Letter to the editor: ‘current advances in development of new docetaxel formulations’

It is with interest that we read the recent paper ‘Current advances in development of new docetaxel formulations’ by Zhang and co-workers in your esteemed journal [1]. The authors have described that several new formulations of docetaxel have been developed to overcome the challenges with organic solvents having undesirable side effects and to improve the selectivity of docetaxel for tumor cells. Further, the authors also state that only a few of these novel formulations have entered clinical trials, and none have been approved so far.

We would like to bring to the Editor’s notice that a novel solvent-free lipid-based formulation of docetaxel, ‘nanosomal docetaxel-lipid suspension (NDLS, DoceAqualip),’ was developed by Intas Pharmaceuticals Ltd., Ahmedabad, India. Docetaxel is added to high-pressure homogenized soy phosphatidylcholine and sodium cholesteryl sulfate in sodium citrate buffer to obtain docetaxel lipid suspension with desired particle size under continuous high-pressure homogenization. Then, the docetaxel lipid suspension is mixed with sucrose solution and filtered through sterile 0.45/0.22-μm polyvinylidene fluoride filters and filled in vials based on 20 mg docetaxel per vial. The vials are lyophilized and reconstituted with 9 mL of sterile water for injection to provide 10 mL of docetaxel lipid suspension for injection containing 2 mg/mL of docetaxel. The reconstituted suspension is further diluted in 5% dextrose/normal saline injection as per the desired dose.

NDLS has been approved by the Directorate General of Health Services, Central Drugs Standard Control Organization, Ministry of Health, Government of India, on 21 August 2013 as docetaxel-lipid suspension for injection 20 mg/80 mg (permission/approval letter for the manufacture of new drug formulation under license number MF-162/2013). NDLS has been approved for the treatment of patients with advanced gastric adenocarcinoma, inoperable locally advanced squamous-cell carcinoma of the head and neck, androgen-independent (hormone refractory) metastatic prostate cancer (HRPC), locally advanced or metastatic breast cancer (MBC), and non-small-cell lung cancer (NSCLC) after failure of prior chemotherapy.

NDLS was developed with generally regarded as safe (GRAS) lipids by the US Food and Drug Administration, based on the patented [2] (WO2008127358, Europe, Japan and Canada) ‘Aqualip’ technology comprising small size (<100 nm) nanosomal lipid-based particles which rely on the enhanced permeability and retention effect that helps drug to infiltrate into the tumor tissue via the leaky vasculature without affecting healthy tissues [3,4].

NDLS at 30, 45, 60, and 75 mg/m² doses in patients (N = 13) with advanced solid tumors demonstrated a dose-proportional increase in maximum plasma concentration (C_max) of free docetaxel, while area under the plasma concentration–time curve (AUC) up to the last measurable concentration (AUC_0-t) and AUC from time 0 extrapolated to infinite time (AUC_0-∞) increased in greater than proportional manner after a single dose of NDLS (30–75 mg/m²). Similarly, C_max, AUC_0-t, and AUC_0-∞ of total docetaxel too increased in greater than proportional manner. No serious adverse events were observed [Data on File]. In another pharmacokinetic dose-ranging study, patients were randomized for the treatment with NDLS at 60, 75, or 100 mg/m² dose (n = 30 in each group). NDLS at 75 and 100 mg/m² resulted in significantly higher efficacy (best overall response rate [ORR], 34.62% and 56%, respectively) compared to 60 mg/m² (best ORR 21.74%) in patients with locally advanced or MBC (N = 90). A dose–response relationship was observed with NDLS [Data on File], which is similar to the originator’s conventional docetaxel with a 19.9% response for the 60 mg/m² increasing to 22.3% for 75 mg/m² and 29.8% for 100 mg/m² [5]. This data shows higher efficacy of NDLS when compared to conventional docetaxel. NDLS, at all three doses, showed acceptable safety and tolerability [Data on File].

NDLS at 75 mg/m² showed greater systemic availability in 28 patients with advanced solid tumors compared with conventional docetaxel, which potentially could translate into greater efficacy [6]. The greater systemic availability of docetaxel could be due to an alteration in tissue distribution resulting from the lipid-based delivery of docetaxel from the NDLS formulation. The docetaxel ratio of NDLS to conventional docetaxel for C_max was 149.3% (90% confidence interval [CI]: 124.4–179.24), and for AUC, it was 119.3% (90% CI: 98.05–145.10). No difference was observed in AUC_0-∞ in Indian patients versus black and white patients, indicating no significant alteration in docetaxel pharmacokinetics by ethnic and racial characteristics [6,7].

In an open-label, randomized, multiple-dose, parallel-group study in MBC patients, NDLS (n = 49) demonstrated an ORR of 35.5% vs. 26.3% with conventional docetaxel (n = 23), indicating a better response. The greater exposure of docetaxel using NDLS formulation could have resulted in the improved therapeutic outcome in patient populations. The safety results were comparable between NDLS and conventional docetaxel [8].

NDLS has also been evaluated in post-marketing studies. A single-center retrospective study (N = 69) demonstrated a promising best ORR (58.9%) and acceptable safety profile of NDLS (75–100 mg/m²) in the treatment of various solid tumors including breast cancer, gastric cancer, HRPC, NSCLC, esophageal cancer, ovarian cancer, soft-tissue sarcoma, and urinary bladder cancer without routine premedication with corticosteroids [9]. Similarly, 39 patients showed an ORR of 35.9% across several cancer types with no acute hypersensitivity reactions in another retrospective study [10]. Several other reports are published that demonstrate the efficacy and tolerability of NDLS in the treatment of gastric cancer, ovarian cancer, cervical cancer, HRPC and NSCLC, and penile cancer [9–14]. Furthermore, a panel of oncology experts in India has recommended using NDLS in patients with metastatic disease and those at risk of hypersensitivity reactions and diabetes and patients in whom steroids need to be avoided [15]. NDLS is currently being evaluated in larger prospective clinical studies in several other cancers.

We would like to communicate through this letter that a novel nanoparticle formulation of docetaxel, devoid of polysorbate 80 and ethanol, is available and approved by the Indian regulatory authority and is presently being used by Indian oncologists across indications.

Declaration of interest

MA Khan, N Joshi and A Chaturvedi are employees of Intas Pharmaceuticals Ltd., India. I Ahmad is an employee of Jina Pharmaceuticals Inc., USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.