2018). 71 3. Sumpter, A. L. & Holford, N. H. Predicting weight using postmenstrual age–neonates to adults. 72 Paediatr Anaesth 21, 309–315 (2011). 73  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4. Wang, C. et al. A bodyweight-dependent allometric exponent for scaling clearance across the 74 human life-span. Pharm. Res. 29, 1570–1581 (2012). 75 5. Lonsdale, D. O. et al. Standard beta–lactam doses fail to achieve PK/PD targets in critically ill 76 patients of all ages, with children particularly at risk: results from the ABDose study. 28th ECCMID 77 meeting, Madrid, Spain O0808, (2018). 78 6. Hennig, S., Standing, J. F., Staatz, C. E. & Thomson, A. H. Population pharmacokinetics of 79 tobramycin in patients with and without cystic fibrosis. Clin Pharmacokinet 52, 289–301 (2013). 80 7. McCune, J. S. et al. Busulfan in infant to adult hematopoietic cell transplant recipients: a 81 population pharmacokinetic model for initial and Bayesian dose personalization. Clin. Cancer Res. 82 20, 754–763 (2014). 83 8. Holford, N. H., Ma, S. C. & Anderson, B. J. Prediction of morphine dose in humans. Paediatr 84 Anaesth 22, 209–222 (2012). 85 9. Calvier, E. A. et al. Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic 86 of 0.75 Fade? Clin Pharmacokinet 56, 273–285 (2017). 87 10. Holford, N., Heo, Y. A. & Anderson, B. A pharmacokinetic standard for babies and adults. J 88 Pharm Sci 102, 2941–2952 (2013). 89 11. Germovsek, E., Barker, C. I., Sharland, M. & Standing, J. F. Scaling clearance in paediatric 90 pharmacokinetics: All models are wrong, which are useful? Br J Clin Pharmacol 83, 777–790 91 (2017). 92 12. Polepally, A. R. et al. Steady-state pharmacokinetics and bioavailability of immediate-release 93 and extended-release formulations of lamotrigine in elderly epilepsy patients: Use of stable isotope 94 methodology. J Clin Pharmacol 55, 1101–1108 (2015). 95  1  2  3  4  5  6  7  8  9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Post natal age (y)CL/F (L/h)0.40.50.60.70.80.90 1 2 3 4 5 6Figure Click here to download Figure Figure1 

Standing, Joseph F.

Anderson, Brian J.

Holford, Nick H.

Johnston, Trevor N.

Knibbe, Catherijne A. J.

Lonsdale, Dagan O.

University of Queensland eSpace

Comment on "Effect of age-related factors on the pharmacokinetics of lamotrigine and potential implications for maintenance dose optimisation in future clinical trials"

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Comment on "Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials".

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The University of Manchester - Institutional Repository

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