Skip to main content
SpringerLink
Log in

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin. The pediatric PBPK model was optimized following development of an adult PBPK model that adequately described literature data. We evaluated the predictability of the pediatric population PBPK model across four age groups and found that 63–93% of the observed data were captured within the 90% prediction interval of the model. We then used the pediatric PBPK model to optimize intravenous clindamycin dosing for a future prospective validation trial. The optimal dosing proposed by this model was 9 mg/kg/dose in children ≤5 months of age, 12 mg/kg/dose in children >5 months–6 years of age, and 10 mg/kg/dose in children 6–18 years of age, all administered every 8 h. The simulated exposures achieved with the dosing regimen proposed were comparable with adult plasma and tissue exposures for the treatment of community-acquired methicillin-resistant Staphylococcus aureus infections. Our model demonstrated the feasibility of using opportunistic pediatric data to develop pediatric PBPK models, extending the reach of this powerful modeling tool and potentially transforming the pediatric drug development field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Huang SM, Rowland M. The role of physiologically based pharmacokinetic modeling in regulatory review. Clin Pharmacol Ther. 2012;91(3):542–9.

    Article  CAS  PubMed  Google Scholar 

  2. Laughon MM, Benjamin DK Jr, Capparelli EV, Kearns GL, Berezny K, Paul IM, et al. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol. 2011;4(5):643–52.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Laughon MM, Benjamin DK Jr. Mechanisms to provide safe and effective drugs for children. Pediatrics. 2014;134(2):e562–3.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cohen-Wolkowiez M, Watt KM, Zhou C, Bloom BT, Poindexter B, Castro L, et al. Developmental pharmacokinetics of piperacillin and tazobactam using plasma and dried blood spots from infants. Antimicrob Agents Chemother. 2014;58(5):2856–65.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gonzalez D, Melloni C, Yogev R, Poindexter BB, Mendley SR, Delmore P, et al. Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents. Clin Pharmacol Ther. 2014;96(4):429–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Herigon JC, Hersh AL, Gerber JS, Zaoutis TE, Newland JG. Antibiotic management of Staphylococcus aureus infections in US children’s hospitals, 1999–2008. Pediatrics. 2010;125(6):e1294–300.

    Article  PubMed  Google Scholar 

  7. Reeves DS, Holt HA, Phillips I, King A, Miles RS, Paton R, et al. Activity of clindamycin against Staphylococcus aureus and Staphylococcus epidermidis from four UK centres. J Antimicrob Chemother. 1991;27(4):469–74.

    Article  CAS  PubMed  Google Scholar 

  8. Wynalda MA, Hutzler JM, Koets MD, Podoll T, Wienkers LC. In vitro metabolism of clindamycin in human liver and intestinal microsomes. Drug Metab Dispos. 2003;31(7):878–87.

    Article  CAS  PubMed  Google Scholar 

  9. Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J. 2013;15(2):455–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Leong R, Vieira ML, Zhao P, Mulugeta Y, Lee CS, Huang SM, et al. Regulatory experience with physiologically based pharmacokinetic modeling for pediatric drug trials. Clin Pharmacol Ther. 2012;91(5):926–31.

    Article  CAS  PubMed  Google Scholar 

  11. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–56.

    Article  CAS  PubMed  Google Scholar 

  12. Gatti G, Flaherty J, Bubp J, White J, Borin M, Gambertoglio J. Comparative study of bioavailabilities and pharmacokinetics of clindamycin in healthy volunteers and patients with AIDS. Antimicrob Agents Chemother. 1993;37(5):1137–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Flaherty JF, Rodondi LC, Guglielmo BJ, Fleishaker JC, Townsend RJ, Gambertoglio JG. Comparative pharmacokinetics and serum inhibitory activity of clindamycin in different dosing regimens. Antimicrob Agents Chemother. 1988;32(12):1825–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Plaisance KI, Drusano GL, Forrest A, Townsend RJ, Standiford HC. Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate. Antimicrob Agents Chemother. 1989;33(5):618–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gatti G, Malena M, Casazza R, Borin M, Bassetti M, Cruciani M. Penetration of clindamycin and its metabolite N-demethylclindamycin into cerebrospinal fluid following intravenous infusion of clindamycin phosphate in patients with AIDS. Antimicrob Agents Chemother. 1998;42(11):3014–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Willmann S, Hohn K, Edginton A, Sevestre M, Solodenko J, Weiss W, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007;34(3):401–31.

    Article  PubMed  Google Scholar 

  17. Edginton AN, Schmitt W, Willmann S. Development and evaluation of a generic physiologically based pharmacokinetic model for children. Clin Pharmacokinet. 2006;45(10):1013–34.

    Article  CAS  PubMed  Google Scholar 

  18. DrugBank Version 4.5. Drug and drug target database. http://www.drugbank.ca. Accessed 6 May 2016.

  19. Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.

    Article  CAS  PubMed  Google Scholar 

  20. Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94(6):1259–76.

    Article  CAS  PubMed  Google Scholar 

  21. Rodgers T, Leahy D, Rowland M. Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat. J Pharm Sci. 2005;94(6):1237–48.

    Article  CAS  PubMed  Google Scholar 

  22. Gordon RC, Regamey C, Kirby WM. Serum protein binding of erythromycin, lincomycin, and clindamycin. J Pharm Sci. 1973;62(7):1074–7.

    Article  CAS  PubMed  Google Scholar 

  23. Kiosz D, Simon C, Malerczyk V. The plasma-protein-binding of Clindamycin Cephazolin and Cephradin in neonates and adults (author’s transl). Klin Padiatr. 1975;187(1):71–80.

    CAS  PubMed  Google Scholar 

  24. Kays MB, White RL, Gatti G, Gambertoglio JG. Ex vivo protein binding of clindamycin in sera with normal and elevated alpha 1-acid glycoprotein concentrations. Pharmacotherapy. 1992;12(1):50–5.

    CAS  PubMed  Google Scholar 

  25. Achour B, Barber J, Rostami-Hodjegan A. Expression of hepatic drug-metabolizing cytochrome p450 enzymes and their intercorrelations: a meta-analysis. Drug Metab Dispos. 2014;42(8):1349–56.

    Article  PubMed  Google Scholar 

  26. Dent CE, Harper CM. Plasma-alkaline-phosphatase in normal adults and in patients with primary hyperparathyroidism. Lancet. 1962;1(7229):559–63.

    Article  CAS  PubMed  Google Scholar 

  27. Flaherty JF Jr, Gatti G, White J, Bubp J, Borin M, Gambertoglio JG. Protein binding of clindamycin in sera of patients with AIDS. Antimicrob Agents Chemother. 1996;40(5):1134–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hayton WL. Maturation and growth of renal function: dosing renally cleared drugs in children. AAPS Pharm Sci. 2000;2(1):E3.

    Article  CAS  Google Scholar 

  29. Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach for the scaling of clearance in children. Clin Pharmacokinet. 2006;45(7):683–704.

    Article  CAS  PubMed  Google Scholar 

  30. Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. BIOSILICO. 2003;1(4):121–4.

    Article  CAS  Google Scholar 

  31. Connelly MA, Brown JT, Kearns GL, Anderson RA, St Peter SD, Neville KA. Pupillometry: a non-invasive technique for pain assessment in paediatric patients. Arch Dis Child. 2014;99(12):1125–31.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285–92.

    Article  PubMed  Google Scholar 

  33. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18–55.

    Article  PubMed  Google Scholar 

  34. Barrett JS, Della Casa Alberighi O, Laer S, Meibohm B. Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther. 2012;92(1):40–9.

    Article  CAS  PubMed  Google Scholar 

  35. Edginton AN, Joshi G. Have physiologically-based pharmacokinetic models delivered? Expert Opin Drug Metab Toxicol. 2011;7(8):929–34.

    Article  CAS  PubMed  Google Scholar 

  36. Cohen-Wolkowiez M, Ouellet D, Smith PB, James LP, Ross A, Sullivan JE, et al. Population pharmacokinetics of metronidazole evaluated using scavenged samples from preterm infants. Antimicrob Agents Chemother. 2012;56(4):1828–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cohen-Wolkowiez M, Benjamin DK Jr, Ross A, James LP, Sullivan JE, Walsh MC, et al. Population pharmacokinetics of piperacillin using scavenged samples from preterm infants. Ther Drug Monit. 2012;34(3):312–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maharaj AR, Edginton AN. Physiologically based pharmacokinetic modeling and simulation in pediatric drug development. CPT Pharmacomet Syst Pharmacol. 2014;3:e150.

    Article  CAS  Google Scholar 

  39. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.

    Article  CAS  PubMed  Google Scholar 

  40. Edginton AN, Theil FP, Schmitt W, Willmann S. Whole body physiologically-based pharmacokinetic models: their use in clinical drug development. Expert Opin Drug Metab Toxicol. 2008;4(9):1143–52.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The assay measuring clindamycin concentrations was performed at OpAns Laboratory (Durham, NC, USA).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Christoph P. Hornik, Kevin Watt & Michael Cohen-Wolkowiez

  2. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA

    Christoph P. Hornik, Huali Wu, Kevin Watt & Michael Cohen-Wolkowiez

  3. School of Pharmacy, University of Waterloo, Waterloo, ON, Canada

    Andrea N. Edginton

  4. UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Daniel Gonzalez

Authors
  1. Christoph P. Hornik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huali Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea N. Edginton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kevin Watt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Cohen-Wolkowiez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christoph P. Hornik.

Ethics declarations

Funding

This work was funded by the National Institutes of Health (1R01-HD076676-01A1; MCW).

Conflict of interest

Christoph P. Hornik receives salary support for research from the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001117) and the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Benjamin under the Best Pharmaceuticals for Children Act). Andrea N. Edginton receives support for research from the National Institutes of Health (1R01-HD076676-01A1; PI: Cohen-Wolkowiez). Kevin Watt receives support from the Pediatric Critical Care and Trauma Scientist Development Program (5K12HD047349) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; 1K23HD075891, 2K24HD058735). Michael Cohen-Wolkowiez receives support for research from the National Institutes of Health (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Diseases (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp). Daniel Gonzalez receives support for research from the NICHD (K23HD083465), the nonprofit organization Thrasher Research Fund (http://www.thrasherresearch.org), and from industry (Cempra, Inc. and Jacobus Pharmaceutical Company, Inc.) for drug development in adults and children. Huali Wu has no conflicts of interest to declare. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Ethical approval

Clinical PK data used in this publication were collected during the POP01 clinical trial (ClinicalTrials.gov identifier: NCT01431326). The POP01 study protocol was reviewed and approved by the Institutional Review Board of each participating institution.

Informed consent

Informed consent and assent, when applicable, was obtained from all participants enrolled in the POP01 clinical trial who contributed clinical PK data used in this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 150 kb)

Supplementary material 2 (TIFF 132 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hornik, C.P., Wu, H., Edginton, A.N. et al. Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data. Clin Pharmacokinet 56, 1343–1353 (2017). https://doi.org/10.1007/s40262-017-0525-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-017-0525-5

Keywords

Search

Navigation