Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.

OBJECTIVES: The response rate to treatment of chronic hepatitis C virus-genotype 1 and 4 infections was recently found to be strongly influenced by many polymorphisms. The aim of our study was to carry out an integrated analysis of the effects of polymorphisms and ribavirin (RBV) plasma exposure on outcome. METHODS: The retrospective analysis included 174 patients. IL28B, CYP27B1, SLC29A1, SLC28A3, and SLC28A2 polymorphisms were genotyped and tested for association with sustained virological response. The impact of RBV plasma exposure during the first 3 months of therapy on outcome was also investigated. RESULTS: Considering patients infected by hepatitis C virus-1/4, 3 polymorphisms (IL28B rs8099917TT, CYP27B1 rs4646536TT, and CNT2 rs11854484TT) were associated with sustained virological response. The number of negative variant allele and low RBV exposure were correlated to percentage increasing to therapy failure, suggesting some degree of cumulative effect of the 4 factors. A cutoff of 2.5 µg/mL of RBV was found to be associated with outcome (area under ROC [AUROC] curve = 0.64, sensitivity = 55.0%, and specificity = 71.2%, P = 0.020). In multivariate logistic regression analyses, each variant allele and RBV plasma exposure cutoff were independently associated with outcome. CONCLUSIONS: In this study, we found that additional polymorphisms and RBV plasma exposure are also able to influence the achievement of response. Regardless of the magnitude of RBV pharmacokinetic exposure, the negative predictive value of the polymorphisms here investigated is much stronger than the positive one.

Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.

BACKGROUND: Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. METHODS: A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. RESULTS: Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 µg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 µg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. CONCLUSIONS: Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human.

The use of nanoparticles (NPs) can support an enhancement of drug distribution, resulting in increased drug penetration into key tissues. Experimental in vitro data can be integrated into computational approaches to simulate NP absorption, distribution, metabolism and elimination (ADME) processes and provide quantitative pharmacokinetic predictions. The aim of this study is to develop a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model to predict the biodistribution of NPs focusing on Doxil. The main processes underpinning NPs ADME were represented considering molecular and cellular mechanisms such as stability in biological fluids, passive permeability and uptake activity by macrophages. A whole-body m-PBPK rat and human models were designed in Simbiology v. 9.6.0 (MATLAB R2019a). The m-PBPK models were successfully qualified across doxorubicin and Doxil® in both rat and human since all PK parameters AUC0-inf, Cmax, t1/2, Vd and Cl were within twofold, with an AUC0-inf absolute average-fold error (AAFE) value of 1.23 and 1.16 and 1.76 and 1.05 for Doxorubicin and Doxil® in rat and human, respectively. The time to maximum concentration in tissues for doxorubicin in both rat and human models was before 30 min of administration, while for Doxil®, the tmax was after 24 h of administration. The organs that accumulate most NP are the spleen, liver and lungs, in both models. The m-PBPK represents a predictive platform for the integration of in vitro and formulation parameters in a physiological context to quantitatively predict the NP biodistribution. Schematic diagram of the whole-body m-PBPK models developed for Doxil® in rat and human physiology.

Evaluating the impact of systematic hydrophobic modification of model drugs on the control, stability and loading of lipid-based nanoparticles.

A significant number of new chemical entities in the drug development pipeline are poorly soluble, therefore routes that facilitate effective administration is of considerable value. Lipid nanoparticles have proved an attractive approach for drug delivery; however, challenges that include optimising drug loading and understanding the impact of drug physiochemical parameters on nanoparticle properties have limited progression. In this work, we investigate the effect of modifying the log P of a model drug on the formation and stability of lipid-based nanoparticles. A range of model drug analogues with systematically varying alkyl chains were produced using a lamivudine (nucleoside analog reverse transcriptase inhibitor) scaffold and processed into lipid nanoparticles by nanoprecipitation. Characterisation included evaluation of particle diameter, size distribution, drug loading and nanoformulation stability. A distinct correlation with the LaMer model of nucleation was observed and log P appeared to strongly influence rates of nucleation. Model drugs with high log P were uniform in particle size and distribution and offered enhanced stability. In addition, various model drug/lipid blends were produced and their physical properties were investigated using dynamic light scattering (DLS) and differential scanning calorimetry (DSC). Complex mixtures of lipids were shown to influence formulation crystallinity and strategies to form uniform and stable lipid based nanoparticles of high drug loading- through manipulation of log P are discussed.

Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.

An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.

Antiretroviral solid drug nanoparticles with enhanced oral bioavailability: production, characterization, and in vitro-in vivo correlation.

Nanomedicine strategies have produced many commercial products. However, no orally dosed HIV nanomedicines are available clinically to patients. Although nanosuspensions of drug particles have demonstrated many benefits, experimentally achieving >25 wt% of drug relative to stabilizers is highly challenging. In this study, the emulsion-templated freeze-drying technique for nanoparticles formation is applied for the first time to optimize a nanodispersion of the leading non-nucleoside reverse transcriptase inhibitor efavirenz, using clinically acceptable polymers and surfactants. Dry monoliths containing solid drug nanoparticles with extremely high drug loading (70 wt% relative to polymer and surfactant stabilizers) are stable for several months and reconstitute in aqueous media to provide nanodispersions with z-average diameters of 300 nm. The solid drug nanoparticles exhibit reduced cytoxicity and increased in vitro transport through model gut epithelium. In vivo studies confirm bioavailability benefits with an approximately four-fold higher pharmacokinetic exposure after oral administration to rodents, and predictive modeling suggests dose reduction with the new formulation may be possible.

Nanomedicines for HIV therapy.

Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment.