Pharmacometrics in pulmonary diseases

AAPS Advances in the Pharmaceutical Sciences Series

Volumn 14, Issue , 2014, Pages

  Kandala, Bhargava ^a   Hochhaus, Günther ^a  

^a UNIVERSITY OF FLORIDA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BUDESONIDE; CORTICOSTEROID; CORTICOTROPIN; HYDROCORTISONE;

ARTICLE; BINDING AFFINITY; BIOAVAILABILITY; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL FEATURE; COMPUTER PROGRAM; DRUG ABSORPTION; DRUG ADMINISTRATION ROUTE; DRUG DELIVERY SYSTEM; DRUG EXPOSURE; FIRST PASS EFFECT; GROWTH RATE; HUMAN; LUNG DISEASE; LYMPHOCYTOPENIA; MATHEMATICAL MODEL; PHARMACODYNAMICS; PHARMACOMETRICS; PHYSICAL CHEMISTRY; PHYSIOLOGICAL PROCESS; RECEPTOR BINDING; SOFT MIST INHALER;

EID: 85065457821     PISSN: 22107371     EISSN: 2210738X     Source Type: Book Series    
DOI: 10.1007/978-1-4939-1304-6_12     Document Type: Article

References (109)

1. Abo T, Kawate T, Itoh K, Kumagai K (1981) Studies on the bioperiodicity of the immune response. I. Circadian rhythms of human T, B, and K cell traffic in the peripheral blood. J Immunol 126:1360–1363.
2. Agoram B, Woltosz WS, Bolger MB (2001) Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev 50(Suppl 1):S41–S67.
3. Ahmed SF, Tucker P, Mushtaq T et al (2002) Short-term effects on linear growth and bone turnover in children randomized to receive prednisolone or dexamethasone. Clin Endocrinol (Oxf) 57:185–191.
4. Ariens EJ (1954) Affinity and intrinsic activity in the theory of competitive inhibition. I. Problems and theory. Arch Int Pharmacodyn Thér 99:32–49.
5. Bates DV, Fish BR, Hatch TF et al (1966) Deposition and retention models for internal dosimetry of the human respiratory tract. Task group on lung dynamics. Health Phys 12:173–207.
6. Beato M, Kalimi M, Feigelson P (1972) Correlation between glucocorticoid binding to specific liver cytosol receptors and enzyme induction in vivo. Biochem Biophys Res Commun 47:1464–1472.
7. Borghardt J, Weber B, Staab A et al (2014) Exapnding the mechanistic knowledge about pulmonary absorption processes using a population pharmacokinetic model for inhaled olodaterol. Respir Drug Deliv 2:417–422.
8. Borgström L, Bondesson E, Morén F et al (1994) Lung deposition of budesonide inhaled via Turbuhaler: a comparison with terbutaline sulphate in normal subjects. Eur Respir J 7:69–73.
9. Bot AI, Tarara TE, Smith DJ et al (2000) Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract. Pharm Res 17:275–283.
10. Brown RA, Schanker LS (1983) Absorption of aerosolized drugs from the rat lung. Drug Metab Dispos 11:355–360.
11. Byron PR (1986) Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. J Pharm Sci 75:433–438.
12. Carroll N, Cooke C, James A (1997) The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 10:292–300.
13. Carstairs JR, Nimmo AJ, Barnes PJ (1985) Autoradiographic visualization of beta-adrenoceptor subtypes in human lung. Am Rev Respir Dis 132:541–547.
14. Chakraborty A, Krzyzanski W, Jusko WJ (1999) Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods. J Pharmacokinet Biopharm 27:23–43.
15. Chaudhuri SR, Lukacova V (2010) Simulating delivery of pulmonary (and intranasal) aerosolised drugs, pp 26–30. ONdrugDelivery. http://www.ondrugdelivery.com/publications/OINDP%20.November%202010/OINDP%20November%202010%20lo%20res.pdf. Accessed 26. Sept 2013.
16. Chrousos GP, Harris AG (1998) Hypothalamic–pituitary–adrenal axis suppression and inhaled corticosteroid therapy. 2. Review of the literature. Neuroimmunomodulation 5:288–308.
17. Dahlberg E, Thalén A, Brattsand R et al (1984) Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16 alpha, 17 alpha-acetalsubstituted glucocorticoids. Mol Pharmacol 25:70–78.
18. Daley-Yates PT, Richards DH (2004) Relationship between systemic corticosteroid exposure and growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model. Clin Ther 26:1905–1919.
19. Daley-Yates PT, Price AC, Sisson JR et al (2001) Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol 51:400–409.
20. Davies CN (1982) Deposition of particles in the human lungs as a function of particle size and breathing pattern: an empirical model. Ann Occup Hyg 26:119–135.
21. DeHaan WH, Finlay WH (2001) In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices. J Aerosol Med 14:361–367.
22. Dellamary LA, Tarara TE, Smith DJ et al (2000) Hollow porous particles in metered dose inhalers. Pharm Res 17:168–174.
23. Derendorf H, Hochhaus G, Rohatagi S et al (1995) Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration. J Clin Pharmacol 35:302–305.
24. Dinh KV, Myers DJ, Noymer PD, Cassella JV (2010) In vitro aerosol deposition in the oropharyngeal region for Staccato loxapine. J Aerosol Med Pulm Drug Deliv 23:253–260. doi:10.1089/jamp.2009.0814.
25. Druzgala P, Hochhaus G, Bodor N (1991) Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J Steroid Biochem Mol Biol 38:149–154.
26. Earp JC, Dubois DC, Molano DS et al (2008a) Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats. J Pharmacol Exp Ther 326:532–545. doi:10.1124/jpet.108.137372.
27. Earp JC, Dubois DC, Molano DS et al (2008b) Modeling corticosteroid effects in a rat model of rheumatoid arthritis II: mechanistic pharmacodynamic model for dexamethasone effects in Lewis rats with collagen-induced arthritis. J Pharmacol Exp Ther 326:546–554. doi:10.1124/jpet.108.137414.
28. Edsbäcker S, Brattsand R (2002) Budesonide fatty-acid esterification: a novel mechanism prolonging binding to airway tissue. Review of available data. Ann Allergy Asthma Immunol 88:609–616. doi:10.1016/S1081-1206(10)61893-5.
29. Edwards DA, Hanes J, Caponetti G et al (1997) Large porous particles for pulmonary drug delivery. Science 276:1868–1871.
30. Fuglsang G, Pedersen S, Borgström L (1989) Dose–response relationships of intravenously administered terbutaline in children with asthma. J Pediatr 114:315–320.
31. Geller DE, Weers J, Heuerding S (2011) Development of an inhaled dry-powder formulation of tobramycin using PulmoSphereTM technology. J Aerosol Med Pulm Drug Deliv 24:175–182. doi:10.1089/jamp.2010.0855.
32. Gobburu JVS, Lesko LJ (2009) Quantitative disease, drug, and trial models. Annu Rev Pharmacol Toxicol 49:291–301. doi:10.1146/annurev.pharmtox.011008.145613.
33. Gonda I (1988) Drugs administered directly into the respiratory tract: modeling of the duration of effective drug levels. J Pharm Sci 77:340–346.
34. Gonda I (2004) Targeting by deposition. In: Hickey AJ (ed) Pharmaceutical inhalation aerosol technology, 2nd edn. Merckel Dekker, New York, pp 65–88.
35. Green SA, Spasoff AP, Coleman RA et al (1996) Sustained activation of a G protein-coupled receptor via “anchored” agonist binding. Molecular localization of the salmeterol exosite within the 2-adrenergic receptor. J Biol Chem 271:24029–24035.
36. Hardy JG, Chadwick TS (2000) Sustained release drug delivery to the lungs: an option for the future. Clin Pharmacokinet 39:1–4. doi:10.2165/00003088-200039010-00001.
37. Harrison TW, Tattersfield AE (2003) Plasma concentrations of fluticasone propionate and budesonide following inhalation from dry powder inhalers by healthy and asthmatic subjects. Thorax 58:258–260.
38. Hickey A, Thompson D (2004) Physiology of the airways. In: Hickey AJ (ed) Pharmaceutical inhalation aerosol technology, 2nd edn. Marcel Dekker, New York, pp 1–29.
39. Hindle M, Longest PW (2010) Evaluation of enhanced condensational growth (ECG) for controlled respiratory drug delivery in a mouth–throat and upper tracheobronchial model. Pharm Res 27:1800–1811. doi:10.1007/s11095-010-0165-z
40. Hindle M, Longest PW (2012) Condensational growth of combination drug-excipient submicrometer particles for targeted high-efficiency pulmonary delivery: evaluation of formulation and delivery device. J Pharm Pharmacol 64:1254–1263. doi:10.1111/j.2042-7158.2012.01476.x
41. Hochhaus G, Möllmann H (1992) Pharmacokinetic/pharmacodynamic characteristics of the beta- 2-agonists terbutaline, salbutamol and fenoterol. Int J Clin Pharmacol Ther Toxicol 30:342–362.
42. Hochhaus G, Chen LS, Ratka A et al (1992a) Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs. J Pharm Sci 81:1210–1215.
43. Hochhaus G, Schmidt EW, Rominger KL, Möllmann H (1992b) Pharmacokinetic/dynamic correlation of pulmonary and cardiac effects of fenoterol in asthmatic patients after different routes of administration. Pharm Res 9:291–297.
44. Hochhaus G, Möllmann H, Derendorf H, Gonzalez-Rothi RJ (1997) Pharmacokinetic/pharmacodynamic aspects of aerosol therapy using glucocorticoids as a model. J Clin Pharmacol 37:881–892.
45. Hong Y, Mager DE, Blum RA, Jusko WJ (2007) Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Pharm Res 24:1088–1097. doi:10.1007/s11095-006-9232-x
46. Issar M, Mobley C, Khan P, Hochhaus G (2004) Pharmacokinetics and pharmacodynamics of drugs delivered to the lungs. In: Hickey A (ed) Pharmaceutical inhalation aerosol technology, 2nd edn. Marcel Dekker, New York, pp 215–252.
47. Iyengar R, Zhao S, Chung S-W et al (2012) Merging systems biology with pharmacodynamics. Sci Transl Med 4:126ps7. doi:10.1126/scitranslmed.3003563.
48. Jeffery PK (1987) The origins of secretions in the lower respiratory tract. Eur J Respir Dis Suppl 153:34–42.
49. Jones HM, Dickins M, Youdim K et al (2012) Application of PBPK modelling in drug discovery and development at Pfizer. Xenobiotica 42:94–106. doi:10.3109/00498254.2011.627477.
50. Jonkers R, van Boxtel CJ, Koopmans RP, Oosterhuis B (1989) A nonsteady-state agonist antagonist interaction model using plasma potassium concentrations to quantify the beta-2 selectivity of beta blockers. J Pharmacol Exp Ther 249:297–302.
51. Jusko WJ (2013) Moving from basic toward systems pharmacodynamic models. J Pharm Sci 102:2930–2940. doi:10.1002/jps.23590.
52. Koopmans RP, Braat MC, Oosterhuis B, van Boxtel CJ (1992) Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model. J Pharmacol Exp Ther 262:503–508.
53. Kraft M, Djukanovic R, Wilson S et al (1996) Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 154:1505–1510. doi:10.1164/ajrccm.154.5.8912772.
54. Labiris NR, Dolovich MB (2003) Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 56:588–599.
55. Lee JY, Garnett CE, Gobburu JVS et al (2011) Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008. Clin Pharmacokinet 50:627–635. doi:10.2165/11593210-000000000-00000.
56. Lesko LJ, Rowland M, Peck CC, Blaschke TF (2000) Optimizing the science of drug development: opportunities for better candidate selection and accelerated evaluation in humans. Pharm Res 17:1335–1344.
57. Lipworth BJ, Jackson CM (2000) Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf 23:11–33.
58. Longest PW, McLeskey JT, Hindle M (2010) Characterization of nanoaerosol size change during enhanced condensational growth. Aerosol Sci Technol 44:473–483. doi:10.1080/02786821003749525.
59. Longest PW, Tian G, Walenga RL, Hindle M (2012) Comparing MDI and DPI aerosol deposition using in vitro experiments and a new stochastic individual path (SIP) model of the conducting airways. Pharm Res 29:1670–1688. doi:10.1007/s11095-012-0691-y
60. Lönnebo A, Grahnén A, Karlsson MO (2007) An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers. Br J Clin Pharmacol 64:125–132. doi:10.1111/j.1365-2125.2007.02867.x
61. Lukacova V, Ray Chaudhuri S, Miller N et al (2010) Simulation of tobramycin pharmacokinetics after pulmonary administration. 37th Annual Meeting & Exposition Controlled Release Society. 37th Annual Meeting and Exposition of the Controlled Release Society, Portland, OR. July 10–14, 2010.
62. Mackie AE, Ventresca GP, Fuller RW, Bye A (1996) Pharmacokinetics of intravenous fluticasone propionate in healthy subjects. Br J Clin Pharmacol 41:539–542.
63. Martonen TB, Katz IM (1993) Deposition patterns of aerosolized drugs within human lungs: effects of ventilatory parameters. Pharm Res 10:871–878.
64. Meibohm B, Derendorf H, Möllmann H et al (1999) Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids. Int J Clin Pharmacol Ther 37:367–376.
65. Milad MA, Ludwig EA, Lew KH et al (1994) The pharmacokinetics and pharmacodynamics of Methylprednisolone in chronic renal failure. Am J Ther 1:49–57.
66. Miller N, Ray Chaudhuri S, Lukacova V et al (2010) Development of physiologically-based pharmacokinetic (PBPK) model for predicting deposition and disposition following inhaled and intranasal administration. Respir Drug Deliv 2:579–584.
67. Miller-Larsson A, Mattsson H, Hjertberg E et al (1998) Reversible fatty acid conjugation of budesonide. Novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 26:623–630.
68. Miyawaki T, Taga K, Nagaoki T et al (1984) Circadian changes of T lymphocyte subsets in human peripheral blood. Clin Exp Immunol 55:618–622.
69. Möllmann H, Wagner M, Meibohm B et al (1998) Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration. Eur J Clin Pharmacol 53:459–467.
70. Nagaraja NV, Pechstein B, Erb K et al (2003) Pharmacokinetic/pharmacodynamic modeling of luteinizing hormone (LH) suppression and LH surge delay by cetrorelix after single and multiple doses in healthy premenopausal women. J Clin Pharmacol 43:243–251.
71. Nave R, Meyer W, Fuhst R, Zech K (2005) Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther 18:390–396. doi:10.1016/j.pupt.2005.02.012.
72. Nave R, Fisher R, Zech K (2006) In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm Drug Dispos 27:197–207. doi:10.1002/bdd.500.
73. Newman SP, Clark AR, Talaee N, Clarke SW (1989) Pressurised aerosol deposition in the human lung with and without an “open” spacer device. Thorax 44:706–710.
74. Newman SP, Brown J, Steed KP et al (1998) Lung deposition of fenoterol and flunisolide delivered using a novel device for inhaled medicines: comparison of RESPIMAT with conventional metered-dose inhalers with and without spacer devices. Chest 113:957–963.
75. Newman S, Salmon A, Nave R, Drollmann A (2006) High lung deposition of 99mTc-labeled ciclesonide administered via HFA-MDI to patients with asthma. Respir Med 100:375–384. doi:10.1016/j.rmed.2005.09.027.
76. Nikander K, Prince I, Coughlin S et al (2010) Mode of breathing-tidal or slow and deep-through the I-neb Adaptive Aerosol Delivery (AAD) system affects lung deposition of (99m)Tc-DTPA. J Aerosol Med Pulm Drug Deliv 23(Suppl 1):S37–S43. doi:10.1089/jamp.2009.0786.
77. Oneda K (1999) Dexamethasone-induced apoptosis in peripheral T lymphocytes from patients with asthma. Arerugi 48:13–22.
78. Palm S, Postler E, Hinrichsen H et al (1996) Twenty-four-hour analysis of lymphocyte subpopulations and cytokines in healthy subjects. Chronobiol Int 13:423–434.
79. Peet CF, Enos T, Nave R et al (2005) Identification of enzymes involved in phase I metabolism of ciclesonide by human liver microsomes. Eur J Drug Metab Pharmacokinet 30:275–286.
80. Petruzzelli S, De Flora S, Bagnasco M et al (1989) Carcinogen metabolism studies in human bronchial and lung parenchymal tissues. Am Rev Respir Dis 140:417–422. doi:10.1164/ajrccm/140.2.417.
81. Pitcairn G, Reader S, Pavia D, Newman S (2005) Deposition of corticosteroid aerosol in the human lung by Respimat Soft Mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler. J Aerosol Med 18:264–272. doi:10.1089/jam.2005.18.264.
82. Rohatagi S, Hochhaus G, Mollmann H et al (1995) Pharmacokinetic and pharmacodynamic evaluation of triamcinolone acetonide after intravenous, oral, and inhaled administration. J Clin Pharmacol 35:1187–1193.
83. Rohatagi S, Bye A, Mackie AE, Derendorf H (1996a) Mathematical modeling of cortisol circadian rhythm and cortisol suppression. Eur J Pharm Sci 4:341–350.
84. Rohatagi S, Täuber U, Richter K, Derendorf H (1996b) Pharmacokinetic/pharmacodynamic modeling of cortisol suppression after oral administration of fluocortolone. J Clin Pharmacol 36:311–314.
85. Rohatagi S, Arya V, Zech K et al (2003) Population pharmacokinetics and pharmacodynamics of ciclesonide. J Clin Pharmacol 43:365–378.
86. Rohatagi S, Luo Y, Shen L et al (2005) Protein binding and its potential for eliciting minimal systemic side effects with a novel inhaled corticosteroid, ciclesonide. Am J Ther 12:201–209.
87. Ryrfeldt A, Andersson P, Edsbäcker S et al (1982) Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid. Eur J Respir Dis Suppl 122:86–95.
88. Schanker LS, Mitchell EW, Brown RA (1986) Species comparison of drug absorption from the lung after aerosol inhalation or intratracheal injection. Drug Metab Dispos 14:79–88.
89. Singh SD, Whale C, Houghton N et al (2003) Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease. Br J Clin Pharmacol 55:375–381.
90. Slayter KL, Ludwig EA, Lew KH et al (1996) Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 59:312–321. doi:10.1016/S0009-9236(96)80009-9.
91. Smith H (1995) Human respiratory tract model for radiological protection. ICRP Publication (1994) 66. Ann. ICRP 24:1–3.
92. Stark JG, Werner S, Homrighausen S et al (2006) Pharmacokinetic/pharmacodynamic modeling of total lymphocytes and selected subtypes after oral budesonide. J Pharmacokinet Pharmacodyn 33:441–459. doi:10.1007/s10928-006-9013-5.
93. Stuart BO (1984) Deposition and clearance of inhaled particles. Environ Health Perspect 55:369–390.
94. Suarez S, Gonzalez-Rothi RJ, Schreier H, Hochhaus G (1998) Effect of dose and release rate on pulmonary targeting of liposomal triamcinolone acetonide phosphate. Pharm Res 15:461–465.
95. Suntres ZE, Shek PN (1998) Liposomes promote pulmonary glucocorticoid delivery. J Drug Target 6:175–182. doi:10.3109/10611869808997891.
96. Thiel CG (1998) Can in vitro particle size measurements be used to predict pulmonary deposition of aerosol from inhalers? J Aerosol Med 11(Suppl 1):S43–S52.
97. Tian G, Longest PW, Li X, Hindle M (2013) Targeting aerosol deposition to and within the lung airways using excipient enhanced growth. J Aerosol Med Pulm Drug Deliv 26:248–265. doi:10.1089/jamp.2012.0997.
98. Tunek A, Sjödin K, Hallström G (1997) Reversible formation of fatty acid esters of budesonide, an antiasthma glucocorticoid, in human lung and liver microsomes. Drug Metab Dispos 25:1311–1317.
99. Tyler WS (1983) Comparative subgross anatomy of lungs. Pleuras, interlobular septa, and distal airways. Am Rev Respir Dis 128:S32–S36.
100. Usmani OS, Biddiscombe MF, Barnes PJ (2005) Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care Med 172:1497–1504. doi:10.1164/rccm.200410-1414OC
101. Van Gossum A, Schmit A, Peny MO (1998) Oral budesonide for lymphocytic colitis. Am J Gastroenterol 93: 270. doi:10.1111/j.1572-0241.1998.270_1.x
102. Vodovotz Y, An G (2010) Systems biology and inflammation. Methods Mol Biol 662:181–201. doi:10.1007/978-1-60761-800-3_9.
103. Wald JA, Law RM, Ludwig EA et al (1992) Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man. J Pharmacokinet Biopharm 20:567–589.
104. Weber B, Hochhaus G (2013) A pharmacokinetic simulation tool for inhaled corticosteroids. AAPS J 15:159–171. doi:10.1208/s12248-012-9420-z
105. Weda M, Zanen P, de Boer AH et al (2008) The therapeutic index of locally acting inhaled drugs as a function of their fine particle mass and particle size distribution: a literature review. Curr Drug Deliv 5:142–147.
106. Weibel E (1963) Morphometry of the human lung, 1st edn. Springer, New York
107. Winkler J, Hochhaus G, Derendorf H (2004) How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids. Proc Am Thorac Soc 1:356–363. doi:10.1513/pats.200403-025MS
108. Xu J, Nave R, Lahu G et al (2010) Population pharmacokinetics and pharmacodynamics of inhaled ciclesonide and fluticasone propionate in patients with persistent asthma. J Clin Pharmacol 50:1118–1127. doi:10.1177/0091270009354994.
109. Zhao P, Zhang L, Grillo JA et al (2011) Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review. Clin Pharmacol Ther 89:259–267. doi:10.1038/clpt.2010.298