495
Views
2
CrossRef citations to date
0
Altmetric
Review

The Impact of Pregnancy on Antihypertensive Drug Metabolism and Pharmacokinetics: Current Status and Future Directions

ORCID Icon, , , ORCID Icon, , & ORCID Icon show all
Pages 1261-1279 | Received 19 Jul 2021, Accepted 02 Nov 2021, Published online: 10 Dec 2021

References

  • Shields KE, Lyerly AD. Exclusion of pregnant women from industry-sponsored clinical trials. Obstet Gynecol. 2013;122(5):1077–1081.
  • Gonzalez D, Boggess KA, Cohen-Wolkowiez M. Lessons learned in pediatric clinical research to evaluate safe and effective use of drugs in pregnancy. Obstet Gynecol. 2015;125(4):953–958.
  • Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, et al. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014;211(6):690 e1–11.
  • Eke AC, Dooley KE, Sheffield JS. Pharmacologic research in pregnant women - time to get it right. N Engl J Med. 2019;380(14):1293–1295.
  • Von Dadelszen P, Magee LA. Preventing deaths due to the hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol. 2016;36:83–102.
  • Malha L, August P. Safety of antihypertensive medications in pregnancy: living with uncertainty. J Am Heart Assoc. 2019;8(15):e013495.
  • Virani SS, Alonso A, Aparicio HJ, et al. Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation. 2021;143(8):e254–e743.
  • Roberts JM, Pearson GD, Cutler JA, et al. Summary of the NHLBI Working Group on research on hypertension during pregnancy. Hypertens Pregnancy. 2003;22(2):109–127.
  • ACOG practice bulletin No. 203: chronic hypertension in pregnancy. Obstet Gynecol. 2019;133(1):e26–e50.
  • Kattah AG, Garovic VD. The management of hypertension in pregnancy. Adv Chronic Kidney Dis. 2013;20(3):229–239.
  • Foo L, Tay J, Lees CC, et al. Hypertension in pregnancy: natural history and treatment options. Curr Hypertens Rep. 2015;17(5):36.
  • Al Khaja KA, Sequeira RP, Alkhaja AK, et al. Drug treatment of hypertension in pregnancy: a critical review of adult guideline recommendations. J Hypertens. 2014;32(3):454–463.
  • Isoherranen N, Thummel KE. Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes? Drug Metab Dispos. 2013;41(2):256–262.
  • Gonzalez D, Rao GG, Bailey SC, et al. Precision dosing: public health need, proposed framework, and anticipated impact. Clin Transl Sci. 2017;10(6):443–454.
  • ACOG practice bulletin No. 222: gestational hypertension and preeclampsia. Obstet Gynecol. 2020;135(6):e237–e260.
  • Butwick AJ, Druzin ML, Shaw GM, et al. Evaluation of US state–level variation in hypertensive disorders of pregnancy. JAMA Network Open. 2020;3(10):e2018741–e2018741.
  • Bello NA, Zhou H, Cheetham TC, et al. Prevalence of hypertension among pregnant women when using the 2017 American College of Cardiology/American Heart Association blood pressure guidelines and association with maternal and fetal outcomes. JAMA Network Open. 2021;4(3):e213808.
  • Granger JP, Alexander BT, Bennett WA, et al. Pathophysiology of pregnancy-induced hypertension. Am J Hypertens. 2001;14(6 Pt 2):178s–185s.
  • Brown MA, Magee LA, Kenny LC, et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72(1):24–43.
  • Braunthal S, Brateanu A. Hypertension in pregnancy: pathophysiology and treatment. SAGE Open Med. 2019;7:2050312119843700.
  • Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: a scientific statement from the American Heart Association. Circulation. 2020;141(23):e884–e903.
  • Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ. 2013;347(nov07 15):f6564.
  • Gilbert WM, Young AL, Danielsen B. Pregnancy outcomes in women with chronic hypertension: a population-based study. J Reprod Med. 2007;52(11):1046–1051.
  • Seely EW, Ecker J. Chronic hypertension in pregnancy. Circulation. 2014;129(11):1254–1261.
  • Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epidemiology and etiology. Pediatr Endocrinol Rev. 2009;6(Suppl 3):332–336.
  • Chappell LC, Enye S, Seed P, et al. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension: a prospective study. Hypertension. 2008;51(4):1002–1009.
  • Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet Gynecol. 1994;171(2):410–416.
  • Scott G, Gillon TE, Pels A, et al. Guidelines-similarities and dissimilarities: a systematic review of international clinical practice guidelines for pregnancy hypertension. Am J Obstet Gynecol. 2020 Aug 20 (online ahead of print). DOI:https://doi.org/10.1016/j.ajog.2020.08.018.
  • Committee on Obstetric Practice. Committee opinion No. 692: emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol. 2017;129(4):e90–e95.
  • Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2018;138(17):e426–e483.
  • Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2018;10:CD002252.
  • Magee LA, Von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med. 2015;372(5):407–417.
  • Labetalol package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 Apr 23]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019425s021lbl.pdf
  • Kaye AB, Bhakta A, Moseley AD, et al. Review of cardiovascular drugs in pregnancy. J Womens Health (Larchmt). 2019;28(5):686–697.
  • Nifedipine package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 Apr 12]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/019684s023lbl.pdf
  • Methyldopa package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 Apr 05]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/13400s086lbl.pdf
  • Hydrochlorothiazide package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 May 12]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/040735s004,040770s003lbl.pdf
  • Hydralazine hydrochloride USP package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 May 12]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/1996/008303s068lbl.pdf
  • Clonidine hydrochloride USP package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 May 01]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017407s034lbl.pdf
  • Amlodipine besylate package insert [Internet]. Silver Spring MD): FDA; [Cited 2021 Apr 24]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019787s042lbl.pdf
  • Atenolol package insert [Internet]. Silver Spring (MD): FDA; [Cited 2021 May 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018240s031lbl.pdf
  • Webster LM, Myers JE, Nelson-Piercy C, et al. Labetalol versus nifedipine as antihypertensive treatment for chronic hypertension in pregnancy: a randomized controlled trial. Hypertension. 2017;70(5):915–922.
  • Easterling T, Mundle S, Bracken H, et al. Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trial. Lancet. 2019;394(10203):1011–1021.
  • Magee LA, Group CS, Von Dadelszen P, et al. Control of hypertension in pregnancy study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa? BJOG. 2016;123(7):1135–1141.
  • Bateman BT, Hernandez-Diaz S, Huybrechts KF, et al. Patterns of outpatient antihypertensive medication use during pregnancy in a Medicaid population. Hypertension. 2012;60(4):913–920.
  • Xie RH, Guo Y, Krewski D, et al. Trends in using beta-blockers and methyldopa for hypertensive disorders during pregnancy in a Canadian population. Eur J Obstet Gynecol Reprod Biol. 2013;171(2):281–285.
  • Cleary KL, Siddiq Z, Ananth CV, et al. Use of antihypertensive medications during delivery hospitalizations complicated by preeclampsia. Obstet Gynecol. 2018;131(3):441–450.
  • Anderson GD, Carr DB. Effect of pregnancy on the pharmacokinetics of antihypertensive drugs. Clin Pharmacokinet. 2009;48(3):159–168.
  • Feghali M, Venkataramanan R, Caritis S. Pharmacokinetics of drugs in pregnancy. Semin Perinatol. 2015;39(7):512–519.
  • Tasnif Y, Morado J, Hebert MF. Pregnancy-related pharmacokinetic changes. Clin Pharmacol Ther. 2016;100(1):53–62.
  • Clark SM, Dunn HE, Hankins GD. A review of oral labetalol and nifedipine in mild to moderate hypertension in pregnancy. Semin Perinatol. 2015;39(7):548–555.
  • Dallmann A, Ince I, Coboeken K, et al. A physiologically based pharmacokinetic model for pregnant women to predict the pharmacokinetics of drugs metabolized via several enzymatic pathways. Clin Pharmacokinet. 2018;57(6):749–768.
  • Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach. Clin Pharmacokinet. 2005;44(10):989–1008.
  • Ayad M, Costantine MM. Epidemiology of medications use in pregnancy. Semin Perinatol. 2015;39(7):508–511.
  • Hodge LS, Tracy TS. Alterations in drug disposition during pregnancy: implications for drug therapy. Expert Opin Drug Metab Toxicol. 2007;3(4):557–571.
  • Nakai A, Sekiya I, Oya A, et al. Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography. Arch Gynecol Obstet. 2002;266(1):25–29.
  • Robson SC, Mutch E, Boys RJ, et al. Apparent liver blood flow during pregnancy: a serial study using indocyanine green clearance. BJOG. 1990;97(8):720–724.
  • Hebert MF, Easterling TR, Kirby B, et al. Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clin Pharmacol Ther. 2008;84(2):248–253.
  • Quinney SK, Mohamed AN, Hebert MF, et al. A semi-mechanistic metabolism model of CYP3A substrates in pregnancy: predicting changes in midazolam and nifedipine pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2012;1(9):e2.
  • Ke AB, Nallani SC, Zhao P, et al. A PBPK model to predict disposition of CYP3A-metabolized drugs in pregnant women: verification and discerning the site of CYP3A induction. CPT Pharmacometrics Syst Pharmacol. 2012;1(9):e3.
  • Dallmann A, Pfister M, van Den Anker J, et al. Physiologically based pharmacokinetic modeling in pregnancy: a systematic review of published models. Clin Pharmacol Ther. 2018;104(6):1110–1124.
  • Abduljalil K, Pansari A, Jamei M. Prediction of maternal pharmacokinetics using physiologically based pharmacokinetic models: assessing the impact of the longitudinal changes in the activity of CYP1A2, CYP2D6 and CYP3A4 enzymes during pregnancy. J Pharmacokinet Pharmacodyn. 2020;47(4):361–383.
  • Ruiz ML, Mottino AD, Catania VA, et al. Hormonal regulation of hepatic drug biotransformation and transport systems. Compr Physiol. 2013;3(4):1721–1740.
  • Soldin OP, Guo TD, Weiderpass E, et al. Steroid hormone levels in pregnancy and 1 year postpartum using isotope dilution tandem mass spectrometry. Fertil Steril. 2005;84(3):701–710.
  • Jeong H, Stika CS. Methods to study mechanisms underlying altered hepatic drug elimination during pregnancy. Semin Perinatol. 2020;44(3):151228.
  • Shuster DL, Bammler TK, Beyer RP, et al. Gestational age-dependent changes in gene expression of metabolic enzymes and transporters in pregnant mice. Drug Metab Dispos. 2013;41(2):332–342.
  • Jeong H. Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes. Expert Opin Drug Metab Toxicol. 2010;6(6):689–699.
  • Jeong H, Choi S, Song JW, et al. Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008;38(1):62–75.
  • Koh KH, Jurkovic S, Yang K, et al. Estradiol induces cytochrome P450 2B6 expression at high concentrations: implication in estrogen-mediated gene regulation in pregnancy. Biochem Pharmacol. 2012;84(1):93–103.
  • Sachar M, Kelly EJ, Unadkat JD. Mechanisms of CYP3A induction during pregnancy: studies in HepaRG cells. AAPS J. 2019;21(3):45.
  • Choi SY, Koh KH, Jeong H. Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013;41(2):263–269.
  • Dickmann LJ, Isoherranen N. Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy. Drug Metab Dispos. 2013;41(2):270–274.
  • Papageorgiou I, Grepper S, Unadkat JD. Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines. Drug Metab Dispos. 2013;41(2):281–290.
  • Zhang Z, Farooq M, Prasad B, et al. Prediction of gestational age-dependent induction of in vivo hepatic CYP3A activity based on HepaRG cells and human hepatocytes. Drug Metab Dispos. 2015;43(6):836–842.
  • Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol. 2015;28(1):38–42.
  • Khatri R, Kulick N, Rementer RJB, et al. Pregnancy-related hormones increase nifedipine metabolism in human hepatocytes by inducing CYP3A4 expression. J Pharm Sci. 2021;110(1):412–421.
  • Chen S, Yueh MF, Evans RM, et al. Pregnane-x-receptor controls hepatic glucuronidation during pregnancy and neonatal development in humanized UGT1 mice. Hepatology. 2012;56(2):658–667.
  • Liao MZ, Gao C, Phillips BR, et al. Pregnancy increases norbuprenorphine clearance in mice by induction of hepatic glucuronidation. Drug Metab Dispos. 2018;46(2):100–108.
  • Chen H, Yang K, Choi S, et al. Up-regulation of UDP-glucuronosyltransferase (UGT) 1A4 by 17beta-estradiol a potential mechanism of increased lamotrigine elimination in pregnancy. Drug Metab Dispos. 2009;37(9):1841–1847.
  • Khatri R, Fallon JK, Sykes C, et al. Pregnancy-related hormones increase UGT1A1-mediated labetalol metabolism in human hepatocytes. Front Pharmacol. 2021;12:655320.
  • Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part II. Clin Pharmacokinet. 1998;35(1):9–36.
  • Rubin PC, Butters L, Kelman AW, et al. Labetalol disposition and concentration-effect relationships during pregnancy. Br J Clin Pharmacol. 1983;15(4):465–470.
  • Rogers RC, Sibai BM, Whybrew WD. Labetalol pharmacokinetics in pregnancy-induced hypertension. Am J Obstet Gynecol. 1990;162(2):362–366.
  • Saotome T, Minoura S, Terashi K, et al. Labetalol in hypertension during the third trimester of pregnancy: its antihypertensive effect and pharmacokinetic-dynamic analysis. J Clin Pharmacol. 1993;33(10):979–988.
  • Carvalho TM, Cavalli Rde C, Cunha SP, et al. Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients. Eur J Clin Pharmacol. 2011;67(1):55–61.
  • Johnson JA, Akers WS, Herring VL, et al. Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs. Pharmacotherapy. 2000;20(6):622–628.
  • Fischer JH, Sarto GE, Hardman J, et al. Influence of gestational age and body weight on the pharmacokinetics of labetalol in pregnancy. Clin Pharmacokinet. 2014;53(4):373–383.
  • Ohman I, Beck O, Vitols S, et al. Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy. Epilepsia. 2008;49(6):1075–1080.
  • Ohman I, Luef G, Tomson T. Effects of pregnancy and contraception on lamotrigine disposition: new insights through analysis of lamotrigine metabolites. Seizure. 2008;17(2):199–202.
  • Pennell PB, French JA, May RC, et al. Changes in seizure frequency and antiepileptic therapy during pregnancy. N Engl J Med. 2020;383(26):2547–2556.
  • Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of vasodilators. Part I. Clin Pharmacokinet. 1998;34(6):457–482.
  • Krecic-Shepard ME, Park K, Barnas C, et al. Race and sex influence clearance of nifedipine: results of a population study. Clin Pharmacol Ther. 2000;68(2):130–142.
  • Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48(3):143–157.
  • Prevost RR, Akl SA, Whybrew WD, et al. Oral nifedipine pharmacokinetics in pregnancy-induced hypertension. Pharmacotherapy. 1992;12(3):174–177.
  • Barton JR, Prevost RR, Wilson DA, et al. Nifedipine pharmacokinetics and pharmacodynamics during the immediate postpartum period in patients with preeclampsia. Am J Obstet Gynecol. 1991;165(4 Pt 1):951–954.
  • Ter Laak MA, Roos C, Touw DJ, et al. Pharmacokinetics of nifedipine slow-release during sustained tocolysis. Int J Clin Pharmacol Ther. 2015;53(1):84–91.
  • Haas DM, Quinney SK, Clay JM, et al. Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic. Am J Perinatol. 2013;30(4):275–281.
  • Juon AM, Kühn-Velten WN, Burkhardt T, et al. Nifedipine gastrointestinal therapeutic system (GITS) as an alternative to slow-release for tocolysis–tolerance and pharmacokinetic profile. Eur J Obstet Gynecol Reprod Biol. 2008;140(1):27–32.
  • Foster TS, Hamann SR, Richards VR, et al. Nifedipine kinetics and bioavailability after single intravenous and oral doses in normal subjects. J Clin Pharmacol. 1983;23(4):161–170.
  • Filgueira GCO, Filgueira OAS, Carvalho DM, et al. Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women. Br J Clin Pharmacol. 2017;83(7):1571–1579.
  • Pirhonen JP, Erkkola RU, Ekblad UU, et al. Single dose of nifedipine in normotensive pregnancy: nifedipine concentrations, hemodynamic responses, and uterine and fetal flow velocity waveforms. Obstet Gynecol. 1990;76(5 Pt 1):807–811.
  • Ferguson JE, Schutz T, Pershe R, et al. Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol. 1989;161(6):1485–1490.
  • Marin TZ, Meier R, Kraehenmann F, et al. Nifedipine serum levels in pregnant women undergoing tocolysis with nifedipine. J Obstet Gynaecol. 2007;27(3):260–263.
  • Papatsonis DN, Bos JM, van Geijn HP, et al. Nifedipine pharmacokinetics and plasma levels in the management of preterm labor. Am J Ther. 2007;14(4):346–350.
  • Silberschmidt AL, Kuhn-Velten WN, Juon AM, et al. Nifedipine concentration in maternal and umbilical cord blood after nifedipine gastrointestinal therapeutic system for tocolysis. BJOG. 2008;115(4):480–485.
  • Myhre E, Rugstad HE, Hansen T. Clinical pharmacokinetics of methyldopa. Clin Pharmacokinet. 1982;7(3):221–233.
  • Campbell NR, Sundaram RS, Werness PG, et al. Sulfate and methyldopa metabolism: metabolite patterns and platelet phenol sulfotransferase activity. Clin Pharmacol Ther. 1985;37(3):308–315.
  • Filgueira GC, Filgueira OA, Carvalho DM, et al. Analysis of nifedipine in human plasma and amniotic fluid by liquid chromatography-tandem mass spectrometry and its application to clinical pharmacokinetics in hypertensive pregnant women. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;993-994:20–25.
  • Han LW, Ryu RJ, Cusumano M, et al. Effect of N-Acetyltransferase 2 genotype on the pharmacokinetics of hydralazine during pregnancy. J Clin Pharmacol. 2019;59(12):1678–1689.
  • Gonçalves PVB, Moreira FL, Benzi JRL, et al. A pilot study of the maternal-fetal pharmacokinetics of furosemide in plasma, urine, and amniotic fluid of hypertensive parturient women under cesarean section. J Clin Pharmacol. 2020;60(12):1655–1661.
  • Morgan JL, Kogutt BK, Meek C, et al. Pharmacokinetics of amlodipine besylate at delivery and during lactation. Pregnancy Hypertens. 2018;11:77–80.
  • Hurst AK, Shotan A, Hoffman K, et al. Pharmacokinetic and pharmacodynamic evaluation of atenolol during and after pregnancy. Pharmacotherapy. 1998;18(4):840–846.
  • Thorley KJ, McAinsh J, Cruickshank JM. Atenolol in the treatment of pregnancy-induced hypertension. Br J Clin Pharmacol. 1981;12(5):725–730.
  • Claessens AJ, Risler LJ, Eyal S, et al. CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance. Drug Metab Dispos. 2010;38(9):1393–1396.
  • Buchanan ML, Easterling TR, Carr DB, et al. Clonidine pharmacokinetics in pregnancy. Drug Metab Dispos. 2009;37(4):702–705.
  • Ke AB, Nallani SC, Zhao P, et al. A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women. Drug Metab Dispos. 2013;41(4):801–813.
  • Mulder EG, Ghossein-Doha C, Cauffman E, et al. Preventing recurrent preeclampsia by tailored treatment of nonphysiologic hemodynamic adjustments to pregnancy. Hypertension. 2021;77(6):2045–2053.
  • Zhou X, Mayer-Hamblett N, Khan U, et al. Residual weighted learning for estimating individualized treatment rules. J Am Stat Assoc. 2017;112(517):169–187.
  • Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med. 2005;24(10):1455–1481.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.