International Journal of Legal Medicine

, Volume 132, Issue 2, pp 415–424 | Cite as

The feasibility of physiologically based pharmacokinetic modeling in forensic medicine illustrated by the example of morphine

  • Nadine Schaefer
  • Daniel Moj
  • Thorsten Lehr
  • Peter H. Schmidt
  • Frank Ramsthaler
Case Report

Abstract

In forensic medicine, expert opinion is often required concerning dose and time of intake of a substance, especially in the context of fatal intoxications. In the present case, a 98-year-old man died 4 days after admission to a hospital due to a femur neck fracture following a domestic fall in his retirement home. As he had obtained high morphine doses in the context of palliative therapy and a confusion of his supplemental magnesium tablets with a diuretic by the care retirement home was suspected by the relatives, a comprehensive postmortem examination was performed. Forensic toxicological GC- and LC-MS analyses revealed, besides propofol, ketamine, and a metamizole metabolite in blood and urine, toxic blood morphine concentrations of approximately 3 mg/l in femoral and 5 mg/l in heart blood as well as 2, 7, and 10 mg/kg morphine in brain, liver, and lung, respectively. A physiologically based pharmacokinetic (PBPK) model was developed and applied to examine whether the morphine concentrations were (i) in agreement with the morphine doses documented in the clinical records or (ii) due to an excessive morphine administration. PBPK model simulations argue against an overdosing of morphine. The immediate cause of death was respiratory and cardiovascular failure due to pneumonia following a fall, femur neck fracture, and immobilization accompanied by a high and probably toxic concentration of morphine, attributable to the administration under palliative care conditions. The presented case indicates that PBPK modeling can be a useful tool in forensic medicine, especially in question of a possible drug overdosing.

Keywords

Palliative care Morphine Physiologically based pharmacokinetic modeling Forensic medicine 

References

  1. 1.
    Lötsch J (2005) Pharmacokinetic–pharmacodynamic modeling of opioids. J Pain Symptom Manag 29(5, Supplement):90–103.  https://doi.org/10.1016/j.jpainsymman.2005.01.012 CrossRefGoogle Scholar
  2. 2.
    Altamura AC, Moliterno D, Paletta S, Maffini M, Mauri MC, Bareggi S (2013) Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol 9(4):423–440.  https://doi.org/10.1517/17425255.2013.759209 CrossRefPubMedGoogle Scholar
  3. 3.
    Schaefer N, Wojtyniak J-G, Kettner M, Schlote J, Laschke MW, Ewald AH, Lehr T, Menger MD, Maurer HH, Schmidt PH (2016) Pharmacokinetics of (synthetic) cannabinoids in pigs and their relevance for clinical and forensic toxicology. Toxicol Lett 253:7–16.  https://doi.org/10.1016/j.toxlet.2016.04.021 CrossRefPubMedGoogle Scholar
  4. 4.
    Marsot A, Audebert C, Attolini L, Lacarelle B, Micallef J, Blin O (2017) Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers. J Pharmacol Toxicol Methods 85:49–54.  https://doi.org/10.1016/j.vascn.2017.02.003 CrossRefPubMedGoogle Scholar
  5. 5.
    Dubois N, Hallet C, Seidel L, Demaret I, Luppens D, Ansseau M, Rozet E, Albert A, Hubert P, Charlier C (2015) Estimation of the time interval between the administration of heroin and the sampling of blood in chronic inhalers. J Anal Toxicol 39(4):300–305.  https://doi.org/10.1093/jat/bkv001 CrossRefPubMedGoogle Scholar
  6. 6.
    Cook DS, Braithwaite RA, Hale KA (2000) Estimating antemortem drug concentrations from postmortem blood samples: the influence of postmortem redistribution. J Clin Pathol 53(4):282–285.  https://doi.org/10.1136/jcp.53.4.282 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Schlender J-F, Meyer M, Thelen K, Krauss M, Willmann S, Eissing T, Jaehde U (2016) Development of a whole-body physiologically based pharmacokinetic approach to assess the pharmacokinetics of drugs in elderly individuals. Clin Pharmacokinet 55(12):1573–1589.  https://doi.org/10.1007/s40262-016-0422-3 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Alqahtani S, Kaddoumi A (2015) Development of physiologically based pharmacokinetic/pharmacodynamic model for indomethacin disposition in pregnancy. PLoS One 10(10):e0139762.  https://doi.org/10.1371/journal.pone.0139762 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mahmood I, Ahmad T, Mansoor N, Sharib SM (2017) Prediction of clearance in neonates and infants (≤ 3 months of age) for drugs that are glucuronidated: a comparative study between allometric scaling and physiologically based pharmacokinetic modeling. J Clin Pharmacol 57(4):476–483.  https://doi.org/10.1002/jcph.837 CrossRefPubMedGoogle Scholar
  10. 10.
    Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N (2015) Physiologically based pharmacokinetic (PBPK) modeling and simulation approaches: a systematic review of published models, applications, and model verification. Drug Metab Dispos 43(11):1823–1837.  https://doi.org/10.1124/dmd.115.065920 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Workgroup EM, Marshall SF, Burghaus R, Cosson V, Cheung SYA, Chenel M, DellaPasqua O, Frey N, Hamrén B, Harnisch L, Ivanow F, Kerbusch T, Lippert J, Milligan PA, Rohou S, Staab A, Steimer JL, Tornøe C, Visser SAG (2016) Good practices in model-informed drug discovery and development: practice, application, and documentation. CPT: Pharmacometrics Syst Pharmacol 5(3):93–122.  https://doi.org/10.1002/psp4.12049 Google Scholar
  12. 12.
    Jones HM, Rowland-Yeo K (2013) Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT: Pharmacometrics Syst Pharmacol 2(8):1–12.  https://doi.org/10.1038/psp.2013.41 Google Scholar
  13. 13.
    Tsamandouras N, Rostami-Hodjegan A, Aarons L (2015) Combining the ‘bottom up’ and ‘top down’ approaches in pharmacokinetic modelling: fitting PBPK models to observed clinical data. Br J Clin Pharmacol 79(1):48–55.  https://doi.org/10.1111/bcp.12234 CrossRefPubMedGoogle Scholar
  14. 14.
    Nestorov I (2007) Whole-body physiologically based pharmacokinetic models. Expert Opin Drug Metab Toxicol 3(2):235–249.  https://doi.org/10.1517/17425255.3.2.235 CrossRefPubMedGoogle Scholar
  15. 15.
    National Guideline C (2012) Opioids in palliative care: safe and effective prescribing of strong opioids for pain in palliative care of adultsGoogle Scholar
  16. 16.
    Lötsch J, Skarke C, Schmidt H, Liefhold J, Geisslinger G (2002) Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 72(2):151–162.  https://doi.org/10.1067/mcp.2002.126172 CrossRefPubMedGoogle Scholar
  17. 17.
    Ing Lorenzini K, Daali Y, Dayer P, Desmeules J (2012) Pharmacokinetic–pharmacodynamic modelling of opioids in healthy human volunteers. A MiniReview. Basic Clin Pharmacol Toxicol 110(3):219–226.  https://doi.org/10.1111/j.1742-7843.2011.00814.x CrossRefPubMedGoogle Scholar
  18. 18.
    Projean D, Morin PE, Tu TM, Ducharme J (2003) Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica 33(8):841–854.  https://doi.org/10.1080/0049825031000121608 CrossRefPubMedGoogle Scholar
  19. 19.
    Stone AN, Mackenzie PI, Galetin A, Houston JB, Miners JO (2003) Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7. Drug Metab Dispos 31(9):1086–1089.  https://doi.org/10.1124/dmd.31.9.1086 CrossRefPubMedGoogle Scholar
  20. 20.
    Mazoit JX, Butscher K, Samii K (2007) Morphine in postoperative patients: pharmacokinetics and pharmacodynamics of metabolites. Anesth Analg 105(1):70–78.  https://doi.org/10.1213/01.ane.0000265557.73688.32 CrossRefPubMedGoogle Scholar
  21. 21.
    Oosten AW, Abrantes JA, Jönsson S, Matic M, van Schaik RHN, de Bruijn P, van der Rijt CCD, Mathijssen RHJ (2016) A prospective population pharmacokinetic study on morphine metabolism in cancer patients. Clin Pharmacokinet :1–14. doi: https://doi.org/10.1007/s40262-016-0471-7
  22. 22.
    Tegeder I, Lötsch J, Geisslinger G (1999) Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 37(1):17–40.  https://doi.org/10.2165/00003088-199937010-00002 CrossRefPubMedGoogle Scholar
  23. 23.
    Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson J, Sawe J (1990) The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 29(3):289–297.  https://doi.org/10.1111/j.1365-2125.1990.tb03638.x CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Franken LG, de Winter BCM, van Esch HJ, van Zuylen L, Baar FPM, Tibboel D, Mathôt RAA, van Gelder T, Koch BCP (2016) Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol. Expert Opin Drug Metab Toxicol 12(6):669–680.  https://doi.org/10.1080/17425255.2016.1179281 CrossRefPubMedGoogle Scholar
  25. 25.
    Achour B, Russell MR, Barber J, Rostami-Hodjegan A (2014) Simultaneous quantification of the abundance of several cytochrome P450 and uridine 5′-diphospho-glucuronosyltransferase enzymes in human liver microsomes using multiplexed targeted proteomics. Drug Metab Dispos 42(4):500–510.  https://doi.org/10.1124/dmd.113.055632 CrossRefPubMedGoogle Scholar
  26. 26.
    Post TM, Freijer JI, Ploeger BA, Danhof M (2008) Extensions to the visual predictive check to facilitate model performance evaluation. J Pharmacokinet Pharmacodyn 35(2):185–202.  https://doi.org/10.1007/s10928-007-9081-1 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Willmann S, Hohn K, Edginton A, Sevestre M, Solodenko J, Weiss W, Lippert J, Schmitt W (2007) Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn 34(3):401–431.  https://doi.org/10.1007/s10928-007-9053-5 CrossRefPubMedGoogle Scholar
  28. 28.
    Claassen K, Thelen K, Coboeken K, Gaub T, Lippert J, Allegaert K, Willmann S (2015) Development of a physiologically-based pharmacokinetic model for preterm neonates: evaluation with in vivo data. Curr Pharm Des 21(39):5688–5698.  https://doi.org/10.2174/1381612821666150901110533 CrossRefPubMedGoogle Scholar
  29. 29.
    Willmann S, Becker C, Burghaus R, Coboeken K, Edginton A, Lippert J, Siegmund H-U, Thelen K, Mück W (2014) Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban. Clin Pharmacokinet 53(1):89–102.  https://doi.org/10.1007/s40262-013-0090-5 CrossRefPubMedGoogle Scholar
  30. 30.
    Thelen K, Coboeken K, Willmann S, Burghaus R, Dressman JB, Lippert J (2011) Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. J Pharm Sci 100(12):5324–5345.  https://doi.org/10.1002/jps.22726 CrossRefPubMedGoogle Scholar
  31. 31.
    Thelen K, Coboeken K, Willmann S, Dressman JB, Lippert J (2012) Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms. J Pharm Sci 101(3):1267–1280.  https://doi.org/10.1002/jps.22825 CrossRefPubMedGoogle Scholar
  32. 32.
    Willmann S, Lippert J, Schmitt W (2005) From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools. Expert Opin Drug Metab Toxicol 1(1):159–168.  https://doi.org/10.1517/17425255.1.1.159 CrossRefPubMedGoogle Scholar
  33. 33.
    Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W (2003) PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. Biosilico 1(4):121–124.  https://doi.org/10.1016/S1478-5382(03)02342-4 CrossRefGoogle Scholar
  34. 34.
    Meyer M, Schneckener S, Ludewig B, Kuepfer L, Lippert J (2012) Using expression data for quantification of active processes in physiologically based pharmacokinetic modeling. Drug Metab Dispos 40(5):892–901.  https://doi.org/10.1124/dmd.111.043174 CrossRefPubMedGoogle Scholar
  35. 35.
    Wheeler DL, Church DM, Federhen S, Lash AE, Madden TL, Pontius JU, Schuler GD, Schriml LM, Sequeira E, Tatusova TA, Wagner L (2003) Database resources of the National Center for biotechnology. Nucleic Acids Res 31(1):28–33.  https://doi.org/10.1093/nar/gkg033 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hasselstrom J, Sawe J (1993) Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 24(4):344–354.  https://doi.org/10.2165/00003088-199324040-00007 CrossRefPubMedGoogle Scholar
  37. 37.
    Avdeef A, Barrett DA, Shaw PN, Knaggs RD, Davis SS (1996) Octanol−, chloroform−, and propylene glycol dipelargonat−water partitioning of morphine-6-glucuronide and other related opiates. J Med Chem 39(22):4377–4381.  https://doi.org/10.1021/jm960073m CrossRefPubMedGoogle Scholar
  38. 38.
    Olsen GD, Bennett WM, Porter GA (1975) Morphine and phenytoin binding to plasma proteins in renal and hepatic failure. Clin Pharmacol Ther 17(6):677–684.  https://doi.org/10.1002/cpt1975176677 CrossRefPubMedGoogle Scholar
  39. 39.
    Chau N, Elliot DJ, Lewis BC, Burns K, Johnston MR, Mackenzie PI, Miners JO (2014) Morphine glucuronidation and glucosidation represent complementary metabolic pathways that are both catalyzed by UDP-glucuronosyltransferase 2B7: kinetic, inhibition, and molecular modeling studies. J Pharmacol Exp Ther 349(1):126–137.  https://doi.org/10.1124/jpet.113.212258 CrossRefPubMedGoogle Scholar
  40. 40.
    Eissing T, Lippert J, Willmann S (2012) Pharmacogenomics of codeine, morphine, and morphine-6-glucuronide: model-based analysis of the influence of CYP2D6 activity, UGT2B7 activity, renal impairment, and CYP3A4 inhibition. Mol Diagn Ther 16(1):43–53.  https://doi.org/10.2165/11597930-000000000-00000 CrossRefPubMedGoogle Scholar
  41. 41.
    Westerling D, Persson C, Hoglund P (1995) Plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide after intravenous and oral administration to healthy volunteers: relationship to nonanalgesic actions. Ther Drug Monit 17(3):287–301.  https://doi.org/10.1097/00007691-199506000-00013 CrossRefPubMedGoogle Scholar
  42. 42.
    Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A (2012) Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care 16(4):R136–R136.  https://doi.org/10.1186/cc11441 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Baselt, R.C, Cravey RH (2014). In: Disposition of toxic drugs and chemicals in man, 10th edition. Biomedical Publications, Seal Beach, California (USA), pp 1399–1403Google Scholar
  44. 44.
    Blinderman CD, Billings JA (2015) Comfort care for patients dying in the hospital. N Engl J Med 373(26):2549–2561.  https://doi.org/10.1056/NEJMra1411746 CrossRefPubMedGoogle Scholar
  45. 45.
    Lee YJ, Suh S-Y, Song J, Lee SS, Seo A-R, Ahn H-Y, Lee MA, Kim C-M, Klepstad P (2015) Serum and urine concentrations of morphine and morphine metabolites in patients with advanced cancer receiving continuous intravenous morphine: an observational study. BMC Palliat Care 14(1):53.  https://doi.org/10.1186/s12904-015-0052-9 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stanski DR, Greenblatt DJ, Lappas DG, Weser JK, Lowenstein E (1976) Kinetics of high-dose intravenous morphine in cardiac surgery patients. Clin Pharm Ther 19(6):752–756.  https://doi.org/10.1002/cpt1976196752 CrossRefGoogle Scholar
  47. 47.
    Chauvin M, Sandouk P, Scherrmann J, Farinotti R, Strumza P, Duvaldestin P (1987) Morphine pharmacokinetics in renal failure. Anesthesiology 66(3):327–331.  https://doi.org/10.1097/00000542-198703000-00011 CrossRefPubMedGoogle Scholar
  48. 48.
    Barnes KJ, Rowland A, Polasek TM, Miners JO (2014) Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins. Eur J Clin Pharmacol 70(9):1097–1106.  https://doi.org/10.1007/s00228-014-1709-7 CrossRefPubMedGoogle Scholar
  49. 49.
    Nolin TD, Naud J, Leblond FA, Pichette V (2008) Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther 83(6):898–903.  https://doi.org/10.1038/clpt.2008.59 CrossRefPubMedGoogle Scholar
  50. 50.
    Glare P, Walsh T (1991) Clinical pharmacokinetics of morphine. Ther Drug Monit 13(1):1–23.  https://doi.org/10.1097/00007691-199101000-00001 CrossRefPubMedGoogle Scholar
  51. 51.
    Staeheli SN, Gascho D, Ebert LC, Kraemer T, Steuer AE (2017) Time-dependent postmortem redistribution of morphine and its metabolites in blood and alternative matrices—application of CT-guided biopsy sampling. Int J Legal Med 131(2):379–389.  https://doi.org/10.1007/s00414-016-1485-2 CrossRefPubMedGoogle Scholar
  52. 52.
    Skopp G, Pötsch L, Klingmann A, Mattern R (2001) Stability of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in fresh blood and plasma and postmortem blood samples. J Anal Toxicol 25(1):2–7.  https://doi.org/10.1093/jat/25.1.2 CrossRefPubMedGoogle Scholar
  53. 53.
    Meyer WW, Peter B, Solth K (1963) Die Organgewichte in den höheren Altersstufen (70–92 Jahre) in ihrer Beziehung zum Alter und Körpergewicht. Virchows Arch Pathol Anat Physiol Klin Med 337(1):17–32.  https://doi.org/10.1007/bf00965815 CrossRefPubMedGoogle Scholar
  54. 54.
    Villesen HH, Banning A-M, Petersen RH, Weinelt S, Poulsen JB, Hansen SH, Christrup LL (2007) Pharmacokinetics of morphine and oxycodone following intravenous administration in elderly patients. Ther Clin Risk Manag 3(5):961–967PubMedPubMedCentralGoogle Scholar
  55. 55.
    Tiseo PJ, Thaler HT, Lapin J, Inturrisi CE, Portenoy RK, Foley KM (1995) Morphine-6-glucuronide concentrations and opioid-related side effects: a survey in cancer patients. Pain 61(1):47–54.  https://doi.org/10.1016/0304-3959(94)00148-8 CrossRefPubMedGoogle Scholar
  56. 56.
    Indelicato RA, Portenoy RK (2002) Opioid rotation in the management of refractory cancer pain. J Clin Oncol 20(1):348–352.  https://doi.org/10.1200/jco.2002.20.1.348 CrossRefPubMedGoogle Scholar
  57. 57.
    Klepstad P, Hilton P, Moen J, Kaasa S, Borchgrevink PC, Zahlsen K, Dale O (2004) Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study. BMC Clin Pharmacol 4(1):7–7.  https://doi.org/10.1186/1472-6904-4-7 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Institute of Legal MedicineSaarland UniversityHomburg (Saar)Germany
  2. 2.Clinical PharmacySaarland UniversitySaarbrückenGermany

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