Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 9/2018

01-09-2018 | Review Article

Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System

Authors: Nithya Srinivas, Kaitlyn Maffuid, Angela D. M. Kashuba

Published in: Clinical Pharmacokinetics | Issue 9/2018

Login to get access

Abstract

Despite contributing significantly to the burden of global disease, the translation of new treatment strategies for diseases of the central nervous system (CNS) from animals to humans remains challenging, with a high attrition rate in the development of CNS drugs. The failure of clinical trials for CNS therapies can be partially explained by factors related to pharmacokinetics/pharmacodynamics (PK/PD), such as lack of efficacy or improper selection of the initial dosage. A focused assessment is needed for CNS-acting drugs in first-in-human studies to identify the differences in PK/PD from animal models, as well as to choose the appropriate dose. In this review, we summarize the available literature from human studies on the PK and PD in brain tissue, cerebrospinal fluid, and interstitial fluid for drugs used in the treatment of psychosis, Alzheimer’s disease and neuro-HIV, and address critical questions in the field. We also explore newer methods to characterize PK/PD relationships that may lead to more efficient dose selection in CNS drug development.
Appendix
Available only for authorised users
Literature
1.
2.
Patel V, Chisholm D, Parikh R, Charlson FJ, Degenhardt L, Dua T, et al. Addressing the burden of mental, neurological, and substance use disorders: key messages from Disease Control Priorities, 3rd edition. Lancet. 2016;387(10028):1672–85.
3.
Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimer’s Res Ther. 2014;6:1–7.CrossRef
4.
Benedetti F, Carlino E, Piedimonte A. Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects. Lancet Neurol. 2016;15(7):736–47.PubMedCrossRef
5.
Kesselheim AS, Hwang TJ, Franklin JM. Two decades of new drug development for central nervous system disorders. Nat Rev. 2015;14(12):815–6.
6.
Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov. 2007;6:521–32.PubMedCrossRef
7.
8.
Choi DW, Armitage R, Brady LS, Coetzee T, Fisher W, Hyman S, et al. Perspective medicines for the mind: policy-based “pull” incentives for creating breakthrough CNS drugs. Neuron. 2013;84(3):554–63.CrossRef
9.
Goetghebeur PJD, Swartz JE. True alignment of preclinical and clinical research to enhance success in CNS drug development: a review of the current evidence. J Psychopharmacol. 2016;586:1–9.
10.
de Lange ECM, Hammarlund-Udenaes M. Translational aspects of blood-brain barrier transport and central nervous system effects of drugs: from discovery to patients. Clin Pharmacol Ther. 2015;97(4):380–94.PubMedCrossRef
11.
12.
Markou A, Chiamulera C, Geyer MA, Tricklebank M. Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology. 2009;34(1):74–89.PubMedCrossRef
13.
Deo AK, Theil FP, Nicolas JM. Confounding parameters in preclinical assessment of blood-brain barrier permeation: an overview with emphasis on species differences and effect of disease states. Mol Pharm. 2013;10(5):1581–95.PubMedCrossRef
14.
Alavijeh MS, Chishty M, Qaiser MZ, Palmer AM. Metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system. Drug Drug Discov. 2005;2:554–71.
15.
Helms HC, Abbott NJ, Burek M, Cecchelli R, Couraud P-O, Deli MA, et al. In vitro models of the blood-brain barrier: An overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab. 2016;0271678X16630991.
16.
Appelt-Menzel A, Cubukova A, Günther K, Edenhofer F, Piontek J, Krause G, et al. Establishment of a human blood-brain barrier co-culture model mimicking the neurovascular unit using induced pluri- and multipotent stem cells. Stem Cell Rep. 2017;8(4):894–906.CrossRef
17.
Palmiotti CA, Prasad S, Naik P, Abul KMD, Sajja RK, Achyuta AH, et al. In vitro cerebrovascular modeling in the 21st century: current and prospective technologies. Pharm Res. 2014;31(12):3229–50.PubMedPubMedCentralCrossRef
18.
Fridén M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M. In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos. 2007;35(9):1711–9.PubMedCrossRef
19.
Wiseman JM, Ifa DR, Zhu Y. Desorption electrospray ionization mass spectrometry: imaging drugs and metabolites in tissues. Proc Natl Acad Sci USA. 2008;105(47):18120–5.PubMedCrossRef
20.
Thompson CG, Bokhart MT, Sykes C, Adamson L, Fedoriw Y, Luciw PA, et al. Mass spectrometry imaging reveals heterogeneous efavirenz distribution within putative HIV reservoirs. Antimicrob Agents Chemother. 2015;59(5):2944–8.PubMedPubMedCentralCrossRef
21.
Shobo A, Bratkowska D, Baijnath S, Naiker S, Somboro AM, Bester LA, et al. Tissue distribution of pretomanid in rat brain via mass spectrometry imaging. Xenobiotica. 2016;46(3):247–52.PubMedCrossRef
22.
Aikawa H, Hayashi M, Ryu S, Yamashita M, Ohtsuka N, Nishidate M, et al. Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging. Sci Rep. 2016;6:23749.PubMedPubMedCentralCrossRef
23.
Varnäs K, Varrone A, Farde L. Modeling of PET data in CNS drug discovery and development. J Pharmacokinet Pharmacodyn. 2013;40(3):267–79.PubMedCrossRef
24.
Shannon RJ, Carpenter KLH, Guilfoyle MR, Helmy A, Hutchinson PJ. Cerebral microdialysis in clinical studies of drugs: pharmacokinetic applications. J Pharmacokinet Pharmacodyn. 2013;40(3):343–58.PubMedPubMedCentralCrossRef
25.
Lindberger M, Tomson T, Lars S. Microdialysis sampling of carbamazepine, phenytoin and phenobarbital in subcutaneous extracellular fluid and subdural cerebrospinal fluid in humans: an in vitro and in vivo study of adsorption to the sampling device. J Pharmacol Toxicol. 2002;91(4):158–65.CrossRef
26.
Gaohua L, Neuhoff S, Johnson TN, Rostami-hodjegan A, Jamei M, Centre BE, et al. Development of a permeability-limited model of the human brain and cerebrospinal fluid (CSF) to integrate known physiological and biological knowledge: estimating time varying CSF drug concentrations and their variability using in vitro data. Drug Metab Pharmacokinet. 2016;31(3):1–49.CrossRef
27.
Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, et al. Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metab Dispos. 2006;34(9):1443–7.PubMedCrossRef
28.
Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010;9:929–39.PubMedCrossRef
29.
Fridén M, Winiwarter S, Jerndal G, Bengtsson O, Hong W, Bredberg U, et al. Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids. J Med Chem. 2009;52(20):6233–43.PubMedCrossRef
30.
Kodaira H, Kusuhara H, Fujita T, Ushiki J, Fuse E, Sugiyama Y. Quantitative evaluation of the impact of active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier on the predictability of the unbound concentrations of drugs in the brain using cerebrospinal fluid concentration as a. J Pharmacol Exp Ther. 2011;339(3):935–44.PubMedCrossRef
31.
Shen DD, Artru AA, Adkison KK. Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev. 2004;56(12):1825–57.PubMedCrossRef
32.
33.
Kassem NA, Deane R, Segal MB, Chen R, Preston JE. Thyroxine (T4) transfer from CSF to choroid plexus and ventricular brain regions in rabbit: contributory role of P-glycoprotein and organic anion transporting polypeptides. Brain Res. 2007;1181(1):44–50.PubMedCrossRef
34.
Westerhout J, Smeets J, Danhof M, De Lange ECM. The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid. J Pharmacokinet Pharmacodyn. 2013;40(3):327–42.PubMedPubMedCentralCrossRef
35.
Nau R, Zysk G, Thiel A, Prange HW. Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man. Eur J Clin Pharmacol. 1993;45(5):469–75.PubMedCrossRef
36.
Nau R, Sörgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev. 2010;23(4):858–83.PubMedPubMedCentralCrossRef
37.
Yilmaz A, Watson V, Dickinson L, Back D. Efavirenz pharmacokinetics in cerebrospinal fluid and plasma over a 24-hour dosing interval. Antimicrob Agents Chemother. 2012;56(9):4583–5.PubMedPubMedCentralCrossRef
38.
Chicano-Piá PV, Cercós-Lletí AC, Romá-Sánchez E. Pharmacokinetic model for tobramycin in acinetobacter meningitis. Ann Pharmacother. 2002;36(1):83–6.PubMedCrossRef
39.
Kühnen E, Pfeifer G, Frenkel C. Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges. Infection. 1987;15(6):422–4.PubMedCrossRef
40.
Capparelli EV, Letendre SL, Ellis RJ, Patel P, Holland D, Mccutchan JA. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2005;49(6):2504–6.PubMedPubMedCentralCrossRef
41.
Rambeck B, Jürgens UH, May TW, Wolfgang Pannek H, Behne F, Ebner A, et al. Comparison of brain extracellular fluid, brain tissue, cerebrospinal fluid, and serum concentrations of antiepileptic drugs measured intraoperatively in patients with intractable epilepsy. Epilepsia. 2006;47(4):681–94.PubMedCrossRef
42.
Hammarlund-Udenaes M. Active-site concentrations of chemicals: are they a better predictor of effect than plasma/organ/tissue concentrations? Basic Clin Pharmacol Toxicol. 2010;106(3):215–20.PubMedCrossRef
43.
Kakee A, Terasaki T, Sugiyama Y. Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. J Pharmacol Exp Ther. 1996;277(3):1550–9.PubMed
44.
Calcagno A, Di Perri G, Bonora S. Pharmacokinetics and pharmacodynamics of antiretrovirals in the central nervous system. Clin Pharmacokinet. 2014;53(10):891–906.PubMedCrossRef
45.
Ahn SM, Byun K, Cho K, Kim JY, Yoo JS, Kim D, et al. Human microglial cells synthesize albumin in brain. PLoS One. 2008;3(7):4–9.CrossRef
46.
Read KD, Braggio S. Assessing brain free fraction in early drug discovery. Expert Opin Drug Metab Toxicol. 2010;6(3):337–44.PubMedCrossRef
47.
Di L, Umland JP, Chang G, Huang Y, Lin Z, Scott DO, et al. Species independence in brain tissue binding using brain homogenates. Drug Metab Dispos. 2011;39(7):1270–7.PubMedCrossRef
48.
Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev. 2001;53(4):569–96.PubMedCrossRef
49.
Hartz AMS, Bauer B. ABC transporters in the CNS—an inventory. Curr Pharmaceutic Biotechnol. 2011;656–73.
50.
Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem. 2011;117(2):333–45.PubMedCrossRef
51.
52.
Zhao R, Raub TJ, Sawada GA, Kasper SC, Bacon JA, Bridges AS, et al. Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood-brain barrier. Drug Metab Dispos. 2009;37(6):1251–8.PubMedPubMedCentralCrossRef
53.
Leggas M, Adachi M, Scheffer G, Sun D, Wielinga P, Du G, et al. MRP4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24(17):7612–21.PubMedPubMedCentralCrossRef
54.
Kalvass JC, Polli JW, Bourdet DL, Feng B, Huang S-M, Liu X, et al. Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther. 2013;94(1):80–94.PubMedCrossRef
55.
van Praag RM, Weverling GJ, Portegies P, Jurriaans S, Zhou XJ, Turner-Foisy ML, et al. Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir. AIDS. 2000;14(9):1187–94.PubMedCrossRef
56.
Toda R, Kawazu K, Oyabu M, Miyazaki T, Kiuchi Y. Comparison of drug permeabilities across the blood-retinal barrier, blood-aqueous humor barrier, and blood-brain barrier. J Pharm Sci. 2011;100(9):3904–11.PubMedCrossRef
57.
Liu X, Chen C. Strategies to optimize brain penetration in drug discovery. Curr Opin Drug Discov Devel. 2005;8(4):505–12.PubMed
58.
Liu X, Smith BJ, Chen C, Callegari E, Becker SL, Chen X, et al. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium: an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther. 2005;313(3):1254–62.PubMedCrossRef
59.
Curley P, Rajoli RKR, Moss DM, Liptrott NJ, Letendre S, Owen A. Efavirenz is predicted to accumulate in brain tissue: and in silico, in vitro and in vivo investigation. Antimicrob Agents Chemother. 2017;61(1):1–10.CrossRef
60.
Kornhuber J, Schoppmeyer K, Riederer P. Affinity of 1-aminoadamantanes for the sigma binding site in post-mortem human frontal cortex. Neurosci Lett. 1993;163(2):129–31.PubMedCrossRef
61.
Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology. 2002;27(2):248–59.PubMedCrossRef
62.
Farde L, Wiesel F, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry. 1988;45(1):71–6.PubMedCrossRef
63.
Mamo D, Kapur S, Shammi CM, Papatheodorou G, Mann S, Therrien F, Pharm D, et al. A PET study of dopamine D 2 and serotonin 5-HT 2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry. 2004;161(5):818–25.PubMedCrossRef
64.
Sato H, Ito C, Tashiro M, Hiraoka K, Shibuya K, Funaki Y, et al. Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers. Psychopharmacology. 2013;230(2):227–34.PubMedCrossRef
65.
Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–70.PubMedCrossRef
66.
67.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10(3):799–812.CrossRef
68.
Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer’s disease scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? Alzheimers Res Ther. 2010;2(4):24.PubMedPubMedCentralCrossRef
69.
Dunlop BW, Mayberg HS. Neuroimaging-based biomarkers for treatment selection in major depressive disorder. Dialog Clin Neurosci. 2014;16(4):479–90.
70.
Ene L, Duiculescu D, Ruta SM. How much do antiretroviral drugs penetrate into the central nervous system? J Med Life. 2011;4(4):432–9.PubMedPubMedCentral
71.
Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789–99.PubMedPubMedCentralCrossRef
72.
Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter CH, Zöchling R, et al. Persistence of haloperidol in human brain tissue. Am J Psychiatry. 1999;156(6):885–90.PubMedCrossRef
73.
Sampedro MC, Unceta N, Gómez-Caballero A, Callado LF, Morentin B, Goicolea MA, et al. Screening and quantification of antipsychotic drugs in human brain tissue by liquid chromatography-tandem mass spectrometry: application to postmortem diagnostics of forensic interest. Forensic Sci Int. 2012;219(1–3):172–8.PubMedCrossRef
74.
Caccia S. Pharmacokinetics and metabolism update for some recent antipsychotics. Expert Opin Drug Metab Toxicol. 2011;7(7):829–46.PubMedCrossRef
75.
Nyberg G, Axelsson R, Mftrtensson E. Cerebrospinal fluid concentrations of thioridazine and its main metabolites in psychiatric patients. Eur J Clin Pharmacol. 1981;19(2):139–48.PubMedCrossRef
76.
Cohen BM, Lipinski JF, Waternaux C. A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites. Psychopharmacology. 1989;97(4):481–8.PubMedCrossRef
77.
Alqahtani S, Kaddoumi A. Development of a physiologically based pharmacokinetic/pharmacodynamic model to predict the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics represented by receptor/transporter occupancy of central nervous system drugs. Clin Pharmacokinet. 2016;55(8):957–69.PubMedCrossRef
78.
Li CH, Stratford RE, Velez de Mendizabal N, Cremers TI, Pollock BG, Mulsant BH, et al. Prediction of brain clozapine and norclozapine concentrations in humans from a scaled pharmacokinetic model for rat brain and plasma pharmacokinetics. J Transl Med. 2014;12(1):203.PubMedPubMedCentralCrossRef
79.
Garver DL. Neuroleptic drug levels and antipsychotic effects: a difficult correlation; potential advantage of free (or derivative) versus total plasma levels. J Clin Psychopharmacol. 1989;9(4):277–81.PubMedCrossRef
80.
Wode-Helgodt BB. Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine. Acta Psychiatr Scand. 1978;58(2):149–73.PubMedCrossRef
81.
Rimón R, Averbuch I, Rozick P, Fijman-Danilovich L, Kara T, Dasberg H, et al. Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients. Psychopharmacology. 1981;73(2):197–9.PubMedCrossRef
82.
Kim E, Howes OD, Kim B-H, Jeong JM, Lee JS, Jang I-J, et al. Predicting brain occupancy from plasma levels using PET: superiority of combining pharmacokinetics with pharmacodynamics while modeling the relationship. J Cereb Blood Flow Metab. 2012;32(4):759–68.PubMedCrossRef
83.
Greenblatt DJ, von Moltke LL, Ehrenberg BL, Harmatz JS, Corbett KE, Wallace DW, et al. Kinetics and dynamics of lorazepam during and after continuous intravenous infusion. Crit Care Med. 2000;28(8):2750–7.PubMedCrossRef
84.
85.
Mochida I, Shimosegawa E, Kanai Y, Naka S, Isohashi K, Horitsugi G, et al. Whole-body distribution of donepezil as an acetylcholinesterase inhibitor after oral administration in normal human subjects: a C-donepezil PET study. Asia Ocean J Nucl Med Biol. 2017;5(1):3–9.PubMedPubMedCentral
86.
Valis M, Masopust J, Vysata O, Hort J, Dolezal R, Tomek J, et al. Concentration of donepezil in the cerebrospinal fluid of AD patients: evaluation of dosage sufficiency in standard treatment strategy. Neurotox Res. 2017;31(1):162–8.PubMedCrossRef
87.
Darreh-Shori T, Meurling L, Pettersson T, Hugosson K, Hellström-Lindahl E, Andreasen N, et al. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer’s disease following chronic donepezil treatment. J Neural Transm. 2006;113(11):1791–801.PubMedCrossRef
88.
Kornhuber J, Quack G. Cerebrospinal fluid and serum concentrations of the N-methyl-d-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett. 1995;195(2):137–9.PubMedCrossRef
89.
Rohrig TP, Hicks CA. Brain tissue: a viable postmortem toxicological specimen. J Anal Toxicol. 2015;39(2):137–9.PubMedCrossRef
90.
Noetzli M, Eap CB. Pharmacodynamic, pharmacokinetic and pharmacogenetic aspects of drugs used in the treatment of alzheimer’s disease. Clin Pharmacokinet. 2013;52(4):225–41.PubMedCrossRef
91.
Cutler NR, Polinsky RJ, Sramek JJ, Enz A, Jhee SS, Mancione L, et al. Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer’s disease. Acta Neurol Scand. 1998;97(4):244–50.PubMedCrossRef
92.
93.
Wattmo C, Jedenius E, Blennow K, Wallin AK. Dose and plasma concentration of galantamine in Alzheimer’s disease: clinical application. Alzheimers Res Ther. 2013;5(1):1–9.CrossRef
94.
Fois AF, Brew BJ. The Potential of the CNS as a reservoir for HIV-1 infection: implications for HIV eradication. Curr HIV/AIDS Rep. 2015;12(2):299–303.PubMedCrossRef
95.
Avalos CR, Price SL, Forsyth ER, Pin JN, Shirk EN, Bullock BT, et al. Quantitation of productively infected monocytes and macrophages of simian immunodeficiency virus-infected macaques. J Virol. 2016;90(12):5643–56.PubMedPubMedCentralCrossRef
96.
Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, et al. Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques. Aids. 2017;31(1):5–14.PubMedCrossRef
97.
Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, et al. Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology. 2013;80:1415–23.PubMedPubMedCentralCrossRef
98.
Decloedt EH, Rosenkranz B, Maartens G, Joska J. Central nervous system penetration of antiretroviral drugs: pharmacokinetic, pharmacodynamic and pharmacogenomic considerations. Clin Pharmacokinet. 2015;54(6):581–98.PubMedCrossRef
99.
Letendre S. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65(1):65.PubMedPubMedCentralCrossRef
100.
Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS. 2009;23(11):1359–66.PubMedPubMedCentralCrossRef
101.
Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2012;25(3):357–65.CrossRef
102.
Baker LM, Paul RH, Heaps-Woodruff JM, Chang JY, Ortega M, Margolin Z, et al. The effect of central nervous system penetration effectiveness of highly active antiretroviral therapy on neuropsychological performance and neuroimaging in HIV infected individuals. J Neuroimmune Pharmacol. 2015;10(3):487–92.PubMedPubMedCentralCrossRef
103.
Marra CM. HIV-associated neurocognitive disorders and central nervous system drug penetration: what next? Antivir Ther. 2015;20(4):365–7.PubMedCrossRef
104.
Caniglia EC, Cain LE, Justice A, Tate J, Logan R, Sabin C, et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology. 2014;83(2):134–41.PubMedPubMedCentralCrossRef
105.
Bumpus N, Ma Q, Best B, Moore D, Ellis RJ, Crescini M, et al. Antiretroviral concentrations in brain tissue are similar to or exceed those in CSF. Conference on Retroviruses and Opportunistic Infections. 2015: Seattle.
106.
Srinivas N, Fallon JK, Sykes C, White N. Shiv infection and drug transporters influence brain tissue concentrations of efavirenz. International AIDS Society. 2017: Paris.
107.
108.
Llorens F, Schmitz M, Ferrer I, Zerr I. CSF biomarkers in neurodegenerative and vascular dementias. Prog Neurobiol. 2016;138–140:36–53.PubMedCrossRef
109.
Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimer’s Dement Transl Res Clin Interv. 2017;3(3):367–84.CrossRef
110.
Le Bastard N, Aerts L, Sleegers K, Martin J-J, Van Broeckhoven C, De Deyn PP, et al. Longitudinal stability of cerebrospinal fluid biomarker levels: fulfilled requirement for pharmacodynamic markers in Alzheimer’s disease. J Alzheimer’s Dis. 2013;33(3):807–22.CrossRef
111.
Kielbasa W, Lobo E. Pharmacodynamics of norepinephrine reuptake inhibition: modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans. J Clin Pharmacol. 2015;55(12):1422–31.PubMedCrossRef
112.
McGuire J, Gill A, Douglas S, Kolson D. Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders. J Neurovirol. 2013;19:S57.CrossRef
113.
Gray LR, Brew BJ, Churchill MJ. Strategies to target HIV-1 in the central nervous system. Curr Opin HIV AIDS. 2016;11(4):371–5.PubMedCrossRef
114.
Ball K, Bouzom F, Scherrmann J-M, Walther B, Declèves X. Physiologically based pharmacokinetic modelling of drug penetration across the blood-brain barrier-towards a mechanistic IVIVE-based approach. AAPS J. 2013;15(4):913–32.PubMedPubMedCentralCrossRef
115.
Trapa PE, Belova E, Liras JL, Scott DO, Steyn SJ. Insights from an integrated physiologically based pharmacokinetic model for brain penetration. J Pharm Sci. 2016;105(2):965–71.PubMedCrossRef
116.
Yamamoto Y, Välitalo PA, van den Berg DJ, Hartman R, van den Brink W, Wong YC, et al. A generic multi-compartmental CNS distribution model structure for 9 drugs allows prediction of human brain target site concentrations. Pharm Res. 2017;34(2):333–51.PubMedCrossRef
117.
Liu X, Wong H, Scearce-Levie K, Watts RJ, Coraggio M, Shin YG, et al. Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processings. Drug Metab Dispos. 2013;41(7):1319–28.PubMedCrossRef
118.
119.
Nguyen M, Yang E, Neelkantan N, Mikhaylova A, Arnold R, Poudel MK, et al. Developing “integrative” zebrafish models of behavioral and metabolic disorders. Behav Brain Res. 2013;256:172–87.PubMedCrossRef
120.
121.
Honeycutt JB, Sheridan PA, Matsushima GK, Garcia JV. Humanized mouse models for HIV-1 infection of the CNS. J Neurovirol. 2015;21(3):301–9.PubMedCrossRef
122.
Ito K, Uchida Y, Ohtsuki S, Aizawa S, Kawakami H, Katsukura Y, et al. Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. J Pharm Sci. 2011;100(9):3939–50.PubMedCrossRef
Metadata
Title
Clinical Pharmacokinetics and Pharmacodynamics of Drugs in the Central Nervous System
Authors
Nithya Srinivas
Kaitlyn Maffuid
Angela D. M. Kashuba
Publication date
01-09-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 9/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-0632-y

Other articles of this Issue 9/2018

Clinical Pharmacokinetics 9/2018 Go to the issue

Systematic Review

Augmented Renal Clearance in Critically Ill Patients: A Systematic Review

Original Research Article

Fetal Physiologically-Based Pharmacokinetic Models: Systems Information on Fetal Biometry and Gross Composition

Review Article

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease

Original Research Article

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A

Original Research Article

Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia

Original Research Article

Pharmacokinetics of the B-Cell Lymphoma 2 (Bcl-2) Inhibitor Venetoclax in Female Subjects with Systemic Lupus Erythematosus