Rare oncology therapeutics: review of clinical pharmacology package of drug approvals (2019-2023) by US FDA, best practices and recommendations.

There are many challenges with rare diseases drug development and rare oncology indications are not different. To understand the regulatory landscape as it relates to application of clinical pharmacology principles in rare oncology product development, we reviewed publicly available information of 39 approvals by US FDA between January 2019 and March 2023. The objective was to understand the expected clinical pharmacology studies and knowledge base in such approvals. Model informed drug development (MIDD) applications were also reviewed, as such approaches are expected to play a critical role in filling clinical pharmacology gaps in rare oncology, where number of clinical trials and size of these trials will perhaps continue to be small. The findings highlighted how clinical pharmacology contributed to the evidence of effectiveness, dose optimization and elucidation of intrinsic and extrinsic factors affecting drug's behavior. Clinical pharmacology studies were often integrated with modeling in many of the NDAs/BLAs. Of the post marketing requirements (PMR) received, 18% were for dose optimization, 49% for DDI, 8% for QTc, 49% for specific population, and 5% for food effect. Two post marketing commitments (PMC) were issued for immunogenicity of the 11 biologics submissions. 15% (6 of 39) of the submissions used maximum tolerated dose (MTD) to advance their molecule into Phase 2 studies. Of them 3 approvals received PMR for dose optimization. 3 + 3 was the most prevalent Phase 1 design with use in 74% of the New Drug Applications (NDA)/Biologic License Applications (BLA) reviewed. Rest used innovative approaches such as BLRM, BOIN or mTPi, with BLRM being the most common. Seamless clinical pharmacology and MIDD approaches are paramount for rare oncology drug development.

First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors.

BACKGROUND: Preclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors. METHODS: This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase. RESULTS: As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments. CONCLUSIONS: NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs. TRIAL REGISTRATION NUMBER: NCT02452268.

A Reactive Oxygen Species-Scavenging 'Stealth' Polymer, Poly(thioglycidyl glycerol), Outperforms Poly(ethylene glycol) in Protein Conjugates and Nanocarriers and Enhances Protein Stability to Environmental and Biological Stressors.

This study addresses well-known shortcomings of poly(ethylene glycol) (PEG)-based conjugates. PEGylation is by far the most common method employed to overcome immunogenicity and suboptimal pharmacokinetics of, for example, therapeutic proteins but has significant drawbacks. First, PEG offers no protection from denaturation during lyophilization, storage, or oxidation (e.g., by biological oxidants, reactive oxygen species); second, PEG's inherent immunogenicity, leading to hypersensitivity and accelerated blood clearance (ABC), is a growing concern. We have here developed an 'active-stealth' polymer, poly(thioglycidyl glycerol)(PTGG), which in human plasma is less immunogenic than PEG (35% less complement activation) and features a reactive oxygen species-scavenging and anti-inflammatory action (∼50% less TNF-α in LPS-stimulated macrophages at only 0.1 mg/mL). PTGG was conjugated to proteins via a one-pot process; molar mass- and grafting density-matched PTGG-lysozyme conjugates were superior to their PEG analogues in terms of enzyme activity and stability against freeze-drying or oxidation; the latter is due to sacrificial oxidation of methionine-mimetic PTGG chains. Both in mice and rats, PTGG-ovalbumin displayed circulation half-lives up to twice as long as PEG-ovalbumin, but most importantly─and differently from PEG─without any associated ABC effect seen either in the time dependency of blood concentration, in the liver/splenic accumulation, or in antipolymer IgM/IgG titers. Furthermore, similar pharmacokinetic results were obtained with PTGGylated/PEGylated liposomal nanocarriers. PTGG's 'active-stealth' character therefore makes it a highly promising alternative to PEG for conjugation to biologics or nanocarriers.

Exploiting the distinctive properties of the bacterial and human MutS homolog sliding clamps on mismatched DNA.

MutS homologs (MSHs) are highly conserved core components of DNA mismatch repair. Mismatch recognition provokes ATP-binding by MSH proteins that drives a conformational transition from a short-lived lesion-searching clamp to an extremely stable sliding clamp on the DNA. Here, we have expanded on previous bulk biochemical studies to examine the stability, lifetime, and kinetics of bacterial and human MSH sliding clamps on mismatched DNA using surface plasmon resonance and single-molecule analysis of fluorescently labeled proteins. We found that ATP-bound MSH complexes bound to blocked-end or very long mismatched DNAs were extremely stable over a range of ionic conditions. These observations underpinned the development of a high-throughput Förster resonance energy transfer system that specifically detects the formation of MSH sliding clamps on mismatched DNA. The Förster resonance energy transfer system is capable of distinguishing between HsMSH2-HsMSH3 and HsMSH2-HsMSH6 and appears suitable for chemical inhibitor screens. Taken together, our results provide additional insight into MSH sliding clamps as well as methods to distinguish their functions in mismatch repair.

The flip-flop configuration of the PABP-dimer leads to switching of the translation function.

Poly(A)-binding protein (PABP) is a translation initiation factor that interacts with the poly(A) tail of mRNAs. PABP bound to poly(A) stimulates translation by interacting with the eukaryotic initiation factor 4G (eIF4G), which brings the 3' end of an mRNA close to its 5' m7G cap structure through consecutive interactions of the 3'-poly(A)-PABP-eIF4G-eIF4E-5' m7G cap. PABP is a highly abundant translation factor present in considerably larger quantities than mRNA and eIF4G in cells. However, it has not been elucidated how eIF4G, present in limited cellular concentrations, is not sequestered by mRNA-free PABP, present at high cellular concentrations, but associates with PABP complexed with the poly(A) tail of an mRNA. Here, we report that RNA-free PABPs dimerize with a head-to-head type configuration of PABP, which interferes in the interaction between PABP and eIF4G. We identified the domains of PABP responsible for PABP-PABP interaction. Poly(A) RNA was shown to convert the PABP-PABP complex into a poly(A)-PABP complex, with a head-to-tail-type configuration of PABP that facilitates the interaction between PABP and eIF4G. Lastly, we showed that the transition from the PABP dimer to the poly(A)-PABP complex is necessary for the translational activation function.

Inclusion of Medium-Chain Triglyceride in Lipid-Based Formulation of Cannabidiol Facilitates Micellar Solubilization In Vitro, but In Vivo Performance Remains Superior with Pure Sesame Oil Vehicle.

Oral sesame oil-based formulation facilitates the delivery of poorly water-soluble drug cannabidiol (CBD) to the lymphatic system and blood circulation. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD. In this work, the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle has been tested in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and MLNs, but with reduced variability. MCT improves the emulsification and micellar solubilization of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle.

Administration in fed state but not controlled release in the colon increases oral bioavailability of DF030263, a promising drug candidate for chronic lymphocytic leukemia.

For treatment of chronic cancers, the oral administration route is preferred as it provides numerous advantages over other delivery routes. However, these benefits of oral chemotherapy can be limited due to unfavorable pharmacokinetics. Accordingly, pharmacokinetic development of chemotherapeutic agents is crucial to the improvement of cancer treatment. In this study, assessment and optimization of biopharmaceutical properties of a promising drug candidate for cyclin-dependent kinase 9 (CDK9) inhibitor (DF030263) was performed to promote oral delivery. Oral bioavailability of DF030263 in fasted rats was 23.8%, and a distinct double-peak phenomenon was observed. A two-site absorption windows mechanism was proposed as a possible explanation to the phenomenon. The two-site absorption window hypothesis was supported by in vitro solubility assays in biorelevant fluids with different pH levels, as well as by in silico simulation by GastroPlus™. Controlled release to the colon was conducted in rats in order to exploit the colonic absorption window but did not improve the oral bioavailability. On the other hand, oral administration at postprandial conditions in rats (performed based on the high in vitro solubility in fed state simulated fluid and reduced pH-dependency) resulted in an almost 3-fold increase in bioavailability to 63.6%. In conclusion, this study demonstrates an efficient in vitro-in vivo-in silico drug development approach for improving the oral bioavailability of DF030263, a promising candidate for the treatment of chronic lymphocytic leukemia.

TRIM28 functions as a negative regulator of aggresome formation.

Selective recognition and elimination of misfolded polypeptides are crucial for protein homeostasis. When the ubiquitin-proteasome system is impaired, misfolded polypeptides tend to form small cytosolic aggregates and are transported to the aggresome and eventually eliminated by the autophagy pathway. Despite the importance of this process, the regulation of aggresome formation remains poorly understood. Here, we identify TRIM28/TIF1ß/KAP1 (tripartite motif containing 28) as a negative regulator of aggresome formation. Direct interaction between TRIM28 and CTIF (cap binding complex dependent translation initiation factor) leads to inefficient aggresomal targeting of misfolded polypeptides. We also find that either treatment of cells with poly I:C or infection of the cells by influenza A viruses triggers the phosphorylation of TRIM28 at S473 in a way that depends on double-stranded RNA-activated protein kinase. The phosphorylation promotes association of TRIM28 with CTIF, inhibits aggresome formation, and consequently suppresses viral proliferation. Collectively, our data provide compelling evidence that TRIM28 is a negative regulator of aggresome formation.Abbreviations: BAG3: BCL2-associated athanogene 3; CTIF: CBC-dependent translation initiation factor; CED: CTIF-EEF1A1-DCTN1; DCTN1: dynactin subunit 1; EEF1A1: eukaryotic translation elongation factor 1 alpha 1; EIF2AK2: eukaryotic translation initiation factor 2 alpha kinase 2; HDAC6: histone deacetylase 6; IAV: influenza A virus; IP: immunoprecipitation; PLA: proximity ligation assay; polypeptidyl-puro: polypeptidyl-puromycin; qRT-PCR: quantitative reverse-transcription PCR; siRNA: small interfering RNA.

Natural sesame oil is superior to pre-digested lipid formulations and purified triglycerides in promoting the intestinal lymphatic transport and systemic bioavailability of cannabidiol.

Lipid-based formulations play a significant role in oral delivery of lipophilic drugs. Previous studies have shown that natural sesame oil promotes the intestinal lymphatic transport and oral bioavailability of the highly lipophilic drug cannabidiol (CBD). However, both lymphatic transport and systemic bioavailability were also associated with considerable variability. The aim of this study was to test the hypothesis that pre-digested lipid formulations (oleic acid, linoleic acid, oleic acid with 2-oleoylglycerol, oleic acid with 2-oleoylglycerol and oleic acid with glycerol) could reduce variability and increase the extent of the intestinal lymphatic transport and oral bioavailability of CBD. The in vivo studies in rats showed that pre-digested or purified triglyceride did not improve the lymphatic transport and bioavailability of CBD in comparison to sesame oil. Moreover, the results suggest that both the absorption of lipids and the absorption of co-administered CBD were more efficient following administration of natural sesame oil vehicle compared with pre-digested lipids or purified trioleate. Although multiple small molecule constituents and unique fatty acid compositions could potentially contribute to a better performance of sesame oil in oral absorption of lipids or CBD, further investigation will be needed to identify the mechanisms involved.

Linker domain function predicts pathogenic MLH1 missense variants.

The pathogenic consequences of 369 unique human HsMLH1 missense variants has been hampered by the lack of a detailed function in mismatch repair (MMR). Here single-molecule images show that HsMSH2-HsMSH6 provides a platform for HsMLH1-HsPMS2 to form a stable sliding clamp on mismatched DNA. The mechanics of sliding clamp progression solves a significant operational puzzle in MMR and provides explicit predictions for the distribution of clinically relevant HsMLH1 missense mutations.

Designing topographically textured microparticles for induction and modulation of osteogenesis in mesenchymal stem cell engineering.

Mesenchymal stem cells are the focus of intense research in bone development and regeneration. The potential of microparticles as modulating moieties of osteogenic response by utilizing their architectural features is demonstrated herein. Topographically textured microparticles of varying microscale features are produced by exploiting phase-separation of a readily soluble sacrificial component from polylactic acid. The influence of varying topographical features on primary human mesenchymal stem cell attachment, proliferation and markers of osteogenesis is investigated. In the absence of osteoinductive supplements, cells cultured on textured microparticles exhibit notably increased expression of osteogenic markers relative to conventional smooth microparticles. They also exhibit varying morphological, attachment and proliferation responses. Significantly altered gene expression and metabolic profiles are observed, with varying histological characteristics in vivo. This study highlights how tailoring topographical design offers cell-instructive 3D microenvironments which allow manipulation of stem cell fate by eliciting the desired downstream response without use of exogenous osteoinductive factors.

Nonsense-mediated mRNA decay factor UPF1 promotes aggresome formation.

Nonsense-mediated mRNA decay (NMD) typifies an mRNA surveillance pathway. Because NMD necessitates a translation event to recognize a premature termination codon on mRNAs, truncated misfolded polypeptides (NMD-polypeptides) could potentially be generated from NMD substrates as byproducts. Here, we show that when the ubiquitin-proteasome system is overwhelmed, various misfolded polypeptides including NMD-polypeptides accumulate in the aggresome: a perinuclear nonmembranous compartment eventually cleared by autophagy. Hyperphosphorylation of the key NMD factor UPF1 is required for selective targeting of the misfolded polypeptide aggregates toward the aggresome via the CTIF-eEF1A1-DCTN1 complex: the aggresome-targeting cellular machinery. Visualization at a single-particle level reveals that UPF1 increases the frequency and fidelity of movement of CTIF aggregates toward the aggresome. Furthermore, the apoptosis induced by proteotoxic stresses is suppressed by UPF1 hyperphosphorylation. Altogether, our data provide evidence that UPF1 functions in the regulation of a protein surveillance as well as an mRNA quality control.

Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling.

The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.

Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer.

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery.

Intradermal and transdermal drug delivery using microneedles - Fabrication, performance evaluation and application to lymphatic delivery.

The progress in microneedle research is evidenced by the transition from simple 'poke and patch' solid microneedles fabricated from silicon and stainless steel to the development of bioresponsive systems such as hydrogel-forming and dissolving microneedles. In this review, we provide an outline on various microneedle fabrication techniques which are currently employed. As a range of factors, including materials, geometry and design of the microneedles, affect the performance, it is important to understand the relationships between them and the resulting delivery of therapeutics. Accordingly, there is a need for appropriate methodologies and techniques for characterization and evaluation of microneedle performance, which will also be discussed. As the research expands, it has been observed that therapeutics delivered via microneedles has gained expedited access to the lymphatics, which makes them a favorable delivery method for targeting the lymphatic system. Such opportunity is valuable in the area of vaccination and treatment of lymphatic disorders, which is the final focus of the review.

A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.

Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have studied the oral absorption and disposition pathways of cordycepin, an adenosine analogue. In vitro biopharmaceutical properties and in vivo oral absorption and disposition of cordycepin were assessed in rats. Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3'-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3'-deoxyinosine to cordycepin 5'-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5'-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3'-deoxyinosine. The novel nucleoside rescue metabolic pathway proposed in this study could be responsible for therapeutic effects of adenosine and other analogues of adenosine following oral administration. These findings may have importance in understanding the physiology and pathophysiology associated with adenosine, as well as drug discovery and development utilising adenosine analogues.

Solid lipid nanoparticles self-assembled from spray dried microparticles.

We report the self-assembly of drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (IMC) and hydrophilic (5-FU) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spray-dried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations.

Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition.

Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI50 values < 90 nM), colony formation and migration. Significant G2/M cell cycle arrest preceded time- and dose-dependent apoptosis-induction in human cancer cell lines corroborated by dose-and time-dependent PARP cleavage and caspase 3/7 activation, in addition to reduced Bcl-2 and Mcl-1 expression. CR potently inhibited PI3K/AKT/mTOR signalling depleting polo-like kinase 1 (PLK-1), c-Myc and STAT-3 expression. Additionally, CR significantly increased the generation of reactive oxygen species (ROS) producing DNA double strand breaks. Preliminary in silico biopharmaceutical assessment of CR predicted >60% bioavailability and rapid absorption; doses of 1-10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.

Prevention of paclitaxel-induced neuropathy by formulation approach.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 µg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 µg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 µg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs.

Quantitative Prediction of Oral Bioavailability of a Lipophilic Antineoplastic Drug Bexarotene Administered in Lipidic Formulation Using a Combined In Vitro Lipolysis/Microsomal Metabolism Approach.

For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.