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

Abstract

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.

Efficacy and Safety of Tenofovir Disoproxil Orotate in Chronic Hepatitis B Patients Previously Treated with Tenofovir Disoproxil Fumarate: Multicenter, Open-Label, Prospective Study

“…TDO has improved stability over TDF, prolonging its shelf life. Furthermore, TDO can lower the cost involved in the manufacture of salt conjugates compared to TDF [ 10 ]. These advantages of TDO can ultimately improve patients’ quality of life.…”

“…A novel orotate form of tenofovir disoproxil (tenofovir disoproxil orotate (TDO)) was developed to reduce manufacturing costs and ultimately provide a cost-effective treatment for patients with chronic hepatitis B. A comparative study of pharmacokinetic analysis has demonstrated that the serum tenofovir concentration-time profiles of TDF and TDO were comparable, with similar maximum concentration (C max ), time to reach C max , and area under the concentration–time curve [ 10 ]. In addition, there were no clinically significant findings in the tolerability assessments after TDF and TDO administration.…”

Comparative pharmacokinetics between tenofovir disoproxil phosphate and tenofovir disoproxil fumarate in healthy subjects

“…In addition, from a long-term perspective, cost reduction, improved accessibility to the drug by the patients, and clinical benefits by developing these salt forms of the drugs are also expected [ 20 ]. For example, tenofovir disoproxil orotate, which has a reduced manufacturing cost, was developed to provide patients with a more cost-effective treatment [ 21 ]. Tenofovir disoproxil phosphate will be a useful substitute for the currently marketed tenofovir disoproxil fumarate if its PK properties and safety are similar to tenofovir disoproxil fumarate, and it is expected to have advantages in terms of its stability and low cost [ 18 ].…”

Toxicity for Aquatic Organisms of Antiretroviral Tenofovir Disoproxil

“…After absorption by human organisms, TDF is de-esterified and after phosphorylation, the TFV molecule acts as an inhibitor of the viral enzyme reverse transcriptase by competing with its natural substrate, adenosine 5'-monophosphate, thus disrupting DNA synthesis and, consequently, viral replication [7]. According to Kim et al [8], after human use of this drug, up to 80% of the TFV is eliminated in unmodified urine, indicating its potential entry into domestic and hospital sewage in its active form. TFV is a very stable molecule [9], leading to concerns about the effects of this drug on aquatic species.…”