View source for Thiotepa

{{Short description|Chemical compound}}
{{Use dmy dates|date=April 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| solubility = 0.19 g/mL (water, 25 °C) <br />
Freely soluble in alcohol, diethyl ether and chloroform
| verifiedrevid = 413808890
| imageL = ThioTEPA.svg
| imageR = Thiotepa-from-xtal-Mercury-3D-balls.png
| widthL = 100
| widthR = 150
| altL = 
| altR = <!-- Clinical data -->
| tradename = Tepadina
| Drugs.com = {{drugs.com|monograph|thiotepa}}
| MedlinePlus = a682821
| DailyMedID = Thiotepa
| pregnancy_AU = D
| routes_of_administration = [[Intravenous therapy|Intravenous]], [[intracavitary]], [[Intravesical drug delivery|intravesical]]
| ATC_prefix = L01
| ATC_suffix = AC01
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Tepadina (Link Medical Products Pty Ltd T/A Link Pharmaceuticals) | website=Therapeutic Goods Administration (TGA) | date=28 September 2022 | url=https://www.tga.gov.au/resources/prescription-medicines-registrations/tepadina-link-medical-products-pty-ltd-ta-link-pharmaceuticals | access-date=29 April 2023 | archive-date=18 March 2023 | archive-url=https://web.archive.org/web/20230318072339/https://www.tga.gov.au/resources/prescription-medicines-registrations/tepadina-link-medical-products-pty-ltd-ta-link-pharmaceuticals | url-status=live }}</ref>
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Cancer therapies | website=[[Health Canada]] | date=8 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/cancer-therapies.html | access-date=13 April 2024}}</ref>
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Thiotepa 100 mg powder for concentrate for solution for infusion | website=(emc) | date=27 October 2022 | url=https://www.medicines.org.uk/emc/product/14220/smpc | access-date=14 August 2024}}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref name="Tepadina FDA label">{{cite web | title=Tepadina- thiotepa injection, powder, for solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=559e353c-2dc0-16ba-e054-00144ff8d46c | access-date=11 August 2021 | archive-date=12 August 2021 | archive-url=https://web.archive.org/web/20210812052344/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=559e353c-2dc0-16ba-e054-00144ff8d46c | url-status=live }}</ref><ref name="Tepylute FDA label">{{Cite web | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216984s000lbl.pdf | title=Highlights of prescribing information | website=www.accessdata.fda.gov}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Tepadina EPAR">{{cite web | title=Tepadina EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tepadina | access-date=30 April 2021 | archive-date=6 March 2021 | archive-url=https://web.archive.org/web/20210306124859/https://www.ema.europa.eu/en/medicines/human/EPAR/tepadina | url-status=live }}</ref>

<!-- Pharmacokinetic data -->| bioavailability = 
| metabolism = [[Liver]] ([[CYP2B6]], [[CYP3A]])
| metabolites = Phase 1: Tetraethylenepentamine (tepa) <br />
Phase 2: Thiotepa-mercapturate
| elimination_half-life = 1.5–4.1 hours
| excretion = [[Kidney]]<br />6 hours for thiotepa<br />8 hours for TEPA

<!-- Identifiers -->| IUPHAR_ligand = 7622
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 52-24-4
| PubChem = 5453
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB04572
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5254
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 905Z5W3GKH
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00583
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| synonyms = N,N',N<nowiki>''</nowiki>(-triethylenethiophosphoramide, INN, Thiotepa, Tepadina, Tepylute
| ChEMBL = 671

<!-- Chemical data -->| drug_name = Thiotepa
| type = Alkylating agent
| IUPAC_name = 1,1{{prime}},1{{pprime}}-Phosphorothioyltriaziridine
| C = 6
| H = 12
| N = 3
| P = 1
| S = 1
| smiles = S=P(N1CC1)(N2CC2)N3CC3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| melting_point = 51.5
| StdInChI = 1S/C6H12N3PS/c11-10(7-1-2-7,8-3-4-8)9-5-6-9/h1-6H2
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FOCVUCIESVLUNU-UHFFFAOYSA-N
}}

'''Thiotepa''' (N,N',N<nowiki>''</nowiki>(-triethylenethiophosphoramide, [[International nonproprietary name|INN]]<ref name="INN">{{cite web | title = International Non-Proprietary Names for Pharmaceutical Preparations. Recommended International Non-Proprietary Names (Rec. I.N.N.): List 4 | url = https://www.who.int/medicines/publications/druginformation/innlists/RL04.pdf | publisher = World Health Organization | access-date = 27 November 2016 | page = 111 | date = March 1962 | archive-date = 18 May 2016 | archive-url = https://web.archive.org/web/20160518192639/http://www.who.int/medicines/publications/druginformation/innlists/RL04.pdf | url-status = dead }}</ref>), sold under the brand name '''Tepadina''' among others, is an [[anti-cancer medication]].<ref name="Tepadina FDA label" /><ref name="Tepadina EPAR" /><ref name="FDA" />

Thiotepa is an [[organophosphorus compound]] with the formula (C<sub>2</sub>H<sub>4</sub>N)<sub>3</sub>PS.<ref name="Maanen2000">{{cite journal | vauthors = Maanen MJ, Smeets CJ, Beijnen JH | title = Chemistry, pharmacology and pharmacokinetics of N,N',N" -triethylenethiophosphoramide (ThioTEPA) | journal = Cancer Treatment Reviews | volume = 26 | issue = 4 | pages = 257–268 | date = August 2000 | pmid = 10913381 | doi = 10.1053/ctrv.2000.0170 }}</ref>

== History ==
Thiotepa and its synthesis were patented in [[1952]] by the [[American Cyanamid]] company. It was made for use in the [[textile industry]] and in the production process of [[plastics]]. However, thiotepa entered human trials in [[1953]] and was found to be effective against [[acute myeloid leukemia]], [[chronic myelogenous leukemia]], and [[Hodgkin's lymphoma]]. The first clinical trial noted a "reasonable margin for safety" between the apparent dose and undesired [[bone marrow suppression]]<ref>{{Cite journal |vauthors=Gallagher SM |year=2014 |title=From the battlefield to the bladder: The development of thioTEPA |journal=World Journal of Clinical Urology |volume=3 |issue=3 |pages=195 |doi=10.5410/wjcu.v3.i3.195 |doi-access=free}}</ref>

In January 2007, the [[European Medicines Agency]] (EMA) designated thiotepa as an [[orphan drug]]. In April 2007, the United States FDA designated thiotepa as a conditioning treatment for use prior to [[hematopoietic stem cell transplantation]].<ref>{{cite web |date=19 March 2010 |title=EMA Grants Adienne Marketing Rights for Tepadina |url=http://www.dddmag.com/news-EMA-Grants-Adienne-Marketing-Rights-for-Tepadina-31910.aspx |access-date=25 November 2011 |publisher=Drug Discovery & Development}}</ref>

In June 2024, the FDA approved a ready-to-dilute liquid formulation of thiotepa to treat breast and [[ovarian cancer]].<ref>{{Cite press release |title=Shorla Oncology Announces FDA Approval for Tepylute, A Novel Formulation to Treat Breast and Ovarian Cancer |date=28 June 2024 |publisher=Shorla Oncology |url=https://www.businesswire.com/news/home/20240628930127/en/Shorla-Oncology-Announces-FDA-Approval-for-TEPYLUTE-A-Novel-Formulation-to-Treat-Breast-and-Ovarian-Cancer |via=Business Wire}}</ref>

== Structure ==  
Thiotepa consists of three [[aziridine]] rings (also known as [[ethylenimine]]s), which are cyclic compounds containing two carbon atoms and one nitrogen atom, all bonded to a [[phosphine sulfide]] group. The phosphine sulfide acts as an activating group, activating the aziridine groups.<ref name="Maanen2000" />

== Reactivity ==  
Thiotepa is a reactive compound that, under [[acid]]ic, neutral, or [[alkaline]] conditions, undergoes [[solvolysis]], leading to potential side reactions such as [[polymerization]] and dimerization into [[piperazine]]s. During acidic degradation, thiotepa reacts with [[chloride]] ions to produce monochloro, dichloro, and trichloro derivatives. Acidic conditions also result in the formation of tepa (N,{{prime|N}},N{{pprime}}-triethylenephosphoramide), the first identified and more reactive [[metabolite]] of thiotepa.<ref name="Maanen2000" />

In alkaline media, thiotepa undergoes degradation, though no detectable byproducts were identified. Like other aziridine-containing compounds, [[hydroxyl]] substitution reactions may release aziridine. This degradation pathway has also been reported for tepa. The stability of thiotepa in biological samples is dependent on [[pH]]. In [[blood plasma|plasma]], the monochloro derivative of thiotepa is formed, while in [[urine]], both monochloro and dichloro derivatives have been found. Thiotepa is most stable between pH 7 and 11. In plasma under [[physiological]] conditions, the compound has a half-life of five days, whereas in urine at 37&nbsp;°C, the half-life is 16 minutes at pH 4 and 21 hours at pH 6.<ref name="Maanen2000" />

== Synthesis ==  
Two separate syntheses of thiotepa have been described in literature. The most prevalent method involves the addition of an excess of aziridine to [[thiophosphoryl chloride]] in the presence of a base such as [[triethylamine]] (TEA) (or another molar equivalent of aziridine) and a suitable solvent (e.g., [[ether]] or [[benzene]]). The first molecule of aziridine reacts with thiophosphoryl chloride to produce dichloridophosphorothionate, which is sufficiently reactive due to the poor overlap of the nitrogen lone pair with the P=S bond, allowing it to react with another two molecules of aziridine <ref name="Timperley2015">{{Cite book | vauthors = Timperley CM, Cooper N |chapter=Thiophosphoryl Compounds |title=Best Synthetic Methods |publisher=Elsevier |year=2015 |pages=563–632 |doi=10.1016/B978-0-08-098212-0.00005-4|isbn=978-0-08-098212-0 }}</ref>
[[File:Thiotepa_synthesis_via_thiophosphoryl_chloride_and_aziridine.png|center|frameless|450x450px|Thiotepa synthesis via thiophosphoryl chloride and aziridine]]
Thiotepa has also been synthesized from [[phosphorus trichloride]] and six molar equivalents of aziridine. The trivalent triamide formed reacts with [[Octasulfur|octasulfur (S<sub>8</sub>)]] in [[benzene]].<ref name="Timperley2015" />

== Medical uses ==
Thiotepa is used in combination with other [[chemotherapy]] agents to treat [[cancer]]. It can be given with or without [[total body irradiation]] (TBI) to prepare the body for [[hematopoietic stem cell transplantation|allogeneic or autologous hematopoietic progenitor cell transplantation]] (HPCT), which replaces damaged [[hematopoiesis|blood-forming cells]] with donor cells. This treatment is used in both adults and children for [[hematologic malignancy|blood cancers]] such as [[Hodgkin lymphoma]] and [[leukemia]]. Thiotepa is also used with high-dose chemotherapy and HPCT support to treat certain [[solid tumor]]s in adults and children.<ref name="EMA">{{cite web |title=Tepadina EPAR |website=[[European Medicines Agency]] (EMA) |date=6 May 2010 |url=https://www.ema.europa.eu/en/medicines/human/EPAR/tepadina |access-date=14 March 2025}}</ref><ref name="FDA">{{cite web |title=URGENT – THIOTEPA UPDATE |website=[[U.S. Food and Drug Administration]] (FDA) |date=25 November 2011 |url=https://www.fda.gov/media/80551/download |archive-url=https://web.archive.org/web/20200919062957/https://www.fda.gov/media/80551/download |url-status=dead |archive-date=19 September 2020 |access-date=14 March 2025}}</ref>

Thiotepa is used in [[palliative care]] for several types of cancer, including [[breast cancer]], [[ovarian cancer]], [[papillary thyroid cancer]], and [[bladder cancer]]. It is also used to control intracavitary effusions caused by [[serosa|serosal]] neoplastic deposits, which refers to fluid buildup resulting from cancer spreading to the lining of body cavities.<ref name="FDA" />

In [[Japan]], a widely used regimen consisting of high-dose thiotepa and [[melphalan]], followed by autologous [[peripheral blood stem cell transplantation|peripheral blood stem cell rescue]], is used to treat [[neuroblastoma|high-risk neuroblastoma]].<ref>{{cite journal | vauthors = Yamazaki F, Yamasaki K, Kiyotani C, Hashii Y, Shioda Y, Hara J, Matsumoto K | title = Thiotepa-melphalan myeloablative therapy for high-risk neuroblastoma | journal = Pediatric Blood & Cancer | volume = 68 | issue = 6 | pages = e28896 | date = June 2021 | pmid = 33788375 | doi = 10.1002/pbc.28896 }}</ref>

=== Administration ===
Thiotepa is mainly administered [[Intravenous therapy|intravenously]] and [[Intravesical drug delivery|intravesically]]. The administered dose regarding different types of cancer variates between 3&nbsp;mg/kg/day to 13&nbsp;mg/kg/day.<ref name="Tepadina EPAR" /> Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa from being administered orally. Thiotepa is also used in the treatment of bladder cancer during this treatment thiotepa is used as intravesical chemotherapy. Thiotepa is frequently administered in combination with other [[chemotherapeutic agents]] such as [[busulfan]] and [[carboplatin]].<ref name=":0">{{cite web | title = Thiotepa for Injection USP | work = SteriMax Inc. | date = 5 April 2022 | url = https://pdf.hres.ca/dpd_pm/00065923.PDF }}</ref>

=== Clinical outcomes ===
In clinical trials the outcome of different types of treatment is compared to identify if a compound or regimen is favourable for the patient. The choice of treatment in the conditioning therapy can have a profound impact on progression-free survival (PNS), overall survival (OS), relapse incidence (RI) and non-relapse mortality (NRM). The studies mentioned summarize key findings comparing various conditioning regimens.

Studies on conditioning regimens for [[hematopoietic cell]] transplant in primary [[central nervous system]] lymphoma (PCNSL) have shown that thiotepa based therapies thiotepa/busulfan/[[cyclophosphamide]] (TBC) and thiotepa/[[carmustine]] (TT-BCNU) improve progression-free survival of PCNSL compared to traditional therapies carmustine/[[etoposide]]/[[cytarabine]]/melphalan (BEAM). Research also suggests that in BEAM if carmustine is exchanged for thiotepa no statistical difference was found in PFS, OS and RI. Furthermore, the capacity of thiotepa to pass the blood-brain barrier may allow optimizing the therapy for patients with Central Nervous System involvement of increased CNS relapse risk.<ref>{{cite journal | vauthors = Scordo M, Wang TP, Ahn KW, Chen Y, Ahmed S, Awan FT, Beitinjaneh A, Chen A, Chow VA, Dholaria B, Epperla N, Farooq U, Ghosh N, Grover N, Hamad N, Hildebrandt GC, Holmberg L, Hong S, Inwards DJ, Jimenez-Jimenez A, Karmali R, Kenkre VP, Khimani F, Klyuchnikov E, Krem MM, Munshi PN, Nieto Y, Prestidge T, Ramakrishnan Geethakumari P, Rezvani AR, Riedell PA, Seo S, Shah NN, Solh M, Yared JA, Kharfan-Dabaja MA, Herrera A, Hamadani M, Sauter CS | title = Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant | journal = JAMA Oncology | volume = 7 | issue = 7 | pages = 993–1003 | date = July 2021 | pmid = 33956047 | pmc = 8283558 | doi = 10.1001/jamaoncol.2021.1074 }}</ref><ref>{{cite journal | vauthors = Sellner L, Boumendil A, Finel H, Choquet S, de Rosa G, Falzetti F, Scime R, Kobbe G, Ferrara F, Delmer A, Sayer H, Amorim S, Bouabdallah R, Finke J, Salles G, Yakoub-Agha I, Faber E, Nicolas-Virelizier E, Facchini L, Vallisa D, Zuffa E, Sureda A, Dreger P | title = Thiotepa-based high-dose therapy for autologous stem cell transplantation in lymphoma: a retrospective study from the EBMT | journal = Bone Marrow Transplantation | volume = 51 | issue = 2 | pages = 212–218 | date = February 2016 | pmid = 26569093 | doi = 10.1038/bmt.2015.273 }}</ref> Another study compared [[total body irradiation]] (TBI) and thiotepa, busulfan and cyclophosphamide/[[fludarabine]] (TTB) as a conditioning regiment of patients with [[acute lymphoblastic leukemia]] undergoing allogenic hematopoietic stem cell transplantation. No statistical difference was found in the overall survival but the RI was higher in the TBI regimen but the NRM was lower with TTB suggesting that TBB might be a viable alternative to TBI.<ref>{{cite journal | vauthors = Mora E, Montoro J, Balaguer A, Rovira M, Cabrero M, Heras I, Ribera JM, Antelo G, Martin AA, Lopez Godino O, Torrent A, Villalba M, Chorao P, Sanz MA, Sanz J | title = Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia | journal = Bone Marrow Transplantation | volume = 59 | issue = 8 | pages = 1137–1145 | date = August 2024 | pmid = 38755458 | doi = 10.1038/s41409-024-02298-z }}</ref>

== Metabolism ==
[[File:Thiotepa_metabolism.png|thumb|348x348px|Biotransformation of thiotepa, (a) thiotepa, (b) tepa, (c) monochlorotepa, (d) GSH conjugate of thioTEPA, (e) thiotepacysteinate, (f) thiotepa-mercapturate.]]
The metabolism of thiotepa primarily takes place in the liver, following both phase 1 and phase 2 [[metabolic pathway]]s. Phase 1 involves reactions which change chemical moieties such as oxidation, reduction, and hydrolysis, while phase 2 includes the addition of endogenous groups to foreign compounds.<ref name=":1">{{Cite book | vauthors = Timbrell JA |title=Principles of biochemical toxicology |date=2009 |publisher=Informa healthcare |isbn=978-0-8493-7302-2 |edition=4th |location=New York}}</ref>

Phase 1 metabolism of thiotepa is predominantly mediated by the [[cytochrome P450]] enzyme system, major [[CYP2B6]] and minor [[CYP3A4]]. In this phase an oxidation and desulfuration reactions convert thiotepa into its more active metabolite tepa.<ref name="Maanen2000" /><ref name=":2">{{cite journal | vauthors = Jacobson PA, Green K, Birnbaum A, Remmel RP | title = Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA | journal = Cancer Chemotherapy and Pharmacology | volume = 49 | issue = 6 | pages = 461–467 | date = June 2002 | pmid = 12107550 | doi = 10.1007/s00280-002-0453-3 }}</ref> Tepa itself exhibits a longer plasma half-life (3 to 24 hours) than thiotepa (1 to 3 hours) and contributes to the overall pharmacological activity of the drug.<ref>{{Citation | vauthors = Howard MD |title=Thiotepa |date=2005 |encyclopedia=Encyclopedia of Toxicology |pages=175–177 |url=https://linkinghub.elsevier.com/retrieve/pii/B0123694000009431 |access-date=2025-03-15 |publisher=Elsevier |language=en |doi=10.1016/b0-12-369400-0/00943-1 |isbn=978-0-12-369400-3|url-access=subscription }}</ref>

In phase 2 thiotepa is detoxified via the conjugation with [[glutathione]] by [[glutathione S-transferase]].<ref name="Maanen2000" /><ref name=":3">{{cite journal | vauthors = Mathias PI, B'hymer C | title = Mercapturic acids: recent advances in their determination by liquid chromatography/mass spectrometry and their use in toxicant metabolism studies and in occupational and environmental exposure studies | journal = Biomarkers | volume = 21 | issue = 4 | pages = 293–315 | date = 2016-05-18 | pmid = 26900903 | pmc = 4894522 | doi = 10.3109/1354750X.2016.1141988 }}</ref> This is followed by the removal of the [[glutamyl]] and [[glycine]] moieties, and concludes with the N-acetylation of the [[cysteine]] conjugate by N-acetylase to form thiotepa-mercapturate. This derivative is more water-soluble, facilitating urinary excretion.<ref name=":3" /> Tepa is not conjugated to glutathione but reacts further in the urine and plasma  to monochloro tepa. The conversion to a β-chloroethyl moiety depends on the pH and the chloride concentration. The formation of monochloride tepa mainly occurs in the urine.<ref>{{cite journal | vauthors = van Maanen MJ, Tijhof IM, Damen JM, Versluis C, van den Bosch JJ, Heck AJ, Rodenhuis S, Beijnen JH | title = A search for new metabolites of N,N',N{{'}}{{'}}-triethylenethiophosphoramide | journal = Cancer Research | volume = 59 | issue = 18 | pages = 4720–4724 | date = September 1999 | pmid = 10493531 | url = https://pubmed.ncbi.nlm.nih.gov/10493531 }}</ref>

Enzymes responsible for metabolising compounds can show varying efficiency in different individuals or populations, this is called [[Gene polymorphism|polymorphism]]. In a study regarding thiotepa metabolism by Ekhart et al., it was found that glutathione S-transferase shows polymorphism. This variation resulted in some patients in slower glutathione conjugation and consequently, to a 45% increase in combined exposure to thiotepa and tepa''.''<ref>{{cite journal | vauthors = Ekhart C, Doodeman VD, Rodenhuis S, Smits PH, Beijnen JH, Huitema AD | title = Polymorphisms of drug-metabolizing enzymes (GST, CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa | journal = British Journal of Clinical Pharmacology | volume = 67 | issue = 1 | pages = 50–60 | date = January 2009 | pmid = 19076156 | pmc = 2668084 | doi = 10.1111/j.1365-2125.2008.03321.x }}</ref>

The [[volume of distribution]] has been reported to range from 40,8 L/m<sup>2</sup> to 75,0 L/m<sup>2</sup>.<ref name="Tepadina EPAR" /> This high value is due to the highly [[Lipophilicity|lipophilic]] character of thiotepa and can therefore easily cross cell membranes and distribute into fatty tissues. In addition, thiotepa can easily cross the [[Blood–brain barrier|blood brain barrier]] and can rapidly penetrate the central nervous system.<ref>{{cite journal | vauthors = Hara J, Matsumoto K, Maeda N, Takahara-Matsubara M, Sugimoto S, Goto H | title = High-dose thiotepa, in conjunction with melphalan, followed by autologous hematopoietic stem cell transplantation in patients with pediatric solid tumors, including brain tumors | journal = Bone Marrow Transplantation | volume = 58 | issue = 2 | pages = 123–128 | date = February 2023 | pmid = 36329150 | pmc = 9902273 | doi = 10.1038/s41409-022-01820-5 }}</ref><ref>{{cite web | work = BC Cancer Drug Manual | title = Thiotepa Monograph | publisher = BC Cancer Provincial Pharmacy | date = 1 December 2024 | url = http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Thiotepa_monograph.pdf }}</ref> In plasma, 70 to 90% of the compound remains unbound to proteins, while the remaining 10–30% is primarily bound to [[gamma globulin]], with minimal binding to [[albumin]].<ref name="EMA" /> Gamma globulin primarily functions as antibodies for the immune system,<ref>{{cite journal | vauthors = Furr M, Pontzer C, Gasper P | title = Lymphocyte phenotype subsets in the cerebrospinal fluid of normal horses and horses with equine protozoal myeloencephalitis | journal = Veterinary Therapeutics | volume = 2 | issue = 4 | pages = 317–324 | date = 2008 | pmc = 7150067 | doi = 10.1016/b978-0-12-370491-7.00026-x | publisher = Elsevier | isbn = 978-0-12-370491-7 }}</ref> while albumin serves as a transport protein.<ref>{{Cite journal | vauthors = Hutapea TP, Madurani KA, Syahputra MY, Hudha MN, Asriana AN, Kurniawan F |date=June 2023 |title=Albumin: Source, preparation, determination, applications, and prospects |url=https://linkinghub.elsevier.com/retrieve/pii/S2468217923000187 |journal=Journal of Science: Advanced Materials and Devices |language=en |volume=8 |issue=2 |pages=100549 |doi=10.1016/j.jsamd.2023.100549|doi-access=free }}</ref>

All metabolites are excreted in the urine, which is nearly complete in 6 to 8 hours, with tepa and thiotepa-mercapturate each accounting for approximately 11.1% of the excretion. In contrast, the excretion of monochloride tepa and thiotepa is significantly lower, at only 0.5% each.<ref name="Maanen2000" /><ref name="EMA" /> The total clearance of thiotepa ranged from 11,4 to 23,2 L/h/m<sup>2</sup>.<ref name="EMA" /> The total excretion of thiotepa and its identified metabolites accounts for 54 to 100% of the total [[Alkylation|alkylating activity]], suggesting the existence of other alkylating metabolites. During the conversion of glutathione conjugates into N-acetylcysteine conjugates, intermediates such as glutathione, cysteinyl glycine, and cysteine conjugates are formed. These metabolites are not detected in urine and, if formed, are likely excreted in bile or rapidly converted into thiotepa-mercapturate.<ref name="Maanen2000" /> Additionally, due to its high lipophilicity, thiotepa is excreted in minor amounts by the skin via sweat.<ref name=":4">{{cite journal | vauthors = Shaker N, Phelps R, Niedt G, Ben Musa R, Bhowmik R, Sangueza OP, Pradhan D | title = Thiotepa-Induced Toxicity: A Clinical Mimic of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Featuring Severe Mucositis, Diffuse Dusky Discoloration, and Skin Sloughing | journal = The American Journal of Dermatopathology | volume = 47 | issue = 4 | pages = 269–273 | date = April 2025 | pmid = 39912674 | doi = 10.1097/DAD.0000000000002923 }}</ref><ref name=":5">{{cite journal | vauthors = Van Schandevyl G, Bauters T | title = Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines | journal = Journal of Oncology Pharmacy Practice | volume = 25 | issue = 3 | pages = 689–693 | date = April 2019 | pmid = 30185131 | doi = 10.1177/1078155218796905 }}</ref>

== Molecular mechanism of action ==
[[File:DNA_alkylation_by_thiotepa.png|thumb|400x400px|Mechanism of alkylation by thiotepa. a): Alkylation of DNA via the N-7 position of guanine. b): General mechanism forming monoalkylated and cross-linked DNA.]]
Thiotepa, as well as its more reactive metabolite, tepa, work as an alkylating agent via its aziridine ring. Due to the basic nature of aziridine and the physiological pH, aziridine is protonated to form the [[Aziridinium|aziridinium ion]], resulting in an [[Electrophile|electrophilic]] moiety that is highly susceptible to [[nucleophile]]s. DNA reacts through the nucleophilic N-7 position of [[guanine]] onto the electrophilic aziridine ring, rendering alkylated [[nucleobases]]. Thiotepa contains three reactive aziridine rings, allowing a single molecule to alkylate multiple nucleobases. Hence, it is a polyfunctional alkylating agent. This property also gives rise to its ability to cross-link DNA strands.<ref>{{cite journal | vauthors = Andrievsky GV, Sukhodub LF, Pyatigorskaya TL, Boryak OA, Shelkovsky VS | title = Direct observation of the alkylation products of deoxyguanosine and DNA by fast atom bombardment mass spectrometry | journal = Biological Mass Spectrometry | volume = 20 | issue = 11 | pages = 665–668 | date = November 1991 | pmid = 1799576 | doi = 10.1002/bms.1200201103 }}</ref><ref>{{cite journal | vauthors = Cohen NA, Egorin MJ, Snyder SW, Ashar B, Wietharn BE, Pan SS, Ross DD, Hilton J | title = Interaction of N,N',N''-triethylenethiophosphoramide and N,N',N''-triethylenephosphoramide with cellular DNA | journal = Cancer Research | volume = 51 | issue = 16 | pages = 4360–4366 | date = August 1991 | pmid = 1714342 | url = https://aacrjournals.org/cancerres/article/51/16/4360/496981/Interaction-of-N-N-N-Triethylenethiophosphoramide }}</ref><ref>{{cite journal | vauthors = Teicher BA, Holden SA, Cucchi CA, Cathcart KN, Korbut TT, Flatow JL, Frei E | title = Combination of N,N',N"-triethylenethiophosphoramide and cyclophosphamide in vitro and in vivo | journal = Cancer Research | volume = 48 | issue = 1 | pages = 94–100 | date = January 1988 | pmid = 3121169 | url = https://pubmed.ncbi.nlm.nih.gov/3121169 }}</ref> Apart from its mechanism of action, it is suggested that thiotepa can function as a [[prodrug]]. Due to its moderate lipophilicity, it first penetrates the cell membrane, followed by hydrolysis to release the more hydrophilic aziridine ring. The aziridine ring can once again alkylate the DNA.<ref>{{cite journal | vauthors = Musser SM, Pan SS, Egorin MJ, Kyle DJ, Callery PS | title = Alkylation of DNA with aziridine produced during the hydrolysis of N,N',N{{'}}{{'}}-triethylenethiophosphoramide | journal = Chemical Research in Toxicology | volume = 5 | issue = 1 | pages = 95–99 | date = 1992-01-01 | pmid = 1374653 | doi = 10.1021/tx00025a016 }}</ref> The highly reactive metabolite tepa can be considered as an active metabolite and alkylates DNA similar to its parent drug. Ultimately, the alkylation of DNA leads to cell damage and can lead to cell death. Cross-linking blocks the separation of DNA strands, inhibiting [[DNA replication|replication]] and the [[Cell proliferation|proliferation of cells]].<ref name=":1" /><ref>{{cite journal | vauthors = Farmer PB | title = Metabolism and reactions of alkylating agents | journal = Pharmacology & Therapeutics | volume = 35 | issue = 3 | pages = 301–358 | date = January 1987 | pmid = 3324117 | doi = 10.1016/0163-7258(87)90099-4 }}</ref>

== Toxicity ==
Thiotepa is associated with a range of side effects. The severity and type of side effects may vary based on the dosage, duration of treatment, and individual patient factors.

=== Myelosuppression ===
Proliferating cells, such as tumour cells, are more sensitive to alkylating agents, rendering these drugs useful for chemotherapy.<ref>{{Cite journal | vauthors = Ralhan R, Kaur J |date= October 2007 |title=Alkylating agents and cancer therapy |url=http://www.tandfonline.com/doi/full/10.1517/13543776.17.9.1061 |journal=Expert Opinion on Therapeutic Patents |language=en |volume=17 |issue=9 |pages=1061–1075 |doi=10.1517/13543776.17.9.1061 |issn=1354-3776|url-access=subscription }}</ref> However, alike drugs of this class, thiotepa is nonselective, which often results in its most important side effect: [[myelosuppression]], the decreased activity of bone marrow. In turn, this can lead to [[leukopenia]], [[thrombocytopenia]], [[infection]], and [[anemia]]. These side effects are often the most severe between 15 and 20 days following low dose treatment.<ref>{{cite journal | vauthors = Betcher DL, Burnham N | title = Thiotepa | journal = Journal of Pediatric Oncology Nursing | volume = 8 | issue = 2 | pages = 95–97 | date = April 1991 | pmid = 1904247 | doi = 10.1177/104345429100800242 }}</ref> Bone marrow has a high turn-over in the production of blood cells, which can be analogously inhibited by alkylating agents. This toxicity is dose-dependent and can be anticipated on.<ref>{{cite journal | vauthors = Soloway MS, Ford KS | title = Thiotepa-induced myelosuppression: review of 670 bladder instillations | journal = The Journal of Urology | volume = 130 | issue = 5 | pages = 889–891 | date = November 1983 | pmid = 6415297 | doi = 10.1016/S0022-5347(17)51554-2 }}</ref><ref>{{cite journal | vauthors = Hagen B | title = Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its correlation to myelosuppressive effects | journal = Cancer Chemotherapy and Pharmacology | volume = 27 | issue = 5 | pages = 373–378 | date = September 1991 | pmid = 1705489 | doi = 10.1007/BF00688860 }}</ref> However, even a low dose can lead to life-threatening situations.<ref>{{cite journal | vauthors = Agnelli G, de Cunto M, Gresele P, del Favero A | title = Early onset life-threatening myelosuppression after low dose of intravesical thiotepa | journal = Postgraduate Medical Journal | volume = 58 | issue = 680 | pages = 380–381 | date = June 1982 | pmid = 6812036 | pmc = 2426344 | doi = 10.1136/pgmj.58.680.380 }}</ref> Higher, and, therefore, more therapeutically effective, doses of thiotepa have successfully been applied by the autologous transplantation of bone marrow.<ref>{{cite journal | vauthors = Lazarus HM, Reed MD, Spitzer TR, Rabaa MS, Blumer JL | title = High-dose i.v. thiotepa and cryopreserved autologous bone marrow transplantation for therapy of refractory cancer | journal = Cancer Treatment Reports | volume = 71 | issue = 7–8 | pages = 689–695 | date = 1987 | pmid = 3111687 | url = https://pubmed.ncbi.nlm.nih.gov/3111687 }}</ref><ref>{{cite journal | vauthors = Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Frei-Lahr D, Lowder J, Bolwell B, Giannone L, Herzig GP | title = High-dose thiotepa with autologous bone marrow transplantation for metastatic malignant melanoma: results of phase I and II studies of the North American Bone Marrow Transplantation Group | journal = Journal of Clinical Oncology | volume = 7 | issue = 2 | pages = 245–249 | date = February 1989 | pmid = 2492594 | doi = 10.1200/JCO.1989.7.2.245 }}</ref><ref>{{cite journal | vauthors = Dimopoulos MA, Alexanian R, Przepiorka D, Hester J, Andersson B, Giralt S, Mehra R, van Besien K, Delasalle KB, Reading C | title = Thiotepa, busulfan, and cyclophosphamide: a new preparative regimen for autologous marrow or blood stem cell transplantation in high-risk multiple myeloma | journal = Blood | volume = 82 | issue = 8 | pages = 2324–2328 | date = October 1993 | pmid = 8104539 | doi = 10.1182/blood.V82.8.2324.2324 }}</ref> In these high-dose therapies, the dose can be as much as a hundred times greater than that of conventional therapy. Despite the use of bone marrow transplantation, complications from the therapy can be fatal.<ref name=":2" />

Monoalkylation of DNA leads to mispairing of bases and, if not repaired, can reside in the DNA sequence. Mutated DNA that does not undergo cell death can find its way into daughter cells and potentially cause genetic disorders such as cancer.<ref name=":1" /> As a result of cell mutation in the bone marrow, chemotherapies with alkylating agents are known to cause [[Acute myeloid leukemia|acute myeloid leukaemia (AML)]] and [[Myelodysplastic syndrome|myelodysplastic syndrome (MDS)]].<ref>{{Cite book |title=Casarett & Doull's essentials of toxicology |date=2021 |publisher=McGraw Hill |isbn=978-1-260-45230-3 | veditors = Klaassen CD, Watkins JB, Casarett LJ, Doull J |edition=4th |location=New York Chicago San Francisco Athens London Madrid Mexico City New Delhi Milan Singapore Sydney Toronto }}</ref>

=== Additional toxic effects ===
Apart from its mutagenic nature, thiotepa can exert skin toxicity, such as redness and [[hyperpigmentation]]. Other less frequent symptoms are [[Desquamation|peeling skin]] and [[mucositis]]. These effects can be unified under the term of "toxic erythema of chemotherapy". Due to thiotepa's excretion via sweat, skin exposure is especially high in regions with a high density of [[sweat gland]]s. Namely, symptoms are more abundant at skin folds, the groin, armpits, and generally obstructed skin where accumulation of sweat can take place. The symptoms can be minimized by washing the skin with water and preventing the use of soap and moisturizers, together with preventing obstructions of the skin, 36 hours after thiotepa administration.<ref name=":4" /><ref name=":5" /> Thiotepa's ability to cross the blood-brain barrier can lead to diseases related to the white brain matter and [[Neurotoxicity|neurotoxic]] symptoms such as memory deficits, dizziness, blurred vision, and others.<ref name=":0" /><ref>{{cite journal | vauthors = Rzeski W, Pruskil S, Macke A, Felderhoff-Mueser U, Reiher AK, Hoerster F, Jansma C, Jarosz B, Stefovska V, Bittigau P, Ikonomidou C | title = Anticancer agents are potent neurotoxins in vitro and in vivo | journal = Annals of Neurology | volume = 56 | issue = 3 | pages = 351–360 | date = September 2004 | pmid = 15349862 | doi = 10.1002/ana.20185 }}</ref> Additionally, neurotoxicity and mucositis are the main dose-limiting factors in high-dose treatment (whereas the main dose-limiting factor, myelosuppression, is remedied by applying transplantation of bone marrow). Other general adverse effects of chemotherapy with thiotepa are infections, [[diarrhea]], [[nausea]], vomiting, [[oedema]] and hair loss.<ref name="Maanen2000" /><ref name="EMA" />

[[In vivo|In-vivo]] experiments in animals displayed additional and potentially important toxicities. Thiotepa has been found to negatively affect [[fertility]] in male and female mice by interfering with [[spermatogenesis]] and impairing [[Ovary|ovarian function]], respectively. It was found to be [[teratogenic]] in mice and rats and fetolethal in rabbits. These effects were seen at doses lower than those used in humans.<ref name="EMA" /> The [[Median lethal dose|LD<sub>50</sub>]] of thiotepa via oral administration is 38&nbsp;mg/kg in mice and 2,3&nbsp;mg/kg in rats.<ref>{{cite web | title = Thiotepa for Injection, USP | work = Sagent Pharmaceuticals, Inc. | date = 20 August 2021 | url = https://www.medline.com/media/catalog/Docs/MSDS/MSD_SDSD94347.pdf }}</ref> For intravenous and intra-arterial injection in rats, the LD<sub>50</sub> values are 9,5&nbsp;mg/kg and 8,8&nbsp;mg/kg, respectively.<ref>{{cite journal | vauthors = Boone IU, Rogers BS, Williams DL | title = Toxicity, metabolism, and tissue distribution of carbon-14 labeled N,N',N"-triethylenethiophosphoramide (Thio-TEPA) in rats | journal = Toxicology and Applied Pharmacology | volume = 4 | issue = 3 | pages = 344–353 | date = May 1962 | pmid = 13871143 | doi = 10.1016/0041-008X(62)90045-5 }}</ref>

Women and men of childbearing potential have to use effective [[Birth control|contraception]] during treatment. A pregnancy test should be performed before treatment is started. Men should not father a child during and a year after cessation of treatment. There is no data on the administration of thiotepa during pregnancy, But as in-vivo animal experiments showed teratogenic effects the use of thiotepa during pregnancy is contraindicated. It is not known whether thiotepa is excreted in human breast milk, but due to its high lipophilicity, this cannot be ruled out. Due to its pharmacological properties and potential for toxicity in newborns/infants breast feeding is contraindicated during treatment with thiotepa.<ref name=":6">{{cite web | title = TEPYLUTE (thiotepa) injection, for intravenous use | work = Shorla Oncology Inc. | publisher = U.S. Food and Drug Administration | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216984s000lbl.pdf }}</ref>

== Drug interactions ==
Thiotepa can have various interactions with other medications or therapies that can impact patient safety and treatment efficacy. [[Aprepitant]], a drug that prevents nausea and vomiting that may occur during chemotherapy, inhibits CYP-enzymes, which decrease the metabolism of thiotepa to tepa. Its importance is relatively minor because inhibition itself is small and due to the variability of thiotepa clearance in different individuals.<ref>{{cite journal | vauthors = de Jonge ME, Huitema AD, Holtkamp MJ, van Dam SM, Beijnen JH, Rodenhuis S | title = Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism | journal = Cancer Chemotherapy and Pharmacology | volume = 56 | issue = 4 | pages = 370–378 | date = October 2005 | pmid = 15838656 | doi = 10.1007/s00280-005-1005-4 }}</ref> The anti-seizure medication [[phenytoin]] induces the CYP3A4 enzyme. This leads to an increased rate of tepa formation from thiotepa, which highly influences its clearance and concentration. Higher local concentrations of the more reactive tepa can potentially induce [[hepatotoxicity]]. Additionally, cytotoxic drugs such as thiotepa can reduce the absorption of phenytoin leading to the increased risk of seizures. It is advised to avoid the use of both drugs simultaneously or decrease thiotepa doses.<ref name=":6" /><ref>{{Cite journal | vauthors = Guillory JK |date=2007-02-08 |title=The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals Edited by Maryadele J. O'Neil, Patricia E. Heckelman, Cherie B. Koch, and Kristin J. Roman. Merck, John Wiley & Sons, Inc., Hoboken, NJ. 2006. xiv + 2564 pp. 18 × 26 cm. ISBN-13 978-0-911910-001. $125.00. |url=https://pubs.acs.org/doi/10.1021/jm068049o |journal=Journal of Medicinal Chemistry |language=en |volume=50 |issue=3 |pages=590 |doi=10.1021/jm068049o |issn=0022-2623|url-access=subscription }}</ref>

Myelosuppressive/myelotoxic agents such as melphalan, busulfan, treosulfan, and cyclophosphamide, as well as the concurrent use of thiotepa, may increase the risk of hematologic adverse reactions and [[pulmonary toxicity]], as they share similar toxicity profiles. Additionally, the use of [[Attenuated vaccine|live attenuated vaccines]] (including yellow fever) poses a risk of systemic and potentially fatal infection, with the risk further heightened in patients who are already [[Immunosuppression|immunosuppressed]] due to their underlying disease. In general, thiotepa is a potent inhibitor of CYP2B6, which can lead to increased plasma levels of drugs that are substrates of this enzyme. In addition to this, it may reduce the levels of potentially active metabolites, such as [[4-Hydroxycyclophosphamide|4-hydroxycyclophosphamide]], from cyclophosphamide. Likewise, co-administration with inhibitors of thiotepa's metabolising enzymes can lead to increased thiotepa plasma concentrations. Finally, prolonged [[apnea]] has been reported by the administration of thiotepa and is thought to be a result of the inhibition of [[pseudocholinesterase]] by thiotepa. For this reason, inhibitors such as [[Suxamethonium chloride|succinylcholine]] and [[Pancuronium bromide|pancuronium]] should be prevented during thiotepa administration to prevent [[respiratory failure]].<ref name="EMA" />

== References ==
{{reflist}}

{{Chemotherapeutic agents}}
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[[Category:Alkylating antineoplastic agents]]
[[Category:1-Aziridinyl compounds]]
[[Category:Cancer treatments]]
[[Category:IARC Group 1 carcinogens]]
[[Category:Organophosphoric amides]]
[[Category:Orphan drugs]]
[[Category:Thiophosphoryl compounds]]