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Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmacokinetic Model of Three Clinical Trials

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Abstract

Purpose

The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age.

Methods

Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n = 119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant.

Results

The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h.

Conclusions

Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.

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Abbreviations

BDE:

Body weight dependent exponent

BSV:

Between-subject variability

CYP:

Cytochrome P450 enzyme

GA:

Gestational age

LLOQ:

Lower limit of quantification

NPDE:

Normalized prediction distribution errors

OFV:

Objective function value

PMA:

Postmenstrual age

PNA:

Postnatal age

PTA:

Probability of target attainment.

TVCL:

Typical clearance

WT:

Body weight

References

  1. Kokki H, Laisalmi M, Vanamo K. Interpleural bupivacaine and intravenous oxycodone for pain treatment after thoracotomy in children. J Opioid Manag. 2006;2(5):290–4.

    Article  Google Scholar 

  2. Lindell-Osuagwu L, Hakkarainen M, Sepponen K, Vainio K, Naaranlahti T, Kokki H. Prescribing for off-label use and unauthorized medicines in three paediatric wards in Finland, the status before and after the European Union Paediatric Regulation. J Clin Pharm Ther. 2014;39(2):144–53.

    Article  CAS  Google Scholar 

  3. Axelin A, Kirjavainen J, Salanterä S, Lehtonen L. Effects of pain management on sleep in preterm infants. Eur J Pain. 2010;14(7):752–8.

    Article  Google Scholar 

  4. El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 6 months to 7 years old. J Clin Pharmacol. 2006;46(4):433–42.

    Article  CAS  Google Scholar 

  5. Pokela ML, Anttila E, Seppälä T, Olkkola KT. Marked variation in oxycodone pharmacokinetics in infants. Paediatr Anaesth. 2005;15(7):560–5.

    Article  Google Scholar 

  6. Kokki M, Heikkinen M, Välitalo P, Hautajärvi H, Hokkanen J, Pitkänen H, et al. Maturation of oxycodone pharmacokinetics in neonates and infants. I. Oxycodone and its metabolites in plasma and urine. Br J Clin Pharmacol. 2016. doi:10.1111/bcp.13164.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen LY, Shen DD. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther. 2006;79(5):461–79.

    Article  CAS  Google Scholar 

  8. Lemberg KK, Heiskanen TE, Neuvonen M, Kontinen VK, Neuvonen PJ, Dahl ML, et al. Does co-administration of paroxetine change oxycodone analgesia: an interaction study in chronic pain patients. Scand J Pain. 2010;1(1):24–33.

    Article  CAS  Google Scholar 

  9. Mikus G, Klimas R. Contribution of oxycodone and its metabolites to the analgesic effect. Br J Anaesth. 2014;112(5):944–5.

    Article  CAS  Google Scholar 

  10. Kokki H, Rasanen I, Reinikainen M, Suhonen P, Vanamo K, Ojanperä I. Pharmacokinetics of oxycodone after intravenous, buccal, intramuscular and gastric administration in children. Clin Pharmacokinet. 2004;43(9):613–22.

    Article  CAS  Google Scholar 

  11. Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM user’s guides. Ellicott City: Icon Development Solutions; 2013.

    Google Scholar 

  12. R Development Core Team: R. A language and environment for statistical computing. Vienna, Austria, 2014, in http://www.R-project.org. Accessed 3 Nov 2016.

  13. Lindbom L, Pihlgren P, Jonsson EN, Jonsson N. PsN-Toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79(3):241–57.

    Article  Google Scholar 

  14. Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.

    Article  CAS  Google Scholar 

  15. Wang C, Peeters MYM, Allegaert K, van Oud-Alblas HJ B, Krekels EHJ, Tibboel D, et al. A bodyweight-dependent allometric exponent for scaling clearance across the human life-span. Pharm Res. 2012;29(6):1570–81.

    Article  CAS  Google Scholar 

  16. Bartelink IH, Boelens JJ, Bredius RGM, Egberts ACG, Wang C, Bierings MB, et al. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet. 2012;51(3):331–45.

    Article  CAS  Google Scholar 

  17. Anderson BJ, Holford NHG. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–32.

    Article  CAS  Google Scholar 

  18. Nguyen THT, Comets E, Mentré F. Extension of NPDE for evaluation of nonlinear mixed effect models in presence of data below the quantification limit with applications to HIV dynamic model. J Pharmacokinet Pharmacodyn. 2012;39(5):499–518.

    Article  Google Scholar 

  19. Kokki M, Broms S, Eskelinen M, Rasanen I, Ojanperä I, Kokki H. Analgesic concentrations of oxycodone—a prospective clinical PK/PD study in patients with laparoscopic cholecystectomy. Basic Clin Pharmacol Toxicol. 2012;110(5):469–75.

    Article  Google Scholar 

  20. Olkkola KT, Hamunen K, Seppälä T, Maunuksela EL. Pharmacokinetics and ventilatory effects of intravenous oxycodone in postoperative children. Br J Clin Pharmacol. 1994;38(1):71–6.

    Article  CAS  Google Scholar 

  21. Wang C, Sadhavisvam S, Krekels EH, Dahan A, Tibboel D, Danhof M, et al. Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. Clin Drug Investig. 2013;33(7):523–34.

    Article  Google Scholar 

  22. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth. 2004;92(2):208–17.

    Article  CAS  Google Scholar 

  23. Anderson BJ, van Lingen RA, Hansen TG, Lin YC, Holford NH. Acetaminophen developmental pharmacokinetics in premature neonates and infants - a pooled population analysis. Anesthesiology. 2002;96(6):1336–45.

    Article  CAS  Google Scholar 

  24. Levine B, Moore KA, Aronica-Pollak P, Fowler DF. Oxycodone intoxication in an infant: accidental or intentional exposures? J Forensic Sci. 2004;49(6):1358–60.

    Article  CAS  Google Scholar 

  25. Armstrong EJ, Jenkins AJ, Sebrosky GF, Balraj EK. An unusual fatality in a child due to oxycodone. Am J Forensic Med Pathol. 2004;25(4):338–41.

    Article  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was funded by a governmental research grant number 507A002 from the Hospital District of Northern Savo, Kuopio, Finland. The authors thank professor Catherijne A.J. Knibbe for her critical comments during the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Division of Pharmacology, Leiden University, Leiden, The Netherlands

    Pyry Välitalo

  2. Department of Anesthesia and Operative Services, Kuopio University Hospital, PO Box 100, FI-70029, Kuopio, Finland

    Merja Kokki & Hannu Kokki

  3. School of Medicine, University of Eastern Finland, Kuopio, Finland

    Merja Kokki & Hannu Kokki

  4. School of Pharmacy, University of Eastern Finland, Kuopio, Finland

    Veli-Pekka Ranta

  5. Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Klaus T. Olkkola

  6. Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Andrew C. Hooker

Authors
  1. Pyry Välitalo
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  2. Merja Kokki
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  3. Veli-Pekka Ranta
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  4. Klaus T. Olkkola
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  5. Andrew C. Hooker
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  6. Hannu Kokki
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Corresponding author

Correspondence to Hannu Kokki.

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Conflicts of Interest

Pyry Välitalo, Merja Kokki, Veli-Pekka Ranta, Klaus Olkkola, Andrew Hooker and Hannu Kokki have no conflicts of interest that are relevant to this work.

Ethical Approval

All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Additional information

Some of the results have been presented in abstract: Kokki H Välitalo P, Kokki M, Ranta VP, Olkkola KT, Hooker AC. Population pharmacokinetics of oxycodone in neonates and infants. Euroanaesthesia 2016 Congress, 28.-30.5.2016, London, UK.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure S1

The distribution of postmenstrual ages (years), postnatal ages (years) and bodyweights (kg) of the patients. (PDF 6 kb)

Figure S2

Typical parameter values in the final model. Between-subject variability of clearance (as standard deviation) decreases with increasing postnatal age (A); Central and peripheral volumes of distribution (l/kg) are highest in preterm neonates (B); Weight-adjusted mature clearance decreases as bodyweight increase (C); Clearance also matures as a function of postmenstrual age (PMA). Typical clearance for a certain pair of bodyweight and PMA is obtained by multiplying mature clearance (panel C) with clearance maturation (panel D, but as a fraction (0–1) and not as a percentage). Solid lines are based on interpolated model predictions and the dashed line in panel D is model extrapolation. (PDF 9 kb)

Figure S3

The random effects (etas) for clearance versus covariates in the base model and in the final model. The shrinkage of eta values for clearance was 1% for both the base model and the final model. The addition of covariates reduced the unexplained variability of clearance from 112% to between 31% (older children) and 60% (newborns). (PDF 45 kb)

Figure S4

The random effects (etas) for volume of distribution versus covariates in the base model and in the final model. Circles represent etas for central volume of distribution and crosses represent etas for peripheral volume of distribution. The shrinkage of eta values for volume of distribution was 8% and 19% for the central and peripheral volumes in the base model, respectively. The corresponding values in the final model were 19% and 21%, respectively. The unexplained variability in central volume of distribution was reduced from 90% to 54%, and variability in peripheral volume of distribution from 83% to 51%, when comparing the base model and the final model, respectively. (PDF 59 kb)

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Välitalo, P., Kokki, M., Ranta, VP. et al. Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmacokinetic Model of Three Clinical Trials. Pharm Res 34, 1125–1133 (2017). https://doi.org/10.1007/s11095-017-2122-6

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  • DOI: https://doi.org/10.1007/s11095-017-2122-6

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