Oral Administration Of Prodrug Research Articles

Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.

e13027 Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]

Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by restricted movements of joints of hand, feet, elbow, knees and neck but principally the synovial joints. Though etiopathology is not exactly known, treatment paradigms are evolving to provide a tighter control over symptoms and disease progression. Current trend is introduction of disease modifying anti-rheumatoid drugs (DMARDs) at early stages. Hydroxychloroquine (HCQ) and nonsteroidal anti-inflammatory drugs (NSAIDs) are two mechanistically different categories widely used in the management of RA where the first arrests the disease progression while the latter offers symptomatic relief. Present work aims at minimizing problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs by designing their mutual ester prodrugs. Synthesis of prodrugs was achieved by CDI coupling and structures were confirmed by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. Prodrugs resisted hydrolysis in acidic environment of the stomach but exhibited significant release in small intestine. Upon oral administration of prodrugs to rats, 40.5-49% HCQ and 53.4-66.8% of NSAIDs were recovered in 8.5-10h in blood. Urine and feces samples pooled over a period of 24h exhibited 2.3-3.5% and 0.75-0.9% of HCQ, respectively, without any presence of intact prodrugs or NSAIDs. Prodrugs were pharmacologically evaluated for analgesic and anti-inflammatory activities using standard animal models. Among all, prodrugs of HCQ with licofelone (HL) and aceclofenac (HA) produced superior analgesia, improved weight gain, normalization of joint diameter/paw volume than HCQ and physical mixtures of HCQ and NSAIDs. Hematological and biochemical studies indicated significant step up in RBC, Hb, platelet count, total protein nutrient (TPN) levels and step down in WBC, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) by the treatment with HL and HA. Through these novel codrugs, problems of slow onset and accumulation of HCQ in non-targeted sites and local gastric intolerance to NSAIDs were well addressed. These dual acting mutual prodrugs of two mechanistically different anti-arthritic agents could be explored further as promising strategy for effective management of RA.

Enabling clinical development of an HIV attachment inhibitor through innovative pharmaceutical development: novel extended‐release delivery of prodrug

BackgroundHIV‐1 attachment inhibitors are a new class of viral entry inhibitors which target viral gp120 preventing attachment of virus to its host cell receptor CD4. This class presents major challenges for development based upon low solubility and short half‐lives. For progression into clinical studies, requirements include reliable and reproducible absorption from a tolerable and convenient oral dosing regimen.MethodsA series of highly soluble prodrugs were designed to overcome the poor absorption caused by the low solubility of the active compounds. A regional absorption study was conducted to assess the uptake of active throughout the gastro‐intestinal tract following oral prodrug delivery. An extended‐release (ER) strategy was subsequently devised to optimise tolerability, decrease peak to trough ratios and reduce frequency of dosing. In silico absorption modelling was used to verify feasibility and drive in vitro testing leading to dosage form development and selection. The performance of the ER dosage form was verified in vivo prior to use in clinical studies.ResultsPhosphonooxymethyl prodrugs with aqueous solubilities in excess of 250 mg/mL were synthesised and shown to be readily converted to parent compound via alkaline phosphatase in vitro. Results of regional absorption studies for the selected compound, BMS‐663068, confirmed the rapid absorption but short half‐life of active following oral administration of prodrug. Delivery to specific regions throughout the GI tract showed absorption of active to be subject to regional variation with an extent of colonic absorption of approximately 40% of intestinal absorption. Incorporation of this data into an in silico model guided development of an ER tablet which releases prodrug over 24 hours and achieves the required exposure, pharmacokinetics and reproducibility in vivo.ConclusionsThe novel approach of combining prodrug synthesis and ER formulation has enabled clinical evaluation of a promising new class of therapeutic entity into Phase 2b studies.

An in-vitro and in-vivo correlative approach to the evaluation of ester prodrugs to improve oral delivery of propranolol.

A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the beta-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration. The in-vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate >> plasma > buffers. The pH-rate profile of the prodrugs showed maximum stability around pH 4.0; the hydrolysis rates were drastically increased over pH 6.8. QSAR analysis revealed hydrophobic (pi) and electronic (sigma) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O-acetyl-, O-butyryl-, O-isovaleryl- and O-cyclopropanoyl-propranolol) were selected for oral administration based on their hydrolysis in-vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranolol were about 2-4-fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0-0.5h. Intact prodrug levels were also observed, which varied depending on their respective stabilities in in-vitro media. A linear relationship between F of propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract A110: A phase 1 study of PF-04929113 (SNX5422), an orally bioavailable heat shock protein 90 (Hsp90) inhibitor administered twice weekly in patients with refractory solid tumor malignancies and lymphoma

Abstract Introduction: Hsp90 inhibitors have the potential for broad anti-cancer effects based on the spectrum of known client proteins and increased effect on mutations that drive malignant transformation and cancer growth. PF-04929113 (SNX5422; 113) is a novel, oral, non-antibiotic, selective Hsp90 inhibitor prodrug, with preclinical anti-tumor activity in multiple tumor models. The objective of this study was to evaluate the tolerability and describe the PK of 113 and its active moiety (PF- 04928473 /SNX2112; 473) in patients with refractory solid tumor malignancies and lymphoma. Methods: Twenty-six subjects have been enrolled to date in this Phase 1, open-label, dose-escalation study. Subjects were treated with oral 113 twice weekly without interruption at doses ranging from 4 to 100 mg/m2. PBMCs were isolated and collected at baseline and various time points after-treatment. Cell lysates from PBMCs were assayed for Hsp70 and AKT protein level using Meso Scale Discovery (MSD) technology. Serial plasma concentrations of 473 were measured by LC-MS/MS after the first dose (Day 1) and after 6 doses (Day 18). PK parameters (mean ± standard deviation) were calculated using non-compartmental methods in WinNonlin v5.0. Results: MTD for this schedule has not yet been reached. So far it has been well tolerated. Related adverse events were mainly low grade (most frequent nausea 31%) with grade ≥ 3 were reported in 8% (diarrhea and arthritis, 1 patient each). Based on results of interim pharmacokinetic analysis for doses 4 to 44 mg/m2, median time to 473 peak plasma concentrations was 2 h (range 0.33–4 h) and median half-life was ∼8.5h both at days 1 and 18. The median (range) CL/Fm at day 1 and day 18 were, 24.7 (12.9–81.2) L/hr and 22.6 (8.6–55.6) L/hr, respectively and was consistent across the dose range. Hsp70 was elevated with drug treatment, and further elevations were noted with increasing weekly dose. Although to date, no patients have achieved PR, several have experienced prolonged stable disease including medullary thyroid cancer (>450 days), lymphoma (>150 days), and esophagus, colon, adenoid cystic, lung carcinoid, and peritoneal mesothelioma (>100 days). Conclusions: This schedule is well tolerated with no significant drug accumulation, few severe toxicities and potential for efficacy based on prolonged stable disease. Maximal concentrations of 113 were observed 2 h after oral administration of prodrug 113. Concentrations achieved were consistent with the preclinical activity. Accrual to the study to establish MTD is ongoing. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A110.

Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited solubility.

Design and synthesis of factor Xa inhibitors and their prodrugs

In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency ( 14, IC 50=0.028 μM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats.

LC/MS DETERMINATION OF THE INTRACELLULAR CONCENTRATION OF TWO NOVEL ARYL PHOSPHORAMIDATE PRODRUGS OF PMPA AND THEIR METABOLITES IN DOG PBMC

LC/MS assays were developed to determine the plasma and intracellular concentrations of two aryl phosphoramidate prodrugs of the nucleotide analog 9-[2-R-(phosphonomethoxy)propyl]adenine. LC/MS was used to demonstrate the presence of high concentrations of PMPA in peripheral blood mononucleocytes following oral administration of prodrugs in dogs. High concentrations of PMPA and active metabolite were detected in MT-2 cells incubated with prodrug using an ion-pairing LC/MS assay.

Lymphatic targeting of anti-HIV nucleosides: distribution of 2′,3′-dideoxyinosine after intravenous and oral administration of dipalmitoylphosphatidyl prodrug in mice

In the search for prodrugs of 2′,3′-dideoxyinosine (ddI) with potential for improving the delivery of the nucleoside analogue to the lymphatic system, we synthesized dipalmitoylphosphatidyl-2′,3′-dideoxyinosine (DPP-ddI) and its pharmacokinetics were investigated in mice. The disposition of ddI in plasma and lymph nodes was examined following intravenous and oral administration of parent nucleoside (100 mg/kg) and DPP-ddI (400 mg/kg, equivalent to 100 mg/kg of ddI). Concentrations of ddI were determined by HPLC. Pharmacokinetic parameters were estimated by area/moment analysis. Intravenous administration of DPP-ddI resulted in a pattern of lower peak concentrations of ddI and more sustained exposure of parent nucleoside in plasma and lymph nodes compared to administration of the parent nucleoside. Both ddI and DPP-ddI yielded similar AUC values in lymph nodes. Oral administration of the prodrug resulted in lower concentrations and AUC values of ddI in plasma and lymph nodes when compared to administration of the parent nucleoside. The bioavailability of ddI following ddI and DPP-ddI administration was 15 and 8%, respectively. The results of the present study demonstrate that DPP-ddI administered intravenously shows potential for targeting and sustaining level of ddI in the nodular lymphatic tissues.