1. To evaluate the safety of a single dose of tenofovir disoproxil fumarate in healthy subjects. 2. To evaluate the pharmacokinetic characteristics of a single dose of tenofovir disoproxil fumarate in healthy subjects.

Start Date12 Dec 2019

Sponsor / Collaborator

Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences

[+3]

100 Clinical Results associated with Octadecyloxyethyl-tenofovir

100 Translational Medicine associated with Octadecyloxyethyl-tenofovir

100 Patents (Medical) associated with Octadecyloxyethyl-tenofovir

Literatures (Medical) associated with Octadecyloxyethyl-tenofovir

01 Nov 2019·Antiviral ResearchQ2 · MEDICINE

Octadecyloxyethyl benzyl tenofovir: A novel tenofovir diester provides sustained intracellular levels of tenofovir diphosphate

Q2 · MEDICINE

Article

Author: Aldern, Kathy A ; Valiaeva, Nadejda ; Hostetler, Karl Y ; Zhang, Xing-Quan ; Beadle, James R ; Schooley, Robert T

Pre-exposure prophylaxis (PrEP) with topically or systemically administered antiretroviral agents can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials using tenofovir-containing agents, HIV-1 acquisition is reduced but not eliminated. Incomplete adherence remains the major contributor to failure. Sustained release or long-acting antiretroviral agents may provide better HIV-1 protection by reducing the clinical impact of incomplete adherence. To reduce dosing frequency, we synthesized a novel tenofovir prodrug, octadecyloxyethyl benzyl tenofovir (ODE-Bn-TFV), that is designed to release TFV slowly in tissues, and showed potent anti-HIV activity in vitro (EC₅₀ = 1.7 nM). In cells exposed to ¹⁴C labeled TFV, ODE-Bn-TFV or the quickly activated monoester ODE-TFV, rapid cellular uptake for both lipophilic analogs was noted, achieving 50-fold higher levels than unmodified TFV after 48 h. Following exposure to ODE-[8-¹⁴C]TFV, the intracellular diphosphate levels were approximately four-fold higher than with ODE-Bn-TFV. However, intracellular TFVpp drug levels fell rapidly yielding a half-life of about two days. TFVpp levels in ODE-Bn-TFV treated cells decreased much more slowly and reached half-maximal levels in about seven days. These results suggest early accumulation of ODE-Bn-TFV followed by sustained intracellular release following cleavage of the ester bonds linking the ODE and benzyl moieties to the active molecular precursor, thereby potentially allowing for less frequent administration than with more rapidly activated forms of tenofovir.

01 Jan 2018·ChemotherapyQ4 · MEDICINE

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Q4 · MEDICINE

Article

Author: Schimmer, Aaron ; Khoury, Haytham ; Beadle, James R ; Minden, Mark D ; He, Ruijuan ; Hostetler, Karl Y

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipivoxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

01 Apr 2011·Journal of Ocular Pharmacology and TherapeuticsQ4 · MEDICINE

Intraocular Pharmacokinetics of a Crystalline Lipid Prodrug, Octadecyloxyethyl-Cyclic-Cidofovir, for Cytomegalovirus Retinitis

Q4 · MEDICINE

Article

Author: Beadle, James R. ; Hoh, Carl ; Freeman, William R. ; Cheng, Lingyun ; Hostetler, Karl Y. ; Tammewar, Ajay

PURPOSETo evaluate the intraocular pharmacokinetics of octadecyloxyethyl-cyclic-cidofovir (ODE-cCDV) after intravitreal injection into rabbit eyes.METHODSTwenty-seven New Zealand red rabbits (27 eyes) received intravitreal injections of (14)C-labeled ODE-cCDV (100 μg drug suspended in 5% dextrose), and ocular tissues were collected from 3 rabbits at each predetermined time point (1 h, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks, and 9 weeks) after the injection. The eye globes were enucleated, and the vitreous, retina, and choroids were separated and harvested into pre-weighed scintillation vials. Levels of ODE-cCDV were measured by counting in a liquid scintillation counter, and pharmacokinetic (PK) parameters were determined. In addition, 3 eyes of 3 animals were used for autoradiography study at day 1, week 3, and week 6.RESULTSODE-cCDV in vitreous as a whole followed a 2-phase first-order elimination, whereas ODE-cCDV in retina and choroid manifested a nearly steady state during the first 3 weeks and then followed a first-order elimination with the apparent elimination half-life of 10.1 and 7.2 days. For vitreous, apparent elimination half-life was 25 days. However, the drug mean residence time was much longer in retina (17.6 days) and choroid (19.6 days) than that in the vitreous (11.6 days). The drug exposure to the retina [area under the curve (AUC) = 1120837.1 ng · day/mL] was greater than the exposure to the vitreous (AUC = 958645.8 ng · day/mL) and the choroid (AUC = 415407.47).CONCLUSIONA crystalline lipid prodrug, ODE-cCDV, has longer vitreous half-life than that in other ocular tissues due to its solid drug depot formation in vitreous. Over time, dissolved free ODE-cCDV from drug depot feeds and accumulates in the retina.

100 Deals associated with Octadecyloxyethyl-tenofovir

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B	Phase 1	-	Agenix Ltd.	-
HIV Infections	Phase 1	CN	Chinese Academy of Medical Sciences	-
HIV Infections	Phase 1	CN	Xinkaiyiyao Science & Technology Shanghai Co. Ltd.	-
HIV Infections	Phase 1	-	Agenix Ltd.	-
Hepatitis B, Chronic	Preclinical	CN	Xinkai Medicine and Chemical Intermediates (Shanghai) Co., Ltd.	12 Dec 2019
Hepatitis B, Chronic	Preclinical	CN	Xinkaiyiyao Science & Technology Shanghai Co. Ltd.	12 Dec 2019
Hepatitis B, Chronic	Preclinical	CN	Institute of Pharmaceutical Biotechnology, Chinese Academy of Medical Sciences	12 Dec 2019

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