ACKNOWLEDGMENTS
The graphical abstract of this manuscript was partly created with BioRender.com.
FUNDING
The project described was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), under Award Number 2UL1TR001425-05A1, and the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledge & Research Coordination Center (KRCC) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under Award Number 1P30HD106451. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and the NICHD. M.W.v.H. was supported by the Rieveschl/Parke-Davis Doctoral Candidacy Scholarship of the University of Cincinnati.
CONFLICT OF INTEREST
T.N.J. is an employee of Certara UK Limited, Simcyp Division. All other authors declared no competing interests for this work.
AUTHOR CONTRIBUTION
M.W.v.H, wrote the manuscript. M.W.v.H, A.A.V., and T.M. designed the research, M.W.v.H, T.N.J, and T.M. performed the research, and M.W.v.H, T.N.J., A.A.V., and T.M. analyzed the data.
REFERENCES
1.      Mattson CL, Tanz LJ, Quinn K, Kariisa M, Patel P, Davis NL. Trends and geographic patterns in drug and synthetic opioid overdose deaths - United States, 2013-2019. MMWR Morb Mortal Wkly Rep. 2021;70:202-7. https://doi.org/10.15585/mmwr.mm7006a4.
2.      Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197:517-32.
3.      Negus SS, Bidlack JM, Mello NK, Furness MS, Rice KC, Brandt MR. Delta opioid antagonist effects of buprenorphine in rhesus monkeys. Behav Pharmacol. 2002;13:557-70. https://doi.org/10.1097/00008877-200211000-00005.
4.      Leander JD. Buprenorphine is a potent kappa-opioid receptor antagonist in pigeons and mice. Eur J Pharmacol. 1988;151:457-61. https://doi.org/10.1016/0014-2999(88)90543-2.
5.      Wnendt S, Krüger T, Janocha E, Hildebrandt D, Englberger W. Agonistic effect of buprenorphine in a nociceptin/OFQ receptor-triggered reporter gene assay. Mol Pharmacol. 1999;56:334-8. https://doi.org/10.1124/mol.56.2.334.
6.      Pergolizzi J, Aloisi AM, Dahan A, Filitz J, Langford R, Likar R, et al. Current knowledge of buprenorphine and its unique pharmacological profile. Pain Pract. 2010;10:428-50. https://doi.org/10.1111/j.1533-2500.2010.00378.x.
7.      Donohue JM, Jarlenski MP, Kim JY, Tang L, Ahrens K, Allen L, et al. Use of medications for treatment of opioid use disorder among US Medicaid enrollees in 11 states, 2014-2018. JAMA. 2021;326:154-64. https://doi.org/10.1001/jama.2021.7374.
8.      Ko JY, D'Angelo DV, Haight SC, Morrow B, Cox S, Salvesen von Essen B, et al. Vital signs: prescription opioid pain reliever use during pregnancy — 34 U.S. jurisdictions, 2019. MMWR Morb Mortal Wkly Rep. 2020;69:897–903. https://doi.org/10.15585/mmwr.mm6928a1.
9.      Hudak ML, Tan RC. Neonatal drug withdrawal. Pediatrics. 2012;129:e540-60. https://doi.org/10.1542/peds.2011-3212.
10.    Wachman EM, Schiff DM, Silverstein M. Neonatal abstinence syndrome: advances in diagnosis and treatment. JAMA. 2018;319:1362-74. https://doi.org/10.1001/jama.2018.2640.
11.    Simon AE, Freund MP, Archer SW, Bremer AA. Toward the use of buprenorphine in infants for neonatal opioid withdrawal syndrome: summary of an NIH workshop. J Perinatol. 2021:1-3. https://doi.org/10.1038/s41372-020-00886-7.
12.    Ng CM, Dombrowsky E, Lin H, Erlich ME, Moody DE, Barrett JS, et al. Population pharmacokinetic model of sublingual buprenorphine in neonatal abstinence syndrome. Pharmacotherapy. 2015;35:670-80. https://doi.org/10.1002/phar.1610.
13.    Mizuno T, McPhail BT, Kamatkar S, Wexelblatt S, Ward L, Christians U, et al. Physiologic indirect response modeling to describe buprenorphine pharmacodynamics in newborns treated for neonatal opioid withdrawal syndrome. Clin Pharmacokinet. 2021;60:249-59. https://doi.org/10.1007/s40262-020-00939-2.
14.    van Hoogdalem MW, McPhail BT, Hahn D, Wexelblatt SL, Akinbi HT, Vinks AA, et al. Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics. Expert Opin Drug Metab Toxicol. 2021;17:87-103. https://doi.org/10.1080/17425255.2021.1837112.
15.    van Hoogdalem MW, Johnson TN, McPhail BT, Kamatkar S, Wexelblatt SL, Ward LP, et al. Physiologically-based pharmacokinetic modeling to investigate the effect of maturation on buprenorphine pharmacokinetics in newborns with neonatal opioid withdrawal syndrome. Clin Pharmacol Ther. 2022;111:496-508. https://doi.org/10.1002/cpt.2458.
16.    Liu AJ, Jones MP, Murray H, Cook CM, Nanan R. Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy. Aust N Z J Obstet Gynaecol. 2010;50:253-8. https://doi.org/10.1111/j.1479-828X.2010.01168.x.
17.    Bakstad B, Sarfi M, Welle-Strand GK, Ravndal E. Opioid maintenance treatment during pregnancy: occurrence and severity of neonatal abstinence syndrome. A national prospective study. Eur Addict Res. 2009;15:128-34. https://doi.org/10.1159/000210042.
18.    Choo RE, Huestis MA, Schroeder JR, Shin AS, Jones HE. Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure. Drug Alcohol Depend. 2004;75:253-60. https://doi.org/10.1016/j.drugalcdep.2004.03.012.
19.    van Hoogdalem MW, Wexelblatt SL, Akinbi HT, Vinks AA, Mizuno T. A review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome. Pharmacol Ther. 2021. https://doi.org/10.1016/j.pharmthera.2021.108045.
20.    Jones HE, Dengler E, Garrison A, O'Grady KE, Seashore C, Horton E, et al. Neonatal outcomes and their relationship to maternal buprenorphine dose during pregnancy. Drug Alcohol Depend. 2014;134:414-7. https://doi.org/10.1016/j.drugalcdep.2013.11.006.
21.    Dashe JS, Sheffield JS, Olscher DA, Todd SJ, Jackson GL, Wendel GD. Relationship between maternal methadone dosage and neonatal withdrawal. Obstet Gynecol. 2002;100:1244-9. https://doi.org/10.1016/s0029-7844(02)02387-6.
22.    Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG. 2009;116:665-71. https://doi.org/10.1111/j.1471-0528.2008.02073.x.
23.    Schuh KJ, Johanson CE. Pharmacokinetic comparison of the buprenorphine sublingual liquid and tablet. Drug Alcohol Depend. 1999;56:55-60. https://doi.org/10.1016/s0376-8716(99)00012-5.
24.    Strain EC, Moody DE, Stoller KB, Walsh SL, Bigelow GE. Relative bioavailability of different buprenorphine formulations under chronic dosing conditions. Drug Alcohol Depend. 2004;74:37-43. https://doi.org/10.1016/j.drugalcdep.2003.11.008.
25.    Chawarski MC, Moody DE, Pakes J, O'Connor PG, Schottenfeld RS. Buprenorphine tablet versus liquid: a clinical trial comparing plasma levels, efficacy, and symptoms. J Subst Abuse Treat. 2005;29:307-12. https://doi.org/10.1016/j.jsat.2005.08.011.
26.    Harris DS, Mendelson JE, Lin ET, Upton RA, Jones RT. Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality. Clin Pharmacokinet. 2004;43:329-40. https://doi.org/10.2165/00003088-200443050-00005.
27.    Nath RP, Upton RA, Everhart ET, Cheung P, Shwonek P, Jones RT, et al. Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations. J Clin Pharmacol. 1999;39:619-23. https://doi.org/10.1177/00912709922008236.
28.    Dong R, Wang H, Li D, Lang L, Gray F, Liu Y, et al. Pharmacokinetics of sublingual buprenorphine tablets following single and multiple doses in Chinese participants with and without opioid use disorder. Drugs R D. 2019;19:255-65. https://doi.org/10.1007/s40268-019-0277-9.
29.    Ciraulo DA, Hitzemann RJ, Somoza E, Knapp CM, Rotrosen J, Sarid-Segal O, et al. Pharmacokinetics and pharmacodynamics of multiple sublingual buprenorphine tablets in dose-escalation trials. J Clin Pharmacol. 2006;46:179-92. https://doi.org/10.1177/0091270005284192.
30.    Kalluri HV, Zhang H, Caritis SN, Venkataramanan R. A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration. Br J Clin Pharmacol. 2017;83:2458-73. https://doi.org/10.1111/bcp.13368.
31.    Zhang H, Kalluri HV, Bastian JR, Chen H, Alshabi A, Caritis SN, et al. Gestational changes in buprenorphine exposure: A physiologically-based pharmacokinetic analysis. Br J Clin Pharmacol. 2018;84:2075-87. https://doi.org/10.1111/bcp.13642.
32.    Silva LL, Silvola RM, Haas DM, Quinney SK. Physiologically based pharmacokinetic modelling in pregnancy: model reproducibility and external validation. Br J Clin Pharmacol. 2021:doi: 10.1111/bcp.15018. https://doi.org/10.1111/bcp.15018.
33.    Johnson TN, Jamei M, Rowland-Yeo K. How does in vivo biliary elimination of drugs change with age? Evidence from in vitro and clinical data using a systems pharmacology approach. Drug Metab Dispos. 2016;44:1090-8. https://doi.org/10.1124/dmd.115.068643.
34.    NCBI. National Center for Biotechnology Information: PubChem Compound Summary for CID 644073, Buprenorphine. 2022. <https://pubchem.ncbi.nlm.nih.gov/compound/644073> Accessed 20 April 2022.
35.    Avdeef A, Barrett DA, Shaw PN, Knaggs RD, Davis SS. Octanol-, chloroform-, and propylene glycol dipelargonat-water partitioning of morphine-6-glucuronide and other related opiates. J Med Chem. 1996;39:4377-81. https://doi.org/10.1021/jm960073m.
36.    Bullingham RE, McQuay HJ, Moore A, Bennett MR. Buprenorphine kinetics. Clin Pharmacol Ther. 1980;28:667-72. https://doi.org/10.1038/clpt.1980.219.
37.    Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet. 2005;44:661-80. https://doi.org/10.2165/00003088-200544070-00001.
38.    Takahashi Y, Ishii S, Arizono H, Nishimura S, Tsuruda K, Saito N, et al. [Pharmacokinetics of buprenorphine hydrochloride (BN•HCl) (1): absorption, distribution, metabolism and excretion after percutaneous (TSN-09: BN•HCl containing tape application) or subcutaneous administration of BN•HCl in rats]. Xenobiot Metab Dispos. 2001;16:569-83. https://doi.org/10.2133/dmpk.16.569.
39.    Hassan HE, Myers AL, Coop A, Eddington ND. Differential involvement of P-glycoprotein (ABCB1) in permeability, tissue distribution, and antinociceptive activity of methadone, buprenorphine, and diprenorphine: in vitro and in vivo evaluation. J Pharm Sci. 2009;98:4928-40. https://doi.org/10.1002/jps.21770.
40.    Holland MJ, Carr KD, Simon EJ. Pharmacokinetics of [3H]-buprenorphine in the rat. Res Commun Chem Pathol Pharmacol. 1989;64:3-16.
41.    Kuhlman JJ, Jr., Lalani S, Magluilo J, Jr., Levine B, Darwin WD. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20:369-78. https://doi.org/10.1093/jat/20.6.369.
42.    Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005;33:689-95. https://doi.org/10.1124/dmd.105.003681.
43.    Chang Y, Moody DE. Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases. Drug Metab Lett. 2009;3:101-7. https://doi.org/10.2174/187231209788654117.
44.    Cubitt HE, Houston JB, Galetin A. Relative importance of intestinal and hepatic glucuronidation-impact on the prediction of drug clearance. Pharm Res. 2009;26:1073-83. https://doi.org/10.1007/s11095-008-9823-9.
45.    Reckitt & Colman Pharmaceuticals. NDA: 20-733 Suboxone® sublingual tablets – Clinical pharmacology/biopharmaceutics review. Richmond, VA: Reckitt & Colman. 2000.
46.    Moore JN, Gastonguay MR, Ng CM, Adeniyi-Jones SC, Moody DE, Fang WB, et al. The pharmacokinetics and pharmacodynamics of buprenorphine in neonatal abstinence syndrome. Clin Pharmacol Ther. 2018;103:1029-37. https://doi.org/10.1002/cpt.1064.
47.    Bullingham RE, McQuay HJ, Porter EJ, Allen MC, Moore RA. Sublingual buprenorphine used postoperatively: ten hour plasma drug concentration analysis. Br J Clin Pharmacol. 1982;13:665-73. https://doi.org/10.1111/j.1365-2125.1982.tb01434.x.
48.    Bai SA, Xiang Q, Finn A. Evaluation of the pharmacokinetics of single- and multiple-dose buprenorphine buccal film in healthy volunteers. Clin Ther. 2016;38:358-69. https://doi.org/10.1016/j.clinthera.2015.12.016.
49.    Lim SCB, Schug S, Krishnarajah J. The pharmacokinetics and local tolerability of a novel sublingual formulation of buprenorphine. Pain Med. 2019;20:143-52. https://doi.org/10.1093/pm/pnx321.
50.    Mendelson J, Upton RA, Everhart ET, Jacob P, 3rd, Jones RT. Bioavailability of sublingual buprenorphine. J Clin Pharmacol. 1997;37:31-7. https://doi.org/10.1177/009127009703700106.
51.    Huestis MA, Cone EJ, Pirnay SO, Umbricht A, Preston KL. Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans. Drug Alcohol Depend. 2013;131:258-62. https://doi.org/10.1016/j.drugalcdep.2012.11.014.
52.    McAleer SD, Mills RJ, Polack T, Hussain T, Rolan PE, Gibbs AD, et al. Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block. Drug Alcohol Depend. 2003;72:75-83. https://doi.org/10.1016/s0376-8716(03)00188-1.
53.    Jönsson M, Mundin G, Sumner M. Pharmacokinetic and pharmaceutical properties of a novel buprenorphine/naloxone sublingual tablet for opioid substitution therapy versus conventional buprenorphine/naloxone sublingual tablet in healthy volunteers. Eur J Pharm Sci. 2018;122:125-33. https://doi.org/10.1016/j.ejps.2018.06.024.
54.    Moody DE, Fang WB, Morrison J, McCance-Katz E. Gender differences in pharmacokinetics of maintenance dosed buprenorphine. Drug Alcohol Depend. 2011;118:479-83. https://doi.org/10.1016/j.drugalcdep.2011.03.024.
55.    Cone EJ, Dickerson SL, Darwin WD, Fudala P, Johnson RE. Elevated drug saliva levels suggest a "depot-like" effect in subjects treated with sublingual buprenorphine. NIDA Res Monogr. 1990;105:569.
56.    Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95:1238-57. https://doi.org/10.1002/jps.20502.
57.    Yassen A, Olofsen E, Romberg R, Sarton E, Teppema L, Danhof M, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007;81:50-8. https://doi.org/10.1038/sj.clpt.6100025.
58.    Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A. Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18:5994-6004. https://doi.org/10.2174/138161212803582469.
59.       Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet. 1997;33:225-44. https://doi.org/10.2165/00003088-199733030-00005.