Background: Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza.
Methods: Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted.
Results: Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose.
Conclusions: This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Davies BE. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 2010; 65 Suppl. 2: ii5–10
Funk DJ, Siddiqui F, Wiebe K, et al. Practical lessons from the first outbreaks: clinical presentation, obstacles, and management strategies for severe pandemic (pH1N1) 2009 influenza pneumonitis. Crit Care Med 2010; 38(4): e30–7
Rowland M, Balant L, Peck C. Physiologically based pharmacokinetics in drug development and regulatory science: a workshop report (Georgetown University, Washington, DC, May 29–30, 2002). AAPS PharmSci 2004; 6(1): E6
Manolis E, Pons G. Proposals for model-based paediatric medicinal development within the current European Union regulatory framework. Br J Clin Pharmacol 2009 Oct; 68(4): 493–501
Rayner CR, Chanu P, Gieschke R, et al. Population pharmacokinetics of oseltamivir when coadministered with probenecid. J Clin Pharmacol 2008; 48(8): 935–47
Jones H, Parrott N, Jorga K, et al. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet 2006; 45(5): 511–42
Yang D, Pearce RE, Wang X, et al. Human carboxylesterases HCE1 and HCE2: ontogenic expression, inter-individual variability and differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. Biochem Pharmacol 2009; 7(7): 238–47
Shi D, Yang D, Prinssen EP, et al. Surge in expression of carboxylesterase-1 during the post-neonatal stage enables a rapid gain of the capacity to activate the anti-influenza pro-drug oseltamivir. J Infect Dis 2011; 203(7): 937–42
Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev 2001; 50 Suppl. 1: S41–67
Dressman JB, Amidon GL, Reppas C, et al. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm Res 1998; 15(1): 11–22
de Zwart LL, Rompelberg CJM, Sips AJAM, et al. Anatomical and physiological differences between various species used in studies on the pharmacokinetics and toxicology of xenobiotics: a review of literature [report no. 623860010]. Bilthoven: Rijksinstitute voor Volksgezondheit en Milieu, 1999 [online]. Available from URL: http://www.rivm.nl/bibliotheek/rapporten/623860010.pdf [Accessed 2011 Jun 14]
Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res 1993; 10(7): 1093–5
Bodé S, Dreyer T, Greisen G. Gastric emptying and small intestinal transit time in preterm infants: a scintigraphic method. J Pediatric Gastroenterol Nutr 2004; 39(4): 378–82
National Center for Health Statistics (NCHS), Centers for Disease Control and Prevention (CDC). National Health and Nutrition Examination Survey data. Hyattsville, MD: CDC, 2010
Price PS, Conolly RB, Chaisson CF, et al. Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol 2003; 33(5): 469–503
Haddad S. Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. J Toxicol Environ Health 2001; 64(6): 453–64
Brown RP, Delp MD, Lindstedt SL, et al. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 1997; 13(4): 407–84
Sweeney RE, Langenberg JP, Maxwell DM. A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes of soman in multiple species. Arch Toxicol 2006; 80(11): 719–31
Parrott N, Lave T. Applications of physiologically based absorption models in drug discovery and development. Mol Pharmaceutics 2008; 5(5): 760–75
Rodgers T, Leahy D, Rowland M. Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst b-blocking drugs in rat. J Pharm Sci 2005; 94(6): 1237–48
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
Rodgers T, Rowland M. Mechanistic approaches to volume of distribution predictions: understanding the processes. Pharmaceutical Research 2007; 24(5): 918–33
Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349(12): 1157–67
Kawai R, Mathew D, Tanaka C, et al. Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther 1998; 287: 457–68
Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010; 202(4): 563–6
Ose A, Ito M, Kusuhara H, et al. Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos 2009; 37: 315–21
Hill G, Cihlar T, Oo C, et al. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion: correlation of in vivo and in vitro studies. Drug Metab Dispos 2003; 30(1): 13–9
Bleasby K, Castle JC, Roberts CJ, et al. Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition. Xenobiotica 2006; 36: 963–88
Lin JH. Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics. Drug Metab Dispos 1998; 26: 1202–12
Edginton AN, Fotaki N. Oral drug absorption in pediatric populations. In: Dressman JB, Reppas C, editors. Oral drug absorption. New York: Informa Healthcare, 2010: 108–26
Freichel C, Prinssen E, Hoffmann G, et al. Oseltamivir is devoid of specific behavioral and other central nervous system effects in juvenile rats at supratherapeutic oral doses. Int J Virol 2009; 5: 119–30
Johnson TN. The problems in scaling adult drug doses to children. Arch Dis Child 2008; 93(3): 207–11
Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 2005; 59(6): 691–704
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
Ginsberg G, Hattis D, Russ A, et al. Physiologically based pharmacokinetic (PBPK) modeling of caffeine and theophylline in neonates and adults: implications for assessing children’s risks from environmental agents. J Toxicol Environ Health 2004; 67(4): 297–329
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: 931–56
Gentry PR, Covington TR, Clewell HJ. Evaluation of the potential impact of pharmacokinetic differences on tissue dosimetry in offspring during pregnancy and lactation. Regul Toxicol Pharmacol 2003; 38(1): 1–16
Pelekis M, Gephart LA, Lerman SE. Physiological-model-based derivation of the adult and child pharmacokinetic intraspecies uncertainty factors for volatile organic compounds. Regul Toxicol Pharmacol 2001; 33(1): 12–20
Pons G. Expectations from PK-PD modelling and simulation in the evaluation of medicinal products in children [presentation]. European Medicines Agency Workshop on Modelling in Paediatric Medicines; 2008 Apr 14–15; London [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500009643.pdf [Accessed 2011 Jun 14]
Hoppu K. Can we get the necessary clinical trials in children and avoid the unnecessary ones? Eur J Clin Pharmacol 2009; 65(8): 747–8
All authors were employees of F. Hoffmann-La Roche Ltd. when this work was carried out. They have no other conflicts of interest to declare.
Electronic supplementary material
About this article
Cite this article
Parrott, N., Davies, B., Hoffmann, G. et al. Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants. Clin Pharmacokinet 50, 613–623 (2011). https://doi.org/10.2165/11592640-000000000-00000
- Renal Clearance
- PBPK Model
- Neuraminidase Inhibitor
- Oseltamivir Carboxylate