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Yuan, Lung-Chi; Dahl, Terrence C.; Oliyai, Reza

doi:10.1023/a:1011044804823

Cited by 31 publications

(13 citation statements)

References 4 publications

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“…pH 2) and intestine (ca. pH 6.8), 19 , 33 with TDF half-lives being substantially greater than the rat or human gut transit times. 55 Thus, chemical instability is not the cause of TDF’s modest bioavailability.…”

Section: Discussionmentioning

confidence: 94%

“…Earlier pH studies indicate that ester prodrugs such as TDF are stable between pH 2 and pH 6, but become increasingly sensitive to chemical hydrolysis as pH rises above pH 6. 8 , 19 As noted, the intestine receives pancreatic secretions containing a mix of amylases, proteases, and lipases. An increase in estimated TDF bioavailability from 25% when fasting to 39% following a high fat meal 10 , 11 , 12 suggests that competitive inhibition of lipases by food may provide a degree of protection.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate

Watkins

Wring

Randolph

et al. 2017

Journal of Pharmaceutical Sciences

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Tenofovir disoproxil fumarate (TDF), the bisphosphonate ester prodrug of tenofovir (TFV), has poor bioavailability due to intestinal degradation and efflux transport. Reformulation using U.S. Food and Drug Administration–approved esterase and efflux inhibitors to increase oral bioavailability could provide lower dose alternatives and reduce costs for patients with HIV in resource-limited settings. Inhibition of mucosal and intracellular esterases was studied in human and rat intestinal extracts (S9), where TDF was protected by the carboxylesterase inhibitor bis-para-nitrophenylphosphate, the ester mix EM1, and the generally recognized-as-safe (GRAS) excipient propylparaben. Permeability studies using Madin-Darby canine kidney and Caco-2 cell monolayers demonstrated that TDF was a substrate for the permeability glycoprotein with permeability glycoprotein inhibitors reducing basolateral to apical transport of TDF. These studies also showed that transport was increased by esterase inhibitors. TDF, TFV, and tenofovir monophosphonate ester transport across Caco-2 monolayers with esterase and efflux inhibitors revealed a maximum 38.7-fold increase in apical to basolateral TDF transport with the potent non-GRAS combination of EM1 and GF120918. Transport was increased 22.8-fold by the GRAS excipients, propylparaben, and d-a-tocopheryl polyethylene glycol 1000 succinate (a vitamin E derivative). TFV pharmacokinetics in rats following oral administration of TDF and GRAS esterase and efflux inhibitors confirmed enhanced bioavailability. Area under the curve increased 1.5- to 2.1-fold with various combinations of parabens and d-a-tocopheryl polyethylene glycol 1000 succinate. This significant inhibition of TDF hydrolysis and efflux in vivo exhibits the potential to safely increase TDF bioavailability in humans.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate

Watkins

Wring

Randolph

et al. 2017

Journal of Pharmaceutical Sciences

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“… 2 The prodrug form increases both the bioavailability and the stability of tenofovir at both pH 2.0 and 7.4. 4 For enhancement of solubility, various salt forms can be conjugated, and the fumaric acid salt form of tenofovir disoproxil is used as the first-line monotherapy for treatment of patients with chronic hepatitis B virus infection. 5 …”

Section: Introductionmentioning

confidence: 99%

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects

Kim¹,

Choi²,

Oh³

et al. 2017

DDDT

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A novel orotic acid salt form of tenofovir disoproxil (DA-2802) was developed and is expected to replace the fumaric acid salt form. The pharmacokinetic (PK) characteristics and tolerability profiles of DA-2802 were compared to those of tenofovir disoproxil fumarate (TDF, Viread®) in healthy subjects. A randomized, open-label, single-dose study was conducted in 36 healthy subjects using a two-treatment, two-period, and two-sequence crossover design. Subjects received a single oral dose of 319 mg DA-2802 or 300 mg TDF, during each period, with a 7-day washout. Serial blood samples were collected pre-dosing and up to 72 hours post-dosing in each period, for determination of serum tenofovir concentration, which was measured by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental method was used to obtain PK parameters of tenofovir. For comparison between the two tenofovir disoproxil salts, the 90% confidence intervals (90% CIs) of geometric mean ratios of DA-2802 to TDF for the maximum concentration (Cmax) and the area under the concentration–time curve to the last quantifiable concentration (AUC0–t) were determined. The tolerability profiles of tenofovir were assessed by evaluation of adverse events and vital signs, physical examination, ECG, and clinical laboratory tests. The serum tenofovir concentration–time profiles of DA-2802 or TDF were comparable in 32 subjects who completed the study. In both profiles, a two-compartmental elimination with first-order elimination kinetics in the terminal phase was reported in a few subjects, showing a secondary peak in the initial phase of elimination. The geometric mean ratio (90% CI) of DA-2802 to TDF was 0.898 (0.815–0.990) for Cmax and 0.904 (0.836–0.978) for AUC0–t. There were no clinically significant findings in the tolerability assessments. DA-2802 showed comparable PK characteristics and tolerability profiles to TDF.

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“…After oral intake, ADV and TD are hydrolyzed at the phosphate vicinity followed by the elimination of the ester group. Here, the drug activity is produced by the ester group free tenofovir (PMPA) for TD and adefovir (PMPA) for ADV [ 9 , 14 , 15 , 16 ]. However, ADV and TD hydrolyze in contact with moisture and generate formaldehyde.…”

Section: Introductionmentioning

confidence: 99%

“…However, ADV and TD hydrolyze in contact with moisture and generate formaldehyde. Formed formaldehyde along with TDF’s amine group induces a condensation reaction, which provokes the formation of an impurity, namely, TD dimer, and consequently decreases the purity of the products [ 14 , 15 , 16 ]. TDF is a hydrophilic salt, which easily degrades in the presence of moisture.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction

Kiyonga

Yoon

et al. 2017

Molecules

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Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal’s properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 °C, RH 75%) and stress storage (60 °C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient.

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Cited by 31 publications

References 4 publications

Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate

Development of a Novel Formulation That Improves Preclinical Bioavailability of Tenofovir Disoproxil Fumarate

A comparative pharmacokinetic and tolerability analysis of the novel orotic acid salt form of tenofovir disoproxil and the fumaric acid salt form in healthy subjects

Crystal Structure Analysis of the First Discovered Stability-Enhanced Solid State of Tenofovir Disoproxil Free Base Using Single Crystal X-ray Diffraction

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