A descriptive systematic review of salivary TDM in neonates and infants.

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Abstract

Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. MethodsDatabases were searched up to and including September 2016. Studies were included based on PICO as follows: P: Infants and neonates being treated with any medication, I: Salivary Therapeutic Drug Monitoring vs C: Traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. ResultsTwenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent /very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Furthermore, any compound with a pKa within physiological range (pH 6 – 8) gave a more varied response. ConclusionThere is significant potential for infantile saliva testing and in particular, for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude any compound with a pKa within physiological range (pH 6 – 8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis.
LanguageEnglish
Pages1-11
JournalBritish Journal of Clinical Pharmacology
Volume1
Early online date14 Feb 2018
DOIs
Publication statusE-pub ahead of print - 14 Feb 2018

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Drug Monitoring
Saliva
Newborn Infant
Primidone
Busulfan
Fluconazole
Phenytoin
Theophylline
Protein Binding
Morphine
Pharmacokinetics

Keywords

  • Therapeutic Drug monitoring (TDM)
  • saliva
  • physicochemical properties
  • pharmacokinetic parameters
  • infants
  • paediatric
  • systematic review

Cite this

@article{eff60c2a0fd74b89bb0c045f0c146cb0,
title = "A descriptive systematic review of salivary TDM in neonates and infants.",
abstract = "Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. MethodsDatabases were searched up to and including September 2016. Studies were included based on PICO as follows: P: Infants and neonates being treated with any medication, I: Salivary Therapeutic Drug Monitoring vs C: Traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. ResultsTwenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent /very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Furthermore, any compound with a pKa within physiological range (pH 6 – 8) gave a more varied response. ConclusionThere is significant potential for infantile saliva testing and in particular, for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude any compound with a pKa within physiological range (pH 6 – 8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis.",
keywords = "Therapeutic Drug monitoring (TDM), saliva, physicochemical properties, pharmacokinetic parameters, infants, paediatric, systematic review",
author = "Laura Hutchinson and M Sinclair and Bernie Reid and Kathryn Burnett and Bridgeen Callan",
note = "Compliant in UIR; evidence uploaded to 'Other files' Reference text: References [1] A. Dasgupta, Handbook of Drug Monitoring Methods, New Jersey: Humana Press Inc, 2008. [2] N. Buchanan, {"}Therapeutic Drug Monitoring,{"} Indian J Pediatr, vol. 53, no. 2, pp. 149-162, 1986. [3] W. Zhao and E. Jacqz-Aigrain, Principles of Therapeutic Drug Monitoring. In Pediatric Clinical Pharmacology., vol. 205, Heidelberg, Ed., Berlin: Springer, 2011, pp. 77-90. [4] G. L. Kearns, S. M. Sbdel-Rahman, S. W. Alander, D. L. Blowey, J. S. Leeder and R. E. Kauffman, {"}Developmental pharmacology—drug disposition, action, and therapy in infants and children,{"} N Engl J Med, vol. 18, no. 349, pp. 1157-1167, Sept 2003. [5] P. A. Routledge, {"}Pharmacokinetics in children,{"} Journal of antimicrobial chemotherapy, vol. 34, no. Suppl A, pp. 19-24, 1994. [6] G. Koren and R. Parker, {"}Interpretation of excessive serum concentrations of digoxin in children,{"} Am J Cardiol , vol. 55, no. 9, pp. 1210-1214, Apr 1985. [7] G. Koren, {"}Therapeutic drug monitoring principles in the neonate,{"} Clin Chem, vol. 43, no. 1, pp. 222-227, Jan 1997. [8] G. W. t Jong, A. G. Vulto, M. de Hoog, K. J. Schimmel, D. Tibboel and J. N. Van den Anker, {"}Unapproved and Off-Label Use of Drugs in a Children's Hospital,{"} N Engl J Med, vol. 343, no. 15, pp. 1125-1125, Oct 2000. [9] S. Conroy, I. Choonara, P. Impicciatore, A. Mohn, H. Arnell, A. Rane and et al, {"}Survey of unlicensed and off label drug use in paediatric wards in European countries,{"} BMJ, vol. 320, no. 7277, pp. 79-82, Jan 2000. [10] A. S. Gross {"}Best practice in therapeutica drug monitoring,{"} Br J Clin Pharmacol, vol. 46, pp.95-99, 1998. [11] S Pichini, I. Alteri, P. Zuccaro, R. Pacifici. {"}Drug monitoring in non conventional biological fluids and matrices,{"} Clin Pharmakinet, vol. 3, pp. 211-228, Nov 1996. [12] D. B. Hawcutt, A. C. Rose, S. Fuerst-Recktenwald, T. Nunn and M. A. Turner, Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates. In Guide to Paediatric Drug Developmentnd Clinical Research, v. d. A. J. Rose K, Ed., Washington D.C: Karger Publishers, 2010. [13] P. M. Edelbroek, J. Van Der Hejjden and L. M. Stolk, {"}Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls,{"} Ther Drug Monit, vol. 31, no. 3, pp. 327-336, Jun 2009. [14] W. Li and F. L. Tse, {"}Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules,{"} Biomed Chromat, vol. 24, no. 1, pp. 49-65, Dec 2010. [15] R. E. Choo and M. A. Huestis, {"}Oral Fluid as a diagnostic Tool,{"} Clin Chem Lab Med, vol. 42, no. 11, pp. 1273-1287, Nov 2004. [16] P. N. Patsalos and D. J. Berry, {"}Therapeutic Drug Monitoring of Antiepileptic Drugs by use of Saliva,{"} Ther Drug Monit, vol. 35, no. 1, pp. 4-29, Feb 2013. [17] R. Gorodischer, P. Burtin, P. Hwang, M. Levine and G. Koren, {"}Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis,{"} Ther Drug Monit, vol. 16, no. 5, pp. 437-443, October 1994. [18] R. Gorodischer and G. Koren, {"}Salivary Excretion of Drugs in Children: Theoretical and Practical Issues in Therapeutic Drug Monitoring,{"} Developmental Pharmacology and Therapeutics, vol. 19, no. 4, pp. 161-177, Jan 1992. [19] S. A. Malone, M. J. Eadie, R. S. Addison, A. W. E. Wright and R. G. Dickson, {"}Monitoring salivary lamotrigine concentrations,{"} Clin Neurosci, vol. 13, no. 9, pp. 902-907, Nov 2006. [20] T. Gordi, T. N. Hai and N. M. Hoai, {"}Use of Saliva and capillary blood samples as substitutes for venous blood sampling in pharmacokinetic investigations of artemisinin,{"} Eur J Clin Pharmacol, vol. 56, no. 8, pp. 561-566, Nov 2000. [21] D. H. Huffman, {"}Relationship between digoxin concentrations in serum and saliva,{"} Clin Pharmacol Ther, vol. 17, no. 3, pp. 310-312, Mar 1975. [22] I. Tsiropoulos, O. Kristensen and N. A. Klitgaard, {"}Saliva and Serum Concentration of Lamotrigine in Patients with Epilepsy,{"} Ther Drug Monit, vol. 22, no. 5, pp. 517-521, Oct 2000. [23] J. J. McAuliffe, A. L. Sherwin, I. E. Leppik, S. A. Fayle and C. E. Pippenger, {"}Salivary levels of anticonvulsants A practical approach to drug monitoring.,{"} Neurology, vol. 27, no. 5, p. 409, May 1977. [24] N. N. Khanna, H. S. Bada and S. M. Somani, {"}Use of salivary concentrations in the prediction of serum caffeine and theophylline concentrations in premature infants.,{"} J Pediatr, vol. 96, no. 3, pp. 494-499, March 1980. [25] M. Berkovitch, T. Bistritzer, M. Aladjem, P. Burtin, T. Dagan, Z. Chen-Levi and et al, {"}Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children,{"} Therapeutic drug monitoring, vol. 20, no. 3, pp. 253-256, Jun 1998. [26] J. Autmizguine, P. Brian Smith, M. Sampson, P. Ovetchkine, M. Cohen-Wolkowiez and K. M Watt, {"}Pharmacokinetic studies in infants using minimal-risk study designs,{"} Current clinical pharmacology, vol. 9, no. 4, pp. 350-358, Nov 2014. [27] B. Bailey, J. Klein and G. Koren, {"}Noninvasive methods for drug measurement in pediatrics,{"} Pediatr Clin North Am, vol. 44, no. 1, pp. 15-26, Feb 1997. [28] O. Technologies, 2017. [Online]. Available: http://ovidsp.uk.ovid.com/sp-3.26.1a/ovidweb.cgi. [Accessed 14th August 2017]. [29] J. W. Toback, P. Gal, N. V. Erkan, C. Roop and H. Robinson, {"}Usefulness of Theophylline Saliva Levels in Neonates.,{"} Ther Drug Monit, vol. 5, no. 2, pp. 185-189, Jun 1983. [30] I. A. Siegel, H. Ben-Aryeh, D. Gozal, A. A. Colin, R. Szargel and D. Laufer, {"}Comparison of Unbound and Total Serum Theophylline Concentrations with Those of Stimulated and Unstimulated Saliva in Asthmatic Children.,{"} Ther Drug Monitor, vol. 12, no. 12, pp. 460-464, Sept 1990. [31] M. Culea, N. Palibroda, P. Chereches-Panta and M. Nanulescu, {"}Comparison of isotopic dilution methods for determination of theophylline in the plasma and saliva of infants and children,{"} Chromatographia, vol. 53, no. S1, pp. 387-389, Jan 2001. [32] P. Chereches-Panta, M. V. Nanukescu, M. Culea and N. Palibroda, {"}Reliability of salivary theophylline in monitoring the treatment for apnoea of prematurity,{"} J Perinatol, vol. 27, pp. 709-712, Aug 2007. [33] J. V. Aranda, D. S. Sitar, W. D. Parsons, P. M. Loughnan and A. H. Neims, {"}Pharmacokinetic aspects of theophylline premature newborns.,{"} N Engl J Med, vol. 295, no. 8, pp. 413-416, Aug 1976. [34] L. Hendeles, S. Burkey, L. Bighley and R. Richardson, {"}Unpredictability of theophylline saliva measurements in chronic obstructive pulmonary disease,{"} J Allergy Clin Immunol, vol. 60, no. 6, pp. 335-338, Dec 1977. [35] J. V. Aranda and T. Turmen, {"}Methylxanthines in apnea of prematurity.,{"} Clinics in Perinatology, vol. 6, no. 1, pp. 87-108, Mar 1979. [36] G. Levy, E. F. Ellis and R. Koysooko, {"}Indirect plasma-theophylline monitoring in asthmatic children by determination of theophylline concentration in saliva.,{"} Pediatrics, vol. 53, no. 6, pp. 873-876, Jun 1974. [37] J. R. Koup and B. A. Hart, {"}Relationship between plasma and whole blood theophylline concentration in neonates,{"} J Pediatr, vol. 94, no. 2, pp. 320-321, Feb 1979. [38] R. E. Behrmann and F. C. Battaglia, {"}Protein binding of human fetal and maternal plasmas to salicylate,{"} J Appl Physiol , vol. 22, pp. 125-130, 1967. [39] S. Wallace, {"}Altered plasma albumin in the newborn infant.,{"} Br J Clin Pharmacol, vol. 4, no. 1, pp. 82-85, Feb 1977. [40] P. L. Morselli and V. Rovei, {"}Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn,{"} Eur J Clin Pharmacol, vol. 18, no. 1, pp. 25-30, Jan 1980. [41] C. E. Cook, E. Amerson, W. K. Poole, P. Lesser and L. O'Tuama, {"}Phenytoin and Phenobarbital concentrations in saliva and plasma measured by radiommunoassay,{"} Clin Pharmacol Ther, vol. 18, no. 6, pp. 742-747, Dec 1975. [42] R. F. Goldsmith and R. A. Ouvrier, {"}Salivary anticonvulsant levels in children: a comparison of methods,{"} Ther Drug Monit, vol. 3, no. 2, pp. 151-158, 1981. [43] J. C. Mucklow, C. J. Bacon, A. M. Hierons, J. K. Webb and M. D. Rawlins, {"}Monitoring of Phenobarbitone and Phenytoin Therapy in Small Children by Salivary Samples,{"} Ther Drug Monit, vol. 3, no. 3, pp. 275-277, Jan 1981. [44] M. Lifshitz, Z. Ben-Zvi and R. Gorodischer, {"}Monitoring Phenytoin Therapy using Citric Acid-Stimulated Saliva in infants and Children,{"} Ther Drug Monit, vol. 12, no. 4, pp. 334-338, Feb 1990. [45] T. Zysset, A. Rudeberg, F. Vassella, A. Kupfer and J. Bircher, {"}Phenytoin therapy for epileptic children: evaluation of salivary and plasma concentrations and of methods of assessing compliance.,{"} Dev Med Child Neurol, vol. 23, no. 1, pp. 66-75, Feb 1981. [46] A. S. Troupin and P. Friel, {"}Anticonvulsant level in saliva, serum, and cerebrospinal fluid.,{"} Epilepsia, vol. 16, no. 2, pp. 223-227, Jun 1975. [47] M. G. Horning, L. Brown, J. Nowlin, K. Letratanangkoon, P. Kellaway and T. E. Zion, {"}Use of saliva in therapeutic drug monitoring.,{"} Clin Chem, vol. 23, no. 2, pp. 157-164, Feb 1977. [48] D. Schmidt and H. J. Kupferberg, {"}Diphenylhydantoin, phenobarbital, and primidone in saliva, plasma, and cerebrospinal fluid,{"} Epilepsia, vol. 16, no. 5, pp. 735-741, Dec 1975. [49] G. F. Blom and P. J. Guelen, The distribution of antiepileptic drugs between serum, saliva and cerebrospinal fluid in: Antiepileptic Drug Monitoring, Pitman, Ed., London: Pippenger, Eds, 1977. [50] R. Gorodischer, P. Burtin, Z. Verjee, P. Hwang and G. Koren, {"}Is Saliva Suitable for Therapeutic Monitoring of Anticonvulsants in Children: An Evaluation in the Routine Clinical Setting,{"} Ther Drug Monit, vol. 19, no. 6, pp. 637-642, Dec 1997. [51] J. C. Mucklow, M. R. Bending, G. C. Kahn and C. T. Dollery, {"}Drug Concentration in Saliva,{"} Clini Pharmacol Ther, vol. 24, no. 5, pp. 563-570, Nov 1978. [52] T. A. Moreland, D. A. Priestman and G. W. Rylance, {"}Saliva carbamazepine levels in children before and during multiple dosing,{"} Br J Clin Pharmacol, vol. 13, no. 5, pp. 647-651, May 1982. [53] C. Knott and F. Reynolds, {"}The place of saliva in antiepileptic drug monitoring,{"} Ther Drug Monit, vol. 6, no. 1, pp. 35-42, Mar 1984. [54] I. M. Friedman, I. F. Litt, R. Henson, D. Holtzman and D. Halverson, {"}Saliva phenobarbital and phenytoin concentrations in epileptic adolescents.,{"} J Pediatr, vol. 98, no. 4, pp. 645-647, Apr 1981. [55] K. Tokugawa, K. Ueda, H. Fujito and T. Kurokawa, {"}Correlation between the saliva and free serum concentration of phenobarbital in epileptic children,{"} Eu J Clin Pharmacol, vol. 145, no. 5, pp. 401-402, Oct 1986. [56] M. V. Miles, M. B. Tennison, R. S. Greenwood and et al, {"}. Evaluation of the Ames Seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.,{"} Ther Drug Monit, vol. 12, no. 5, pp. 501-510, Sept 1990. [57] M. V. Miles, M. B. Tennison and R. S. Greenwood, {"}Intraindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.,{"} Ther Drug Monit, vol. 13, no. 2, pp. 166-171, Mar 1991. [58] E. Zalzstein, N. Zucker and M. Lifshitz, {"}Digoxin concentration in saliva and plasma in infants, children, and adolescents with heart disease,{"} Current Therapeutic Research, vol. 64, no. 9, pp. 743-749, Nov 2003. [59] N. Krivoy, N. Rogin, Z. Greif, H. Ben-Aryeh, D. Gutman and G. Alroy, {"}Relationship between digoxin concentration in serum and saliva in infants,{"} J Pediatr, vol. 99, no. 5, pp. 810-811, Nov 1981. [60] M. Berkovitch, M. Goldman, R. Silverman, Z. Chen-Levi, R. Greenberg, O. Marcus and et al, {"}Therapeutic drug monitoring of oce daily gentamycin in serum and saliva in children,{"} Eu J Pediatr, vol. 159, pp. 697-698, Aug 2000. [61] S. Mahmod, M. H. Al-Hakiem, J. Landon, D. S. Smith and E. J. Shaw, {"}Aminoglycoside antibiotics do not appear in saliva,{"} Clin Chem, vol. 29, no. 5, pp. 988-989, May 1983. [62] E. A. Kopecky, S. Jacobson, J. Klein, B. Kapur and G. Koren, {"}Correlation of Morphine Sulfate in Blood Plasma and Saliva in Pediatric Patients,{"} Ther Drug Monit, vol. 19, no. 5, pp. 530-534, Jun 1997. [63] M. Ryan, S. A. Grim, M. V. Miles, P. H. Tang, T. A. Fakhoury, R. H. Strawsbury and et al, {"}Correlation of Lamotrigine Concentrations Between Serum and Saliva,{"} Pharmacotherapy, vol. 23, no. 12, pp. 1550-1557, Dec 2003. [64] M. Rauh, D. Stachel, M. Kuhlen, M. Groschl, W. Holter and W. Rascher, {"}Quantification of busulfan in Saliva and Plasma in Haematopoietic Stem Cell Transplantation in Children,{"} Clin Pharmacokin, vol. 45, no. 3, pp. 305-316, Mar 2006. [65] K. C. M. Van Der Elst, M. Van Alst, M. N. Lub-de Hooge, K. Van Hateren, J. G. Kosterink, J. W. Alffennaar and et al, {"}Clinical Validation of the Analysis of Fluconazole in Oral Fluid in Hospitalised Children,{"} Antimicro agents Chemother, vol. 58, no. 11, pp. 6742-6746, Nov 2014. [66] S. N. De Wilt, K. T. M. Kerkvliet, M. G. A. Wezenberg, S. Ottink, W. C. Hop, A. G. Vulto and et al, {"}Use of Saliva in Therapeutic Drug Monitoring of Caffeine in Preterm Infants,{"} Ther Drug Monit, vol. 23, no. 3, pp. 250-254, June 2001. [67] H. S. Bada, N. N. Khanna, S. M. Somani and A. A. Tin, {"}Interconversion of theophylline and caffeine in newborn infants,{"} J Pediatr, vol. 94, no. 6, pp. 993-995, Jun 1979. [68] T. C. Lee, B. G. Charles, P. A. Steer and V. J. Flenady, {"}Saliva as a Valid Alternative to Serum in Monitoring Intravenous Caffeine Treatment for Apnea of Prematurity,{"} Ther Drug Monit, vol. 18, no. 3, pp. 288-293, Jun 1996. [69] F. Z. Chioukh, A. Chaabane, H. B. Hamida, K. Ben Ameur, K. Aouam and K. Monastiri, {"}Saliva as an alternative to plasma in therapeutic drug monitoring of caffeine in preterm infants,{"} J Matern Fetal Med, vol. 27, no. S1, p. 398, 2014. [70] N. R. Dobson, X. Liu, L. M. Rhein, R. A. Darnall, M. J. Corwin, B. L. McEntire and et al, {"}Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy,{"} Br J Clin Pharmacol, vol. 82, pp. 754-761, Apr 2016. [71] K. Y. Chee, D. Lee, D. Byron, D. Naidoo and A. Bye, {"}A simple collection method for saliva in children: potential for home monitoring of carbamazepine therapy,{"} Br J Clin Pharmacol, vol. 35, no. 3, pp. 311-313, Mar 1993. [72] H. Bartels, E. Gunther and S. Wallis, {"}Flow-dependent salivary primidone levels in epileptic children,{"} Epilepsia, vol. 20, no. 4, pp. 431-436, Aug 1979. [73] W. Schramm, T. M. Annesley, G. J. Siegel, J. C. Sakellares and R. H. Smith, {"}Measurement of Phenytoin and Carbamazepine in an Ultrafiltrate of Saliva.,{"} Ther Drug Monitor, vol. 13, no. 5, pp. 452-460, Sep 1991. [74] H. G. Westenberg, E. Van Der Kleijn, T. T. Oei and R. A. De Zeeuw, {"}Kinetics of carbamazepine and carbamazepine‐epoxide, determined by use of plasma and saliva,{"} Clin Pharmacol and Ther, vol. 23, no. 3, pp. 320-328, Mar 1978. [75] R. Chambers, M. Homeida, K. R. Hunter and R. H. Teague, {"}Salivary carbamazepine concentrations,{"} The Lancet, vol. 309, no. 8012, pp. 656-657, Mar 1977. [76] G. W. Rylance, T. A. Moreland and G. M. Butcher, {"}Carbamazepine dose-frequency requirement in children,{"} Arch Dis Child , vol. 54, no. 6, pp. 454-458, Jun 1979. [77] L. Rui-Rui, X. Y. Sheng, L. Y. Ma, H. X. Yao, L. X. Cai, C. Y. Chen and et al, {"}Saliva and Plasma Monohydroxcarbazepine Concentrations in Pediatric Patients With Epilepsy,{"} Ther Drug Monit, vol. 38, no. 3, pp. 365-370, Jun 2016. [78] B. B. Gallagher and I. P. Baumel, {"}Primidone. Absorption, distribution, and excretion,{"} Antiepileptic Drugs, pp. 357-359, 1972. [79] M. Tennison, I. Ali and M. V. Miles, {"}Feasibility and Acceptance of Salivary Monitoring of antiepileptic Drugs via the US Postal Service,{"} Ther Drug Monit, vol. 26, no. 3, pp. 295-299, June 2004. [80] A. Tal, M. Aviram and R. Gorodischer, {"}Variations in theophylline concentrations detected by 24 hour saliva concentration profiles in ambulatory children with asthma,{"} J Allergy Clin Immunol , vol. 86, no. 2, pp. 238-243, Aug 1990. [81] H.P.Chang, G.C. Anderson and C.E.Wood. “Feasible and valid saliva collection for cortisol in transitional newborn infants”. Nursing Research, vol. 44, no. 2, pp. 117-119, Mar 1995. [82] A.M. Bermejo, A.C.S. Lucas and M.J. Tabernero. “Saliva/plasma ratio of methadone and EDDP”. J Anal Toxicol, vol. 24, no. 1, pp. 70-72, Jan, 2000. [83] F. Quattrocchi, H.T. Karnes, J.D. Robinson and L. Hendeles. “Effect of Serum Separator Blood Collection Tubes on Drug Concentrations”. Ther Drug Monit. Vol. 5, no.3 , pp. 359-362, Sep 1983. [84] A. Dasgupta, R. Dean, S. Saldana, G. Kinnaman and R.W. McLawhon. “Absorption of Therapeutic Drugs by Barrier Gels in Serum Separator Blood Collection Tubes: Volume-and Time-dependent Reduction in Total and Free Drug Concentrationsa”. Am J Clin Pathol, vol. 101, no. 4, pp. 456-461, Jan, 1994. [85] P. Marquet, F.L. Sauvage, V. Loustaud-Ratti, G. Babany, A. Rousseau and G. Lachatre. “Stability of ribavirin concentrations depending on the type of blood collection tube and preanalytical conditions”. Ther Drug Monit, vol. 32, no. 2, pp. 237-241, Apr, 2010. [86] R. Koysooko, E.F. Ellis and G. Levy. “Relationship between theophylline concentration in plasma and saliva of man”. Clin Pharmacol and Ther, vol. 15, no. 5, pp. 454-460, May, 1974. [87] F. Plavsic, J. Culig, I. Bakran and B.Vrhovac. “Theophylline concentration in saliva as a guide for individualization of its therapeutic use”. Brit J Clin Pharmaco, vol. 1, no 11, pp 533-4, May 1981. [88] J. Culig, A. Johnston and P. Turner, {"}Saliva theophylline concentrations after a single oral dose.,{"} Br J Clin Pharmacol, vol. 13, no. 2, pp. 243-245, 1982. [89] C.H. Knott, M. Bateman and F. Reynolds. “Do saliva concentrations predict plasma unbound theophylline concentrations? A problem re‐examined”. Brit J Clin Pharmaco, vol.1, no. 17, pp9-14, Jan 1984. [90] P. Ebden, D. Leopold, D. Buss, A.P. Smith and P.A. Routledge. “Relationship between saliva and free and total plasma theophylline concentrations in patients with chronic airflow obstruction”. Thorax, vol.1, no.40, pp. 526-529, Jul 1985. [91] J.W. Paxton, B. Whiting and K.W. Stephen. “Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay”. Brit J Clin Pharmaco, vol.1, no.4, pp.185-191, Apr 1977. [92] C. Knott, A. Hamshaw-Thomas and F. Reynolds. “Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy”. Br Med J, vol.2, no. 284, pp.3-6, Jan 1982. [93] L.M. Tsanaclis, J. Allen, E. Perucca et al. “Effect of valproate on free plasma phenytoin concentrations”. Br J Clin Pharmacol, vol.18, no.1, pp. 17-20, Jul 1984. [94] H.G. Van. “Comparative study of the levels of anticonvulsants and their free fractions in venous blood, saliva and capillary blood in man”. J Pharmacol, vol.15, no.1, pp 27-35, Jan 1984. [95] C. Knott, C.P. Williams and F. Reynolds. “Phenytoin kinetics during pregnancy and the puerperium”. BJOG: An International Journal of Obstetrics & Gynaecology, vol. 1, no. 93, pp. 1030-1037, Oct 1986. [96] P.V. Luoma, J.E. Heikkinen and P.R. Ylostalo. “Phenobarbital pharmacokinetics and salivary and serum concentrations in pregnancy”. Ther Drug Monit, vol. 4, pp. 65-68, Mar 1982. [97] D. Shen. “Saliva phenobarbital concentration in epileptics. Chung Hua Shen Ching Ching Shen Ko Tsa Chih, vol. 22, no. 6, pp. 369-370, 1989. [98] W.J. Jusko, L. Gerbracht, L.H. Golden and J.R. Koup, J. R. “Digoxin concentrations in serum and saliva”. Commun Chem Pathol Pharmacol, vol.10, no.1, pp. 189-192, Jan 1975. [99] W.J.F, Van der Vijgh. “Comparison of salivary digoxin concentration with plasma levels in man”. Neth. J. Med, vol. 18, pp. 269-272, 1975. [100] P.H. Jourbert, F.O. Muller and B.M. Aucamp. “Salivary digoxin concentration in saliva and serum”. Brit J Clin Pharmaco, vol. 3, pp. 673-674, Aug 1976. [101] H. Allonen, E. Iisalo, L. Kangas, R. Lammintausta and M. Salonen. “Estimation of pharmacokinetic parameters of digoxin from serum, saliva and urine”. Int J Clin Pharmacol Biopharm, vol. 16, no. 9, pp.420-423, Sept 1978. [102] J. Lazowski, A. Lypka, and P. Borkowski. “The relationship between digoxin concentration in saliva and serum”. Polski tygodnik lekarski, vol. 30, no. 33, pp. 1709 -1711, Oct 1978. [103] S. Mahmod, D.S. Smith and J. Landon. “Radioimmunoassay of salivary digoxin by simple adaptation of a kit method for serum digoxin: saliva/serum ratio and correlation”. Ther Drug Monit, vol. 1, no. 9, pp. 91-96, Mar 1987. [104] A.F. Cohen, L. Ashby, D. Crowley et al. “Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol, Vol. 20, no. 6, pp. 619-629, Dec 1985. [105] Z. Trnavska, H. Krejcova, Z. Ykaczykovam et al. “Pharmacokinetics of lamotrigine (Lamictal) in plasma and saliva”. Eur J Drug Metab Pharmacokinet, vol. 3, pp. 211-215, Jan 1991. [106] T. Incecayir, I. Agabeyoglu and K.Gucuyener. “Comparison of plasma and saliva concentrations of lamotrigine in healthy volunteers. Arzneimittelforschung, vol. 57, no. 8, pp. 517-521, Aug 2007. [107] C.H. Koks CH, K.M. Crommentuyn, R.M. Hoetelmans, R.A. Math{\^o}t RA and J.H. Beijnen. “Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?” Ther Drug Monit, vol. 1, no.23, pp. 499-453, Aug 2001. [108] C.H. Koks, H. Rosing, P.L. Meenhorst, A. Bult and J.H. Beijnen. “High-performance liquid chromatographic determination of the antifungal drug fluconazole in plasma and saliva of human immunodeficiency virus-infected patients”. J Chromatog, vol. 20, no. 663, pp. 345-351, Jan 1995. [109] J.W. Paxton and R.A. Donald. “Concentrations and kinetics of carbamazepine in whole saliva, parotid saliva, serum ultrafiltrate, and serum”. Clin Pharmacol Ther, vol. 28, no. 5, pp. 695-702, Nov 1980. [110] O. Kristensen and H.F. Larsen. “Value of saliva samples in monitoring carbamazepine concentrations in epileptic patients”. Acta Neurol Scand, vol. 1, no. 61, pp. 344-350, Jun 1980. [111] J.J. MacKichan, P.K. Duffner and M.E. Cohen. “Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine-10, 11-epoxide in epileptic patients”. Br J Clin Pharmacol, vol. 12, no. 1, pp. 31-37, Jul 1981. [112] A. Vasudev, K.D. Tripathi and V. Puri. “Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring”. Neurology India, vol. 1, no. 50, pp. 60, Jan, 2002. [113] S. Đorđević, V. Kilibarda and T. Stojanović. “Determination of carbamazepine in serum and saliva samples by high performance liquid chromatography with ultraviolet detection”. Vojnosanitetski pregled, vol. 66, no.5, pp. 347-352, 2009. [114] S. Djordjević, V. Kilibarda, S. Vučinić, T. Stojanović and B. Antonijević. “Toxicokinetics and correlation of carbamazepine salivary salivary and serum concentrations in acute poisonings”. Military Medical and Pharmaceutical Journal of Serbia, vol. 1, no. 69, pp. 389, May 2012. [115] M. Thiesohn and G. Heimann. “Disposition of the anti-epileptic oxcarbazepine and its metabolites in healthy volunteers”. Eur J Clin Pharmacol, vol. 1, no. 22, pp. 545-551, Aug 1982. [116] O. Kristensen, N.A. Klitgaard, B. Jonsson et al. “Pharmacokinetics of 10-OH-carbazepine, the main metabolite of the antiepileptic oxcarbazepine from serum and saliva concentrations”. Acta Neurol Scand, vol. 1, no. 68, pp. 145-150, Sept 1983. [117] N. A. Klitgaard and O. Kristensen, {"}Use of saliva for monitoring oxcarbazepine therapy in epileptic patients.,{"} Eu J Clin Pharmacol, vol. 31, no. 1, pp. 91-94, Jan 1986. [118] J. M. Cardot, P. Degen, G. Flesch, P. Menge and W. Dieterle, {"}Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state,{"} Biopharm Drug Dispos, vol. 16, no. 7, pp. 603-614, Oct 1995. [119] M. V. Miles, P. H. Tang and M. A. Ryan, {"}Feasibility and limitations of oxcarbazepine monitoring using salivary monohydroxycarbamazepine (MHD).,{"} Therapeutic Drug Monitoring, vol. 1, no. 26, pp. 300-304, June 2004. [120] E. Zylber‐Katz, L. Granit and M. Levy. “Relationship between caffeine concentrations in plasma and saliva”. Clin Pharmacol and Ther, vol. 1, no. 36, pp. 133-137, Jul 1984. [121] R. Newton, L.J. Broughton, M.J. Lind, P.J. Morrison, H.J. Rogers and I.D. Bradbrook. “Plasma and salivary pharmacokinetics of caffeine in man”. Eu J Clin Pharmaco, vol. 1, no. 21, pp. 45-52, Jan 1981.",
year = "2018",
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TY - JOUR

T1 - A descriptive systematic review of salivary TDM in neonates and infants.

AU - Hutchinson, Laura

AU - Sinclair, M

AU - Reid, Bernie

AU - Burnett, Kathryn

AU - Callan, Bridgeen

N1 - Compliant in UIR; evidence uploaded to 'Other files' Reference text: References [1] A. Dasgupta, Handbook of Drug Monitoring Methods, New Jersey: Humana Press Inc, 2008. [2] N. Buchanan, "Therapeutic Drug Monitoring," Indian J Pediatr, vol. 53, no. 2, pp. 149-162, 1986. [3] W. Zhao and E. Jacqz-Aigrain, Principles of Therapeutic Drug Monitoring. In Pediatric Clinical Pharmacology., vol. 205, Heidelberg, Ed., Berlin: Springer, 2011, pp. 77-90. [4] G. L. Kearns, S. M. Sbdel-Rahman, S. W. Alander, D. L. Blowey, J. S. Leeder and R. E. Kauffman, "Developmental pharmacology—drug disposition, action, and therapy in infants and children," N Engl J Med, vol. 18, no. 349, pp. 1157-1167, Sept 2003. [5] P. A. Routledge, "Pharmacokinetics in children," Journal of antimicrobial chemotherapy, vol. 34, no. Suppl A, pp. 19-24, 1994. [6] G. Koren and R. Parker, "Interpretation of excessive serum concentrations of digoxin in children," Am J Cardiol , vol. 55, no. 9, pp. 1210-1214, Apr 1985. [7] G. Koren, "Therapeutic drug monitoring principles in the neonate," Clin Chem, vol. 43, no. 1, pp. 222-227, Jan 1997. [8] G. W. t Jong, A. G. Vulto, M. de Hoog, K. J. Schimmel, D. Tibboel and J. N. Van den Anker, "Unapproved and Off-Label Use of Drugs in a Children's Hospital," N Engl J Med, vol. 343, no. 15, pp. 1125-1125, Oct 2000. [9] S. Conroy, I. Choonara, P. Impicciatore, A. Mohn, H. Arnell, A. Rane and et al, "Survey of unlicensed and off label drug use in paediatric wards in European countries," BMJ, vol. 320, no. 7277, pp. 79-82, Jan 2000. [10] A. S. Gross "Best practice in therapeutica drug monitoring," Br J Clin Pharmacol, vol. 46, pp.95-99, 1998. [11] S Pichini, I. Alteri, P. Zuccaro, R. Pacifici. "Drug monitoring in non conventional biological fluids and matrices," Clin Pharmakinet, vol. 3, pp. 211-228, Nov 1996. [12] D. B. Hawcutt, A. C. Rose, S. Fuerst-Recktenwald, T. Nunn and M. A. Turner, Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates. In Guide to Paediatric Drug Developmentnd Clinical Research, v. d. A. J. Rose K, Ed., Washington D.C: Karger Publishers, 2010. [13] P. M. Edelbroek, J. Van Der Hejjden and L. M. Stolk, "Dried blood spot methods in therapeutic drug monitoring: methods, assays, and pitfalls," Ther Drug Monit, vol. 31, no. 3, pp. 327-336, Jun 2009. [14] W. Li and F. L. Tse, "Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules," Biomed Chromat, vol. 24, no. 1, pp. 49-65, Dec 2010. [15] R. E. Choo and M. A. Huestis, "Oral Fluid as a diagnostic Tool," Clin Chem Lab Med, vol. 42, no. 11, pp. 1273-1287, Nov 2004. [16] P. N. Patsalos and D. J. Berry, "Therapeutic Drug Monitoring of Antiepileptic Drugs by use of Saliva," Ther Drug Monit, vol. 35, no. 1, pp. 4-29, Feb 2013. [17] R. Gorodischer, P. Burtin, P. Hwang, M. Levine and G. Koren, "Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis," Ther Drug Monit, vol. 16, no. 5, pp. 437-443, October 1994. [18] R. Gorodischer and G. Koren, "Salivary Excretion of Drugs in Children: Theoretical and Practical Issues in Therapeutic Drug Monitoring," Developmental Pharmacology and Therapeutics, vol. 19, no. 4, pp. 161-177, Jan 1992. [19] S. A. Malone, M. J. Eadie, R. S. Addison, A. W. E. Wright and R. G. Dickson, "Monitoring salivary lamotrigine concentrations," Clin Neurosci, vol. 13, no. 9, pp. 902-907, Nov 2006. [20] T. Gordi, T. N. Hai and N. M. Hoai, "Use of Saliva and capillary blood samples as substitutes for venous blood sampling in pharmacokinetic investigations of artemisinin," Eur J Clin Pharmacol, vol. 56, no. 8, pp. 561-566, Nov 2000. [21] D. H. Huffman, "Relationship between digoxin concentrations in serum and saliva," Clin Pharmacol Ther, vol. 17, no. 3, pp. 310-312, Mar 1975. [22] I. Tsiropoulos, O. Kristensen and N. A. Klitgaard, "Saliva and Serum Concentration of Lamotrigine in Patients with Epilepsy," Ther Drug Monit, vol. 22, no. 5, pp. 517-521, Oct 2000. [23] J. J. McAuliffe, A. L. Sherwin, I. E. Leppik, S. A. Fayle and C. E. Pippenger, "Salivary levels of anticonvulsants A practical approach to drug monitoring.," Neurology, vol. 27, no. 5, p. 409, May 1977. [24] N. N. Khanna, H. S. Bada and S. M. Somani, "Use of salivary concentrations in the prediction of serum caffeine and theophylline concentrations in premature infants.," J Pediatr, vol. 96, no. 3, pp. 494-499, March 1980. [25] M. Berkovitch, T. Bistritzer, M. Aladjem, P. Burtin, T. Dagan, Z. Chen-Levi and et al, "Clinical relevance of therapeutic drug monitoring of digoxin and gentamicin in the saliva of children," Therapeutic drug monitoring, vol. 20, no. 3, pp. 253-256, Jun 1998. [26] J. Autmizguine, P. Brian Smith, M. Sampson, P. Ovetchkine, M. Cohen-Wolkowiez and K. M Watt, "Pharmacokinetic studies in infants using minimal-risk study designs," Current clinical pharmacology, vol. 9, no. 4, pp. 350-358, Nov 2014. [27] B. Bailey, J. Klein and G. Koren, "Noninvasive methods for drug measurement in pediatrics," Pediatr Clin North Am, vol. 44, no. 1, pp. 15-26, Feb 1997. [28] O. Technologies, 2017. [Online]. Available: http://ovidsp.uk.ovid.com/sp-3.26.1a/ovidweb.cgi. [Accessed 14th August 2017]. [29] J. W. Toback, P. Gal, N. V. Erkan, C. Roop and H. Robinson, "Usefulness of Theophylline Saliva Levels in Neonates.," Ther Drug Monit, vol. 5, no. 2, pp. 185-189, Jun 1983. [30] I. A. Siegel, H. Ben-Aryeh, D. Gozal, A. A. Colin, R. Szargel and D. Laufer, "Comparison of Unbound and Total Serum Theophylline Concentrations with Those of Stimulated and Unstimulated Saliva in Asthmatic Children.," Ther Drug Monitor, vol. 12, no. 12, pp. 460-464, Sept 1990. [31] M. Culea, N. Palibroda, P. Chereches-Panta and M. Nanulescu, "Comparison of isotopic dilution methods for determination of theophylline in the plasma and saliva of infants and children," Chromatographia, vol. 53, no. S1, pp. 387-389, Jan 2001. [32] P. Chereches-Panta, M. V. Nanukescu, M. Culea and N. Palibroda, "Reliability of salivary theophylline in monitoring the treatment for apnoea of prematurity," J Perinatol, vol. 27, pp. 709-712, Aug 2007. [33] J. V. Aranda, D. S. Sitar, W. D. Parsons, P. M. Loughnan and A. H. Neims, "Pharmacokinetic aspects of theophylline premature newborns.," N Engl J Med, vol. 295, no. 8, pp. 413-416, Aug 1976. [34] L. Hendeles, S. Burkey, L. Bighley and R. Richardson, "Unpredictability of theophylline saliva measurements in chronic obstructive pulmonary disease," J Allergy Clin Immunol, vol. 60, no. 6, pp. 335-338, Dec 1977. [35] J. V. Aranda and T. Turmen, "Methylxanthines in apnea of prematurity.," Clinics in Perinatology, vol. 6, no. 1, pp. 87-108, Mar 1979. [36] G. Levy, E. F. Ellis and R. Koysooko, "Indirect plasma-theophylline monitoring in asthmatic children by determination of theophylline concentration in saliva.," Pediatrics, vol. 53, no. 6, pp. 873-876, Jun 1974. [37] J. R. Koup and B. A. Hart, "Relationship between plasma and whole blood theophylline concentration in neonates," J Pediatr, vol. 94, no. 2, pp. 320-321, Feb 1979. [38] R. E. Behrmann and F. C. Battaglia, "Protein binding of human fetal and maternal plasmas to salicylate," J Appl Physiol , vol. 22, pp. 125-130, 1967. [39] S. Wallace, "Altered plasma albumin in the newborn infant.," Br J Clin Pharmacol, vol. 4, no. 1, pp. 82-85, Feb 1977. [40] P. L. Morselli and V. Rovei, "Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn," Eur J Clin Pharmacol, vol. 18, no. 1, pp. 25-30, Jan 1980. [41] C. E. Cook, E. Amerson, W. K. Poole, P. Lesser and L. O'Tuama, "Phenytoin and Phenobarbital concentrations in saliva and plasma measured by radiommunoassay," Clin Pharmacol Ther, vol. 18, no. 6, pp. 742-747, Dec 1975. [42] R. F. Goldsmith and R. A. Ouvrier, "Salivary anticonvulsant levels in children: a comparison of methods," Ther Drug Monit, vol. 3, no. 2, pp. 151-158, 1981. [43] J. C. Mucklow, C. J. Bacon, A. M. Hierons, J. K. Webb and M. D. Rawlins, "Monitoring of Phenobarbitone and Phenytoin Therapy in Small Children by Salivary Samples," Ther Drug Monit, vol. 3, no. 3, pp. 275-277, Jan 1981. [44] M. Lifshitz, Z. Ben-Zvi and R. Gorodischer, "Monitoring Phenytoin Therapy using Citric Acid-Stimulated Saliva in infants and Children," Ther Drug Monit, vol. 12, no. 4, pp. 334-338, Feb 1990. [45] T. Zysset, A. Rudeberg, F. Vassella, A. Kupfer and J. Bircher, "Phenytoin therapy for epileptic children: evaluation of salivary and plasma concentrations and of methods of assessing compliance.," Dev Med Child Neurol, vol. 23, no. 1, pp. 66-75, Feb 1981. [46] A. S. Troupin and P. Friel, "Anticonvulsant level in saliva, serum, and cerebrospinal fluid.," Epilepsia, vol. 16, no. 2, pp. 223-227, Jun 1975. [47] M. G. Horning, L. Brown, J. Nowlin, K. Letratanangkoon, P. Kellaway and T. E. Zion, "Use of saliva in therapeutic drug monitoring.," Clin Chem, vol. 23, no. 2, pp. 157-164, Feb 1977. [48] D. Schmidt and H. J. Kupferberg, "Diphenylhydantoin, phenobarbital, and primidone in saliva, plasma, and cerebrospinal fluid," Epilepsia, vol. 16, no. 5, pp. 735-741, Dec 1975. [49] G. F. Blom and P. J. Guelen, The distribution of antiepileptic drugs between serum, saliva and cerebrospinal fluid in: Antiepileptic Drug Monitoring, Pitman, Ed., London: Pippenger, Eds, 1977. [50] R. Gorodischer, P. Burtin, Z. Verjee, P. Hwang and G. Koren, "Is Saliva Suitable for Therapeutic Monitoring of Anticonvulsants in Children: An Evaluation in the Routine Clinical Setting," Ther Drug Monit, vol. 19, no. 6, pp. 637-642, Dec 1997. [51] J. C. Mucklow, M. R. Bending, G. C. Kahn and C. T. Dollery, "Drug Concentration in Saliva," Clini Pharmacol Ther, vol. 24, no. 5, pp. 563-570, Nov 1978. [52] T. A. Moreland, D. A. Priestman and G. W. Rylance, "Saliva carbamazepine levels in children before and during multiple dosing," Br J Clin Pharmacol, vol. 13, no. 5, pp. 647-651, May 1982. [53] C. Knott and F. Reynolds, "The place of saliva in antiepileptic drug monitoring," Ther Drug Monit, vol. 6, no. 1, pp. 35-42, Mar 1984. [54] I. M. Friedman, I. F. Litt, R. Henson, D. Holtzman and D. Halverson, "Saliva phenobarbital and phenytoin concentrations in epileptic adolescents.," J Pediatr, vol. 98, no. 4, pp. 645-647, Apr 1981. [55] K. Tokugawa, K. Ueda, H. Fujito and T. Kurokawa, "Correlation between the saliva and free serum concentration of phenobarbital in epileptic children," Eu J Clin Pharmacol, vol. 145, no. 5, pp. 401-402, Oct 1986. [56] M. V. Miles, M. B. Tennison, R. S. Greenwood and et al, ". Evaluation of the Ames Seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.," Ther Drug Monit, vol. 12, no. 5, pp. 501-510, Sept 1990. [57] M. V. Miles, M. B. Tennison and R. S. Greenwood, "Intraindividual variability of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.," Ther Drug Monit, vol. 13, no. 2, pp. 166-171, Mar 1991. [58] E. Zalzstein, N. Zucker and M. Lifshitz, "Digoxin concentration in saliva and plasma in infants, children, and adolescents with heart disease," Current Therapeutic Research, vol. 64, no. 9, pp. 743-749, Nov 2003. [59] N. Krivoy, N. Rogin, Z. Greif, H. Ben-Aryeh, D. Gutman and G. Alroy, "Relationship between digoxin concentration in serum and saliva in infants," J Pediatr, vol. 99, no. 5, pp. 810-811, Nov 1981. [60] M. Berkovitch, M. Goldman, R. Silverman, Z. Chen-Levi, R. Greenberg, O. Marcus and et al, "Therapeutic drug monitoring of oce daily gentamycin in serum and saliva in children," Eu J Pediatr, vol. 159, pp. 697-698, Aug 2000. [61] S. Mahmod, M. H. Al-Hakiem, J. Landon, D. S. Smith and E. J. Shaw, "Aminoglycoside antibiotics do not appear in saliva," Clin Chem, vol. 29, no. 5, pp. 988-989, May 1983. [62] E. A. Kopecky, S. Jacobson, J. Klein, B. Kapur and G. Koren, "Correlation of Morphine Sulfate in Blood Plasma and Saliva in Pediatric Patients," Ther Drug Monit, vol. 19, no. 5, pp. 530-534, Jun 1997. [63] M. Ryan, S. A. Grim, M. V. Miles, P. H. Tang, T. A. Fakhoury, R. H. Strawsbury and et al, "Correlation of Lamotrigine Concentrations Between Serum and Saliva," Pharmacotherapy, vol. 23, no. 12, pp. 1550-1557, Dec 2003. [64] M. Rauh, D. Stachel, M. Kuhlen, M. Groschl, W. Holter and W. Rascher, "Quantification of busulfan in Saliva and Plasma in Haematopoietic Stem Cell Transplantation in Children," Clin Pharmacokin, vol. 45, no. 3, pp. 305-316, Mar 2006. [65] K. C. M. Van Der Elst, M. Van Alst, M. N. Lub-de Hooge, K. Van Hateren, J. G. Kosterink, J. W. Alffennaar and et al, "Clinical Validation of the Analysis of Fluconazole in Oral Fluid in Hospitalised Children," Antimicro agents Chemother, vol. 58, no. 11, pp. 6742-6746, Nov 2014. [66] S. N. De Wilt, K. T. M. Kerkvliet, M. G. A. Wezenberg, S. Ottink, W. C. Hop, A. G. Vulto and et al, "Use of Saliva in Therapeutic Drug Monitoring of Caffeine in Preterm Infants," Ther Drug Monit, vol. 23, no. 3, pp. 250-254, June 2001. [67] H. S. Bada, N. N. Khanna, S. M. Somani and A. A. Tin, "Interconversion of theophylline and caffeine in newborn infants," J Pediatr, vol. 94, no. 6, pp. 993-995, Jun 1979. [68] T. C. Lee, B. G. Charles, P. A. Steer and V. J. Flenady, "Saliva as a Valid Alternative to Serum in Monitoring Intravenous Caffeine Treatment for Apnea of Prematurity," Ther Drug Monit, vol. 18, no. 3, pp. 288-293, Jun 1996. [69] F. Z. Chioukh, A. Chaabane, H. B. Hamida, K. Ben Ameur, K. Aouam and K. Monastiri, "Saliva as an alternative to plasma in therapeutic drug monitoring of caffeine in preterm infants," J Matern Fetal Med, vol. 27, no. S1, p. 398, 2014. [70] N. R. Dobson, X. Liu, L. M. Rhein, R. A. Darnall, M. J. Corwin, B. L. McEntire and et al, "Salivary caffeine concentrations are comparable to plasma concentrations in preterm infants receiving extended caffeine therapy," Br J Clin Pharmacol, vol. 82, pp. 754-761, Apr 2016. [71] K. Y. Chee, D. Lee, D. Byron, D. Naidoo and A. Bye, "A simple collection method for saliva in children: potential for home monitoring of carbamazepine therapy," Br J Clin Pharmacol, vol. 35, no. 3, pp. 311-313, Mar 1993. [72] H. Bartels, E. Gunther and S. Wallis, "Flow-dependent salivary primidone levels in epileptic children," Epilepsia, vol. 20, no. 4, pp. 431-436, Aug 1979. [73] W. Schramm, T. M. Annesley, G. J. Siegel, J. C. Sakellares and R. H. Smith, "Measurement of Phenytoin and Carbamazepine in an Ultrafiltrate of Saliva.," Ther Drug Monitor, vol. 13, no. 5, pp. 452-460, Sep 1991. [74] H. G. Westenberg, E. Van Der Kleijn, T. T. Oei and R. A. De Zeeuw, "Kinetics of carbamazepine and carbamazepine‐epoxide, determined by use of plasma and saliva," Clin Pharmacol and Ther, vol. 23, no. 3, pp. 320-328, Mar 1978. [75] R. Chambers, M. Homeida, K. R. Hunter and R. H. Teague, "Salivary carbamazepine concentrations," The Lancet, vol. 309, no. 8012, pp. 656-657, Mar 1977. [76] G. W. Rylance, T. A. Moreland and G. M. Butcher, "Carbamazepine dose-frequency requirement in children," Arch Dis Child , vol. 54, no. 6, pp. 454-458, Jun 1979. [77] L. Rui-Rui, X. Y. Sheng, L. Y. Ma, H. X. Yao, L. X. Cai, C. Y. Chen and et al, "Saliva and Plasma Monohydroxcarbazepine Concentrations in Pediatric Patients With Epilepsy," Ther Drug Monit, vol. 38, no. 3, pp. 365-370, Jun 2016. [78] B. B. Gallagher and I. P. Baumel, "Primidone. Absorption, distribution, and excretion," Antiepileptic Drugs, pp. 357-359, 1972. [79] M. Tennison, I. Ali and M. V. Miles, "Feasibility and Acceptance of Salivary Monitoring of antiepileptic Drugs via the US Postal Service," Ther Drug Monit, vol. 26, no. 3, pp. 295-299, June 2004. [80] A. Tal, M. Aviram and R. Gorodischer, "Variations in theophylline concentrations detected by 24 hour saliva concentration profiles in ambulatory children with asthma," J Allergy Clin Immunol , vol. 86, no. 2, pp. 238-243, Aug 1990. [81] H.P.Chang, G.C. Anderson and C.E.Wood. “Feasible and valid saliva collection for cortisol in transitional newborn infants”. Nursing Research, vol. 44, no. 2, pp. 117-119, Mar 1995. [82] A.M. Bermejo, A.C.S. Lucas and M.J. Tabernero. “Saliva/plasma ratio of methadone and EDDP”. J Anal Toxicol, vol. 24, no. 1, pp. 70-72, Jan, 2000. [83] F. Quattrocchi, H.T. Karnes, J.D. Robinson and L. Hendeles. “Effect of Serum Separator Blood Collection Tubes on Drug Concentrations”. Ther Drug Monit. Vol. 5, no.3 , pp. 359-362, Sep 1983. [84] A. Dasgupta, R. Dean, S. Saldana, G. Kinnaman and R.W. McLawhon. “Absorption of Therapeutic Drugs by Barrier Gels in Serum Separator Blood Collection Tubes: Volume-and Time-dependent Reduction in Total and Free Drug Concentrationsa”. Am J Clin Pathol, vol. 101, no. 4, pp. 456-461, Jan, 1994. [85] P. Marquet, F.L. Sauvage, V. Loustaud-Ratti, G. Babany, A. Rousseau and G. Lachatre. “Stability of ribavirin concentrations depending on the type of blood collection tube and preanalytical conditions”. Ther Drug Monit, vol. 32, no. 2, pp. 237-241, Apr, 2010. [86] R. Koysooko, E.F. Ellis and G. Levy. “Relationship between theophylline concentration in plasma and saliva of man”. Clin Pharmacol and Ther, vol. 15, no. 5, pp. 454-460, May, 1974. [87] F. Plavsic, J. Culig, I. Bakran and B.Vrhovac. “Theophylline concentration in saliva as a guide for individualization of its therapeutic use”. Brit J Clin Pharmaco, vol. 1, no 11, pp 533-4, May 1981. [88] J. Culig, A. Johnston and P. Turner, "Saliva theophylline concentrations after a single oral dose.," Br J Clin Pharmacol, vol. 13, no. 2, pp. 243-245, 1982. [89] C.H. Knott, M. Bateman and F. Reynolds. “Do saliva concentrations predict plasma unbound theophylline concentrations? A problem re‐examined”. Brit J Clin Pharmaco, vol.1, no. 17, pp9-14, Jan 1984. [90] P. Ebden, D. Leopold, D. Buss, A.P. Smith and P.A. Routledge. “Relationship between saliva and free and total plasma theophylline concentrations in patients with chronic airflow obstruction”. Thorax, vol.1, no.40, pp. 526-529, Jul 1985. [91] J.W. Paxton, B. Whiting and K.W. Stephen. “Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay”. Brit J Clin Pharmaco, vol.1, no.4, pp.185-191, Apr 1977. [92] C. Knott, A. Hamshaw-Thomas and F. Reynolds. “Phenytoin-valproate interaction: importance of saliva monitoring in epilepsy”. Br Med J, vol.2, no. 284, pp.3-6, Jan 1982. [93] L.M. Tsanaclis, J. Allen, E. Perucca et al. “Effect of valproate on free plasma phenytoin concentrations”. Br J Clin Pharmacol, vol.18, no.1, pp. 17-20, Jul 1984. [94] H.G. Van. “Comparative study of the levels of anticonvulsants and their free fractions in venous blood, saliva and capillary blood in man”. J Pharmacol, vol.15, no.1, pp 27-35, Jan 1984. [95] C. Knott, C.P. Williams and F. Reynolds. “Phenytoin kinetics during pregnancy and the puerperium”. BJOG: An International Journal of Obstetrics & Gynaecology, vol. 1, no. 93, pp. 1030-1037, Oct 1986. [96] P.V. Luoma, J.E. Heikkinen and P.R. Ylostalo. “Phenobarbital pharmacokinetics and salivary and serum concentrations in pregnancy”. Ther Drug Monit, vol. 4, pp. 65-68, Mar 1982. [97] D. Shen. “Saliva phenobarbital concentration in epileptics. Chung Hua Shen Ching Ching Shen Ko Tsa Chih, vol. 22, no. 6, pp. 369-370, 1989. [98] W.J. Jusko, L. Gerbracht, L.H. Golden and J.R. Koup, J. R. “Digoxin concentrations in serum and saliva”. Commun Chem Pathol Pharmacol, vol.10, no.1, pp. 189-192, Jan 1975. [99] W.J.F, Van der Vijgh. “Comparison of salivary digoxin concentration with plasma levels in man”. Neth. J. Med, vol. 18, pp. 269-272, 1975. [100] P.H. Jourbert, F.O. Muller and B.M. Aucamp. “Salivary digoxin concentration in saliva and serum”. Brit J Clin Pharmaco, vol. 3, pp. 673-674, Aug 1976. [101] H. Allonen, E. Iisalo, L. Kangas, R. Lammintausta and M. Salonen. “Estimation of pharmacokinetic parameters of digoxin from serum, saliva and urine”. Int J Clin Pharmacol Biopharm, vol. 16, no. 9, pp.420-423, Sept 1978. [102] J. Lazowski, A. Lypka, and P. Borkowski. “The relationship between digoxin concentration in saliva and serum”. Polski tygodnik lekarski, vol. 30, no. 33, pp. 1709 -1711, Oct 1978. [103] S. Mahmod, D.S. Smith and J. Landon. “Radioimmunoassay of salivary digoxin by simple adaptation of a kit method for serum digoxin: saliva/serum ratio and correlation”. Ther Drug Monit, vol. 1, no. 9, pp. 91-96, Mar 1987. [104] A.F. Cohen, L. Ashby, D. Crowley et al. “Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam. Br J Clin Pharmacol, Vol. 20, no. 6, pp. 619-629, Dec 1985. [105] Z. Trnavska, H. Krejcova, Z. Ykaczykovam et al. “Pharmacokinetics of lamotrigine (Lamictal) in plasma and saliva”. Eur J Drug Metab Pharmacokinet, vol. 3, pp. 211-215, Jan 1991. [106] T. Incecayir, I. Agabeyoglu and K.Gucuyener. “Comparison of plasma and saliva concentrations of lamotrigine in healthy volunteers. Arzneimittelforschung, vol. 57, no. 8, pp. 517-521, Aug 2007. [107] C.H. Koks CH, K.M. Crommentuyn, R.M. Hoetelmans, R.A. Mathôt RA and J.H. Beijnen. “Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?” Ther Drug Monit, vol. 1, no.23, pp. 499-453, Aug 2001. [108] C.H. Koks, H. Rosing, P.L. Meenhorst, A. Bult and J.H. Beijnen. “High-performance liquid chromatographic determination of the antifungal drug fluconazole in plasma and saliva of human immunodeficiency virus-infected patients”. J Chromatog, vol. 20, no. 663, pp. 345-351, Jan 1995. [109] J.W. Paxton and R.A. Donald. “Concentrations and kinetics of carbamazepine in whole saliva, parotid saliva, serum ultrafiltrate, and serum”. Clin Pharmacol Ther, vol. 28, no. 5, pp. 695-702, Nov 1980. [110] O. Kristensen and H.F. Larsen. “Value of saliva samples in monitoring carbamazepine concentrations in epileptic patients”. Acta Neurol Scand, vol. 1, no. 61, pp. 344-350, Jun 1980. [111] J.J. MacKichan, P.K. Duffner and M.E. Cohen. “Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine-10, 11-epoxide in epileptic patients”. Br J Clin Pharmacol, vol. 12, no. 1, pp. 31-37, Jul 1981. [112] A. Vasudev, K.D. Tripathi and V. Puri. “Correlation of serum and salivary carbamazepine concentration in epileptic patients: implications for therapeutic drug monitoring”. Neurology India, vol. 1, no. 50, pp. 60, Jan, 2002. [113] S. Đorđević, V. Kilibarda and T. Stojanović. “Determination of carbamazepine in serum and saliva samples by high performance liquid chromatography with ultraviolet detection”. Vojnosanitetski pregled, vol. 66, no.5, pp. 347-352, 2009. [114] S. Djordjević, V. Kilibarda, S. Vučinić, T. Stojanović and B. Antonijević. “Toxicokinetics and correlation of carbamazepine salivary salivary and serum concentrations in acute poisonings”. Military Medical and Pharmaceutical Journal of Serbia, vol. 1, no. 69, pp. 389, May 2012. [115] M. Thiesohn and G. Heimann. “Disposition of the anti-epileptic oxcarbazepine and its metabolites in healthy volunteers”. Eur J Clin Pharmacol, vol. 1, no. 22, pp. 545-551, Aug 1982. [116] O. Kristensen, N.A. Klitgaard, B. Jonsson et al. “Pharmacokinetics of 10-OH-carbazepine, the main metabolite of the antiepileptic oxcarbazepine from serum and saliva concentrations”. Acta Neurol Scand, vol. 1, no. 68, pp. 145-150, Sept 1983. [117] N. A. Klitgaard and O. Kristensen, "Use of saliva for monitoring oxcarbazepine therapy in epileptic patients.," Eu J Clin Pharmacol, vol. 31, no. 1, pp. 91-94, Jan 1986. [118] J. M. Cardot, P. Degen, G. Flesch, P. Menge and W. Dieterle, "Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state," Biopharm Drug Dispos, vol. 16, no. 7, pp. 603-614, Oct 1995. [119] M. V. Miles, P. H. Tang and M. A. Ryan, "Feasibility and limitations of oxcarbazepine monitoring using salivary monohydroxycarbamazepine (MHD).," Therapeutic Drug Monitoring, vol. 1, no. 26, pp. 300-304, June 2004. [120] E. Zylber‐Katz, L. Granit and M. Levy. “Relationship between caffeine concentrations in plasma and saliva”. Clin Pharmacol and Ther, vol. 1, no. 36, pp. 133-137, Jul 1984. [121] R. Newton, L.J. Broughton, M.J. Lind, P.J. Morrison, H.J. Rogers and I.D. Bradbrook. “Plasma and salivary pharmacokinetics of caffeine in man”. Eu J Clin Pharmaco, vol. 1, no. 21, pp. 45-52, Jan 1981.

PY - 2018/2/14

Y1 - 2018/2/14

N2 - Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. MethodsDatabases were searched up to and including September 2016. Studies were included based on PICO as follows: P: Infants and neonates being treated with any medication, I: Salivary Therapeutic Drug Monitoring vs C: Traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. ResultsTwenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent /very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Furthermore, any compound with a pKa within physiological range (pH 6 – 8) gave a more varied response. ConclusionThere is significant potential for infantile saliva testing and in particular, for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude any compound with a pKa within physiological range (pH 6 – 8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis.

AB - Saliva, as a matrix, offers many benefits over blood in therapeutic drug monitoring (TDM), in particular for infantile TDM. However, the accuracy of salivary TDM in infants remains an area of debate. This review explored the accuracy, applicability and advantages of using saliva TDM in infants and neonates. MethodsDatabases were searched up to and including September 2016. Studies were included based on PICO as follows: P: Infants and neonates being treated with any medication, I: Salivary Therapeutic Drug Monitoring vs C: Traditional methods and O: accuracy, advantages/disadvantages and applicability to practice. Compounds were assessed by their physicochemical and pharmacokinetic properties, as well as published quantitative saliva monitoring data. ResultsTwenty-four studies and their respective 13 compounds were investigated. Four neutral and two acidic compounds, oxcarbazepine, primidone, fluconazole, busulfan, theophylline and phenytoin displayed excellent /very good correlation between blood plasma and saliva. Lamotrigine was the only basic compound to show excellent correlation with morphine exhibiting no correlation between saliva and blood plasma. Furthermore, any compound with a pKa within physiological range (pH 6 – 8) gave a more varied response. ConclusionThere is significant potential for infantile saliva testing and in particular, for neutral and weakly acidic compounds. Of the properties investigated, pKa was the most influential with both logP and protein binding having little effect on this correlation. To conclude any compound with a pKa within physiological range (pH 6 – 8) should be considered with extra care, with the extraction and analysis method examined and optimized on a case-by-case basis.

KW - Therapeutic Drug monitoring (TDM)

KW - saliva

KW - physicochemical properties

KW - pharmacokinetic parameters

KW - infants

KW - paediatric

KW - systematic review

U2 - 10.1111/bcp.13553

DO - 10.1111/bcp.13553

M3 - Article

VL - 1

SP - 1

EP - 11

JO - British Journal of Clinical Pharmacology

T2 - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

ER -