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Pharmacy World and Science

, Volume 19, Issue 3, pp 142–151 | Cite as

Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm

  • D.J. Touw
  • A.A.T.M.M. Vinks
  • C. Neef
Article

Abstract

The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a nonparametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic 2– and 3–dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non–renal clearance and the non–renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h–1 were also included. In this population, intravenous tobramycin could be best described by median (± dispersion factor) volume of distribution per unit of total body weight of 0.28 ± 0.05 L/kg, elimination rate constant of 0.25 ± 0.10 h–1 and elimination rate constant per unit of creatinine clearance of 0.0008 ± 0.0009 h–1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non–renal elimination rate constant fixed at 0.01 h–1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

Population modelling Pharmacokinetics Tobramycin Cystic fibrosis 

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References

  1. 1.
    Dodge WF, Jelliffe RW, Richardson CJ, McCleery RA, Hokanson JA, Snodgrass WR. Gentamicin population pharmacokinetic models for low birth weight infants using a new nonparametric method. Clin Pharmacol Ther 1991;50:25-31.Google Scholar
  2. 2.
    Eleveld EA, Neef C, Guchelaar HJ. Population pharmacokinetics of tobramycin [abstract]. Pharm World Sci 1995;17(Suppl M):8.Google Scholar
  3. 3.
    Levy J, Smith AL, Koup JR, Williams-Warren J, Ramsey B. Disposition of tobramycin in patients with cystic fibrosis: a prospectice controlled study. J Pediatr 1984;105:117-24.Google Scholar
  4. 4.
    Horrevorts AM, Degener JE, Dzoljic-Danilovic G, Michel MF, Kerrebijn KF, Driessen O, et al. Pharmacokinetics of tobramycin in patients with cystic fibrosis: implications for the dosing interval. Chest 1985;88:260-4.Google Scholar
  5. 5.
    Touw DJ, Vinks AATMM, Heijerman HGM, Hermans J, Bakker W. Suggestions for the optimization of the initial tobramycin dose in adolescent and adult patients with cystic fibrosis. Ther Drug Monit 1994;16:125-31.Google Scholar
  6. 6.
    Touw DJ, Vinks AATMM, Jacobs F, Heijerman HGM, Bakker W. Creatinine clearance as predictor of tobramycin elimination constant in adult patients with cystic fibrosis. Ther Drug Monit 1996;18:562-9.Google Scholar
  7. 7.
    Steimer JL, Mallet A, Mentre F. Estimating interindividual pharmacokinetic variability. In: Rowland M, et al., editors. Variability in drug therapy: description, estimation, and control. New York: Raven Press, 1985:65-109.Google Scholar
  8. 8.
    Beal S, Sheiner L. NONMEM Users guide-part 1: User's basic guide. Technical report of the division of clinical pharmacology, University of San Francisco, 1980.Google Scholar
  9. 9.
    Schumitzky A. Nonparametric EM algorithms for estimating prior distributions. Applied Mathematics and Computation 1991;45:143-57.Google Scholar
  10. 10.
    Jelliffe RW. User's manual for the PC programs from the USC Laboratory of Applied Pharmacokinetics. Los Angeles: University of Southern California School of Medicine, 1989.Google Scholar
  11. 11.
    Jelliffe RW, Schumitzky A, Van Guilder M. User manual for version 10.6 of the USC*PACK collection of PC programs. University of Southern California, 1995.Google Scholar
  12. 12.
    Touw DJ, Vinks AATMM, Heijerman HGM, Bakker W. Prospective evaluation of a dose-prediction algorithm for intravenous tobramycin in adolescent and adult patient with cystic fibrosis. Ther Drug Monit 1996; 18:118-23.Google Scholar
  13. 13.
    Jelliffe RW, Jelliffe SM. A computer program for estimation of creatinine clearance from unstable serum creatinine levels, age, sex and weight. Math Biosci 1987;14:17-24.Google Scholar
  14. 14.
    Proost JH, Meijer DK, MW/PHARM, an integrated software package for drug dosage regimen calculation and therapeutic drug monitoring. Comput Biol Med 1992;22:155-63.Google Scholar
  15. 15.
    Ng PK. Determining aminoglycoside dosage and blood levels using a programmable calculator. Am J Hosp Pharm 1980;37:225-31.Google Scholar
  16. 16.
    Dodge WF, Jelliffe RW, Richardson CJ, Bellanger RA, Hokanson JA, Snodgrass WR. Population pharmacokinetic models: measures of central tendency. Drug Invest 1993;5:206-11.Google Scholar
  17. 17.
    Dodge WF, Jelliffe RW, Zwischenberger JB, Bellanger RA, Hokanson JA, Snodgrass WR. Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation. Ther Drug Monit 1994;16:552-9.Google Scholar
  18. 18.
    Buffington DE, Lampasona V, Chandler MHH. Computers in pharmacokinetics. Choosing software for clinical decision making. Clin Pharmacokinet 1993;25:205-16.Google Scholar
  19. 19.
    Jelliffe RW, Schumitzky A, Van Guilder M. Nonpharmacokinetic clinical factors affecting aminoglycoside therapeutic precision. A simulation study. Drug Invest 1992;4:20-9.Google Scholar
  20. 20.
    Jelliffe RW. Explicit determination of laboratory assay error patterns. A useful aid in therapeutic drug monitoring. American Society of Clinical Pathologists Check Sample Continuing Education Program. Drug Monitoring and Toxicology No. DM-89-4, 1989.Google Scholar
  21. 21.
    Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokin Biopharm 1977;5:445-79.Google Scholar
  22. 22.
    Touw DJ, Vinks AATMM, Heijerman HGM, Bakker W. Validation of tobramycin monitoring in adolescent and adult patients with cystic fibrosis. Ther Drug Monit 1993;15:52-9.Google Scholar
  23. 23.
    Vožeh S, Schmidlin O, Taeschner W. Pharmacokinetic drug data. Clin Pharmacokinet 1988;15:254-82.Google Scholar
  24. 24.
    Cameron JS. Renal function testing. In: Cameron S, Davidson AM, Grünfeld, Kerr D, Ritz E, editors. Oxford textbook of clinical nephrology. Vol 1. Oxford: Oxford University Press, 1992:24-49.Google Scholar
  25. 25.
    Hedman A, Adan-Abi Y, Alvan G, Strandvik B, Arvidsson A. Influence of the glomerular filtration rate on renal clearance of ceftazidime in cystic fibrosis. Clin Pharmacokinet. 1988;15:57-65.Google Scholar
  26. 26.
    Hedman A, Alvan G, Strandvik B, Arvidsson A. Increased renal clearance of cefsulodin due to higher glomerular filtration rate in cystic fibrosis. Clin Pharmacokinet 1990;18:168-75.Google Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • D.J. Touw
    • 1
    • 2
  • A.A.T.M.M. Vinks
    • 3
  • C. Neef
    • 4
  1. 1.Department of PharmacyAcademic Hospital Vrije UniversiteitAmsterdam
  2. 2.Adult Cystic Fibrosis CentreLeyenburg Hospital, Department of PulmonologyThe HagueThe Netherlands
  3. 3.The Hague Hospitals Central PharmacyThe HagueThe Netherlands
  4. 4.Department of PharmacyMedisch Spectrum TwenteEnschedeThe Netherlands

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