Reduced Drug Exposure Research Articles

Strategy and validation of a nonclinical generic plug-and-play antidrug antibody method for human monoclonal antibody biotherapeutics.

The measurement of antidrug antibodies (ADA) in nonclinical studies provides limited value becausethe formation and incidence of nonclinical ADA does not translate to clinical experience. The formation and presence of ADA in nonclinical species can, however, correlate to reduced drug exposure and safety observations including vasculitis and immune complex disease. Generic ADA methods for humanized monoclonal antibody biotherapeutics mitigate the need to develop bespoke ADA methods during nonclinical drug development. A drug-tolerant, sensitive, generic ADA immunoassay has been developed and validated for measuring ADA in cynomolgus monkey serum samples, allowing for immediate qualification of future monoclonal antibody biotherapeutics. This approach allows us to differentiate complexed and free ADA in a rapidly deployable manner when needed.

Effect of Obesity on the Exposure of Long-acting Cabotegravir and Rilpivirine: A Modeling Study.

Obesity is increasingly prevalent among people with human immunodeficiency virus (HIV, PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in silico trials using physiologically based pharmacokinetic (PBPK) modeling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/ overweight (body mass index [BMI] <30 kg/m2) and in obese (BMI >30 kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60 kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (area under the curve [AUC]) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25 kg/m2). Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35 kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40 kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration, but this was less frequent with the monthly administration. Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.

Generation of evidence-based carboplatin dosing guidelines for neonates and infants

BackgroundTo optimally dose childhood cancer patients it is essential that we apply evidence-based dosing approaches. Carboplatin is commonly dosed to achieve a cumulative target exposure (AUC) in children, with target AUC values of 5.2–7.8 mg/ml.min defined. To achieve these exposures patients are dosed at 6.6 mg/kg/day or 4.4 mg/kg for patients <5 kg. The current study uses real world clinical pharmacology data to optimise body weight-based doses to effectively target AUCs of 5.2–7.8 mg/ml.min in infants.MethodsCarboplatin exposures were determined across 165 treatment cycles in 82 patients ≤10 kg. AUC and clearance values were determined by Bayesian modelling from samples collected on day 1. These parameters were utilised to assess current dosing variability, determine doses required to achieve target AUC values and predict change in AUC using the modified dose.ResultsNo significant differences in clearance were identified between patients <5 kg and 5–10 kg. Consequently, for patients <5 kg, 4.4 mg/kg dosing was not sufficient to achieve a target AUC of 5.2 mg/ml.min, with <55% of patients within 25% of this target. Optimised daily doses for patients ≤10 kg were 6 mg/kg and 9 mg/kg for cumulative carboplatin target exposures of 5.2 and 7.8 mg/ml.min, respectively.ConclusionsAdoption of these evidence-based carboplatin doses in neonates and infants will reduce drug exposure variability and positively impact treatment.

Anti-EGFR conjugated nanoparticles to deliver Alpelisib as targeted therapy for head and neck cancer

BackgroundHead and neck squamous cell carcinoma (SCC) is one of the most prevalent and deadly cancers worldwide. Even though surgical approaches, radiation therapy, and therapeutic agents are commonly used, the prognosis of this cancer remains poor, with a tendency towards recurrence and metastasis. Current targeted therapeutic options for these patients are limited to monoclonal antibodies against EGFR or PD-1 receptors. Thus, there is an urgent need to introduce new molecularly targeted therapies for treating head and neck SCC. EGFR can be used as a target to improve the ability of nanoparticles to bind to tumor cells and deliver chemotherapeutic agents. In fact, over 90% of head and neck SCCs overexpress EGFR, and other tumor types, such as colorectal and glioblastoma, show EGFR overexpression. The PI3K/mTOR signaling pathway is one of the most commonly altered oncogenic pathways in head and neck SCC. Alpelisib is a specific PI3Kα inhibitor indicated for PIK3CA mutant advanced breast cancer that showed promising activity in clinical trials in head and neck SCC. However, its use is associated with dose-limiting toxicities and treatment-related adverse effects.ResultsWe generated polylactide (PLA) polymeric nanoparticles conjugated to anti-EGFR antibodies via chemical cross-linking to a polyethyleneimine (PEI) coating. Antibody-conjugated nanoparticles (ACNP) displayed low polydispersity and high stability. In vivo, ACNP showed increased tropism for EGFR-expressing head and neck tumors in a xenograft model compared to non-conjugated nanoparticles (NP). Alpelisib-loaded nanoparticles were homogeneous, stable, and showed a sustained drug release profile. Encapsulated Alpelisib inhibited PI3K pathway activation in the different cell lines tested that included wild type and altered PIK3CA. Alpelisib-NP and Alpelisib-ACNP decreased by 25 times the half-maximal inhibitory concentration compared to the free drug and increased the bioavailability of the drug in the cells. Herein we propose an efficient strategy to treat head and neck SCC based on nanotechnology.ConclusionsAnti-EGFR-conjugated polymeric nanoparticles are an effective delivery system to increase drug efficiency and bioavailability in head and neck cancer cells. This strategy can help reduce drug exposure in disease-free organs and decrease drug-associated unwanted side effects.

Model predictive control of cancer cellular dynamics: a new strategy for therapy design

Recent advancements in cybergenetics have led to the development of new computational and experimental platforms that enable us to robustly steer cellular dynamics by applying external feedback control. Such technologies have never been applied to regulate intracellular dynamics of cancer cells. Here, we show in silico that adaptive model predictive control (MPC) can effectively be used to steer the simulated signalling dynamics of Non-Small Cell Lung Cancer (NSCLC) cells to resemble those of wild type cells. Our optimisation-based control algorithm enables tailoring the cost function to force the controller to alternate different drugs and/or reduce drug exposure, minimising both drug-induced toxicity and resistance to treatment. Our results pave the way for new cybergenetics experiments in cancer cells, and, longer term, can support the design of improved drug combination therapies in biomedical applications.

Does Food Affect the Pharmacokinetics of Non-orally Delivered Drugs? A Review of Currently Available Evidence.

The food effects for orally administered drugs have been widely investigated and reviewed. In contrast, our knowledge of food effects for non-orally administered drugs is scarce. In this review paper, we did a literature survey to collect clinical food effect data for non-orally administered drugs. Our survey retrieved 18 drugs, including thirteen intravenously (IV), two subcutaneously (SC), one intradermally (ID), one pulmonary, and one rectally administered drug. The food effect data show that food intake can increase the absorption of SC and ID administered peptides and proteins with MW < 30kDa by 30-50%. On the other hand, food intake can increase the elimination of IV and inhaled drugs with moderate and high hepatic extraction and reduce drug exposure by up to 35%. The food effect knowledge can be used to mitigate potential efficacy and safety risks of non-orally administered drugs.

Increased CD8+ T-cell Infiltration and Efficacy for Multikinase Inhibitors After PD-1 Blockade in Hepatocellular Carcinoma.

Immune checkpoint blockade combined with antiangiogenic therapy induces vascular normalization and antitumor immunity and is efficacious in hepatocellular carcinoma (HCC); but whether and how initial immunotherapy affects the efficacy of subsequent antiangiogenic therapy are unknown. We evaluated a cohort of HCC patients (n = 25) who received the pan-vascular endothelial growth factor receptor multikinase inhibitor sorafenib after initial therapy with an antiprogrammed cell death protein (PD)-1 antibody and found superior outcomes in these patients (12% overall response rate to sorafenib and a median overall survival of 12.1 months). To prove this potential benefit, we examined the impact of an anti-PD-1 antibody on response to subsequent sorafenib treatment in orthotopic models of murine HCC. Prior anti-PD-1 antibody treatment amplified HCC response to sorafenib therapy and increased survival (n = 8-9 mice per group, hazard ratio = 0.28, 95% confidence interval = 0.09 to 0.91; 2-sided P = .04). Anti-PD-1 therapy showed angioprotective effects on HCC vessels to subsequent sorafenib treatment, which enhanced the benefit of this therapy sequence in a CD8+ T-cell-dependent manner. This priming approach using immunotherapy provides an immediately translatable strategy for effective HCC treatment while reducing drug exposure.

Randomized Trial on Echocardiography-Guided Ductus Arteriosus Treatment to Reduce Necrotizing Enterocolitis.

ObjectivePatent ductus arteriosus (PDA) approach remains controversial. We aim to evaluate whether echocardiography-guided (EchoG) PDA closure (to reduce drug exposure) and 24-h continuous ibuprofen infusion (24 h-IB) (to reduce peak concentration), compared with EchoG PDA closure plus conventional bolus (bolus-IB), reduces severe bowel adverse event rate in preterm infants with hemodynamically significant (hs) PDA.Study DesignThe study design is a multicenter, blinded, randomized controlled trial. Infants with <28 weeks of gestation underwent routine echocardiographic assessment (18–72 h of birth); infants with 28–33 weeks were screened only in cases where PDA was clinically suspected. HsPDA was considered if ductal diameter >1.5 mm and indicators of pulmonary overflow, systemic hypoperfusion, or both were present. Pharmacodynamic effect of CYP450 genotypes was also analyzed.ResultsOne hundred forty-six infants [median gestational age 26 (25–28) weeks; median birth weight 881 (704–1,100) g] were randomized to 24 h-IB (n = 70) or bolus-IB (n = 76) study group at 86 (58–140) h from birth. Groups were comparable regarding perinatal and neonatal clinical data, but higher prevalence of male sex in the bolus-IB group was found. Neither severe bowel adverse event rate [10% (24 h-IB) and 2.6% (bolus-IB), p = 0.1] nor ductal closure rate was different between the study groups. Postnatal age and peripheral SaO2 at treatment start and pulmonary hemorrhage were associated with severe bowel events, independent of treatment group allocation. CYP2C8 genetic polymorphisms were associated with ibuprofen efficacy (p = 0.03).ConclusionsIbuprofen intravenous continuous infusion compared with bolus infusion in preterm infants with hsPDA shows similar rates of success and does not reduce the prevalence of severe bowel events.

Pharmacokinetic Simulation Analysis of Less Frequent Nivolumab and Pembrolizumab Dosing: Pharmacoeconomic Rationale for Dose Deescalation.

Nivolumab and pembrolizumab, anti-programmed cell death protein 1 monoclonal antibodies, have revolutionized oncology but are expensive. Using an interventional pharmacoeconomic approach, these drugs can be administered less often to reduce costs and increase patient convenience while maintaining efficacy. Both drugs are good candidates for less frequent dosing because of long half-lives and no evidence of a relationship of dose to efficacy. Established population pharmacokinetic models for both nivolumab and pembrolizumab were used to simulate profiles for multiple dosing regimens on 1000 randomly generated virtual patients. Simulations were initially performed on standard dose regimens to validate these in silico predictions. Next, simulations of nivolumab 0.3 mg/kg every 3 weeks revealed that >95% of patients maintained ≥1.5 μg/mL at steady state, which was inferred as the minimum effective concentration (MEC) for both drugs. Various alternative dosing regimens were simulated for both drugs to determine which regimen(s) can maintain this MEC in >95% of patients. Extended dosing regimens of nivolumab 240 mg every 4weeks and 480 mg every 8 weeks along with pembrolizumab 200 mg every 6 weeks were simulated, showing that >95% of patients maintained MEC or greater. These simulations demonstrate the potential to reduce drug exposure by at least 50%, thus substantially reducing patient visits (as well as costs), while maintaining equivalent efficacy. These models provide the scientific justification for an ongoing prospective randomized clinical trial comparing standard interval fixed dosing with extended interval fixed dosing, and ultimately an efficacy-driven comparative trial.

Patient-maintained versus anaesthetist-controlled propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia: a randomised controlled trial

BackgroundPatient-maintained propofol TCI sedation (PMPS) allows patients to titrate their own target-controlled infusion (TCI) delivery of propofol sedation using a handheld button. The aim of this RCT was to compare PMPS with anaesthetist-controlled propofol TCI sedation (ACPS) in patients undergoing elective primary lower-limb arthroplasty surgery under spinal anaesthesia. MethodsIn this single-centre open-label investigator-led study, adult patients were randomly assigned to either PMPS or ACPS during their surgery. Both sedation regimes used Schnider effect-site TCI modelling. The primary outcome measure was infusion rate adjusted for weight (expressed as mg kg−1 h−1). Secondary outcomes measures included depth of sedation, occurrence of sedation-related adverse events and time to medical readiness for discharge from the postanaesthsia care unit (PACU). ResultsEighty patients (48 female) were randomised. Subjects using PMPS used 39.3% less propofol during the sedation period compared with subjects in group ACPS (1.56 [0.57] vs 2.57 [1.33] mg kg−1 h−1; P<0.001), experienced fewer discrete episodes of deep sedation (0 vs 6; P=0.0256), fewer airway/breathing adverse events (odds ratio [95% confidence interval]: 2.94 [1.31–6.64]; P=0.009) and were ready for discharge from PACU more quickly (8.94 [5.5] vs 13.51 [7.2] min; P=0.0027). ConclusionsPatient-maintained propofol sedation during lower-limb arthroplasty under spinal anaesthesia results in reduced drug exposure and fewer episodes of sedation-related adverse events compared with anaesthetist-controlled propofol TCI sedation. To facilitate further investigation of this procedural sedation technique, PMPS-capable TCI infusion devices should be submitted for regulatory approval for clinical use. Clinical trial registrationISRCTN29129799.

The effect of activated charcoal on drug exposure following intravenous administration: A meta-analysis.

Activated charcoal both reduces primary drug absorption and enhances drug elimination. However, the two mechanisms of action overlap and are indistinguishable from each other. In order to estimate the extend of enhanced elimination, we summarized the effect of activated charcoal on intravenously administered drugs, where reduced drug exposure can be attributed to enhanced elimination. We performed a meta-analysis of randomized controlled studies evaluating the effect of orally administered activated charcoal on the systemic exposure of intravenously administered drugs. We searched the bibliographic databases PubMed, Embase and Cochrane. Meta-regression analyses of selected physiochemical drug properties on the effect sizes of activated charcoal were performed. All but one of 21 included studies used multiple-dose activated charcoal (MDAC). MDAC reduced the median half-life of the intravenously administered study drugs by 45.7% (interquartile range: 15.3%-51.3%) and area under the concentration time curve by 47.0% (interquartile range: 36.4%-50.2%). MDAC significantly improved drug elimination across nine different intravenously administered drugs, but we were unable to identify factors allowing extrapolation to other drugs. The results offer a possible and plausible rationale for the previously observed effects of single-dose activated charcoal beyond the timeframe where ingested drug is present in the gastro-intestinal tract.

Assessment of Vedolizumab Disease-Drug-Drug Interaction Potential in Patients With Inflammatory Bowel Diseases.

Disease‐drug‐drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti‐inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well‐established positive benefit‐risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4β‐hydroxycholesterol‐to‐cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.

CN23 Increased patient and occupational safety for home infusion of cytotoxic and other hazardous drugs

There is an increasing demand for intravenous (IV) oncology therapy in a homecare setting. From a healthcare system point of view, up to 90% of the costs could be cut comparing IV therapy given at home to the same care conducted in a hospital setting. From the patient perspective, several studies have shown that the overall experience of treatment is much improved in a homecare setting without a lesser clinical outcome. Side effects such as nausea and vomiting are decreased by the reduced physical and psychological stress and the risk for hospital-acquired infections is reduced. Homecare pose a lesser invasion of the patient’s life. This is especially true for children with cancer where families testify to not feeling as affected by the illness and children describes how they felt less ill and more normal when being treated in their own home, leading to an increase in their quality of life. Shifting IV therapy from the hospital to the home will pose a challenge with regards to risk management. A literature study has been performed to investigate which risks has been documented so far and if they affect patients, caregivers and/or the home infusion nurses. Two of the most important safety issues are identified to be the risk of vascular air embolism and IV-line dislodgement. A proof-of-concept device to address these specific risks has been developed. The disposable closed system device consists of an automatic vent to remove air combined with a weak link connector that disconnects when the IV line is forcefully pulled. The vent eliminates the need for manual removal of air bubbles, thus reducing drug exposure and disruption to flow rates. The connector has valves that seal the system on both sides to retain all liquids in the event of a pulled IV line, reducing injury from dislodgement and drug exposure. Feasibility testing of the device has shown a 99.97% success at air removal compared to standard IV delivery methods and reduction in dislodgment frequency of 92%. A novel device for reducing risks for air embolism and IV-line dislodgement can strongly increase the safety for patients and nurses during IV chemotherapy therapy at home.

Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: An in vitro Study.

Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines.Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits.Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung® petite kits, two iLA-ActivveMiniLung® kits, two iLA-ActivveiLA® kits, and two iLA-Activve X-lung® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h.Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin.Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.

Abstract 2287: Bispecific anti-PD1 checkpoint inhibitors antibodies (BiCKI), an optimized platform designed to tackle anti-PD-(L)1 primary and secondary resistance mechanisms

Abstract Although Anti PD(L)1 therapy lead to impressive therapeutic responses by reinvigorating T cells, primary and secondary resistances occur de novo or during treatment impeding the full efficacy of the drug. To tackle this resistance mechanisms and reduced the immunotoxicity of combination therapy, we designed a 2nd generation of anti-PD1 antibody by fusing immune protein to the Fc portion of the antibody, named BiCKI®. The anti PD1 will more selectively drive the immune active drug on antigen-experienced (PD1+) T cells, through cis-targeting mechanism. These bifunctional molecules were designed with an optimized anti-PD1 backbone for bispecific format, fused to an active protein domain to the C-ter of heavy and/or light chains. Different protein candidate were successfully fused to the optimized anti-PD1, such as cytokines, costimulatory molecules, or dominant negative receptors with PD1/PDL1 full antagonistic activity. In contrast to combination, BiCKI® antibodies enable the simultaneous dual-binding specificity in a single drug allowing a synergistic activation. Each BiCKI® is selected on its synergistic capacity to re-activate of anti-tumor T cell responses or TCR signaling in cell-based assays. Bispecific antibody development in clinic has been hampered by difficult manufacturing process, reduced pharmacokinetic (PK) and drug exposure. Both anti PD-1 CDRs and VH/VL framework sequences were carefully selected and optimized for bioproductivity and biostability of the molecule. A 2 to 15-fold increased productivity in mammalian cells was observed versus the non-optimized anti-PD1 antibody or other anti-PD-1 bispecific backbones as Pembrolizumab or Nivolumab. We also evaluated the impact of the Fc isotype,linker flexibility and affinity of the fused compound on the PK profile of different bispecifics fused to costimulatory molecules or cytokines. The IgG isotype with reduced FcgR binding property, of the anti-PD-1 backbone was associated with a better PK profile with some exceptions for cytokine. The presence or length of a linker between Fc domain and the fused protein has a small impact the PK and drug efficacy. More importantly, the affinity of the fused compound has an impact the PK profile of BiCKI® For example, the anti-PD-1 fused to wild-type IL-7 cytokine possesses a high affinity for the CD127/CD132 receptors but display a reduced drug exposure both in mouse and cynomolgus. This potential difficulty was solved with further improved products including IL-7 mutants having reduced affinity for CD127 and/or CD132. While significant correlation between IL7 affinity and PK has been observed, increased PK and drug exposure could be achieved using optimized combination of Fc isotype a linker length design and BiCKI-IL7 mutants retaining significant IL7R signaling. Conclusion: Our BICKI® platform was designed to overcome major hurdles of bispecific antibody development, we improved its manufacturability and drug exposure by selectively designing the structure of bispecific antibodies. By fusing costimulatory molecule, cytokines or dominant negative receptor to the anti PD-1 blocking antibody, we can generate and select various efficient bispecific molecules acting in synergy to counteract primary and secondary resistance mechanisms of anti-PD(L)1 therapies. Citation Format: Caroline Mary, Aurore Morello, Virginie Thepenier, Géraldine Teppaz, Justine Durand, Nicolas Poirier. Bispecific anti-PD1 checkpoint inhibitors antibodies (BiCKI), an optimized platform designed to tackle anti-PD-(L)1 primary and secondary resistance mechanisms [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2287.

Lipid Drug Carriers for Cancer Therapeutics: An Insight into Lymphatic Targeting, P-gp, CYP3A4 Modulation and Bioavailability Enhancement.

In the treatment of cancer, chemotherapy plays an important role though the efficacy of anti-cancer drug administered orally is limited, due to their poor solubility in physiological medium, inability to cross biological membrane, high Para-glycoprotein (P-gp) mediated drug efflux, and pre-systemic metabolism. These all factors cumulatively reduce drug exposure at the target site leading to multidrug resistance (MDR). Lipid based carriers systems has been explored to overcome solubility and permeability related issues of anti-cancer drugs. The lipid based formulations have also been reported to circumvent the effect of P-gp and CYP3A4. Further long chain triglycerides (LCT) has shown their ability to access Lymphatic route over Medium Chain Triglycerides, as the former has been extensively used for targeting anti-cancer drugs at proliferating cells through lymphatic route. Therefore this review tries to reflect the usefulness of lipid based drug carriers systems (viz. liposome, solid lipid nanoparticle, nano-lipid carriers, self-emulsifying, lipidic pro-drugs) in targeting lymphatic system and overcoming issues related to solubility and permeability of anti-cancer drugs. Moreover, we have also tried to reflect how critically lipid based carriers are important in maximizing therapeutic safety and efficacy of anti-cancer drugs.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

IntroductionAntiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure.ObjectiveWe explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer.ResultsAmong the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist.ConclusionsThese results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Clinical Impact of Antibodies against Ustekinumab in Psoriasis: An Observational, Cross-Sectional, Multicenter Study

Ustekinumab is an effective treatment for psoriasis, but response varies between patients. The formation of anti-drug antibodies (ADAs) may explain part of this variation by reducing the free ustekinumab level. Currently, published analyses of the clinical impact of ADAs are incomplete. In this observational cross-sectional multicenter study of 340 patients, we evaluated the impact of ADAs on ustekinumab level and clinical response as assessed by the PASI. Circulating ADA levels were measured using two assays: a drug-sensitive radioimmunoassay and a drug-tolerant ELISA. Circulating ustekinumab levels were measured using an ELISA. ADAs were detected in 3.8% (95% confidence interval [CI]= 3.2-4.2) and in 10.6% (95% CI= 7.9-13.9) of patients using the radioimmunoassay and drug-tolerant ELISA, respectively. At least 85% of the ADAs were neutralizing. Compared with patients negative for ADAs, ADA positivity in the radioimmunoassay and drug-tolerant ELISA were associated with lower median ustekinumab levels (-0.62 μg/ml [95% CI=-1.190 to-0.30] and-0.74 μg/ml [95% CI=-1.09 to-0.47], respectively) and higher absolute PASI (6.6 [95% CI= 3.0-9.9] and 1.9 [95% CI= 0.4-4.0], respectively). Absence of detectable ustekinumab regardless of ADA status correlated with poor clinical outcome (median sample PASI 10.1, 6.5 [95% CI= 3.9-8.8] compared with patients positive for ustekinumab). In conclusion, substantially reduced drug exposure resulting from ADAs formation is associated with impaired clinical response.

A Randomized Controlled Trial of Three- versus Five-Day Artemether-Lumefantrine Regimens for Treatment of Uncomplicated Plasmodium falciparum Malaria in Pregnancy in Africa.

Artemether-lumefantrine antimalarial efficacy in pregnancy could be compromised by reduced drug exposure. Population-based simulations suggested that therapeutic efficacy would be improved if the treatment duration was increased. We assessed the efficacy, tolerability, and pharmacokinetics of an extended 5-day regimen of artemether-lumefantrine compared to the standard 3-day treatment in 48 pregnant women and 48 nonpregnant women with uncomplicated falciparum malaria in an open-label, randomized clinical trial. Babies were assessed at birth and 1, 3, 6, and 12 months. Nonlinear mixed-effects modeling was used to characterize the plasma concentration-time profiles of artemether and lumefantrine and their metabolites. Both regimens were highly efficacious (100% PCR-corrected cure rates) and well tolerated. Babies followed up to 1 year had normal development. Parasite clearance half-lives were longer in pregnant women (median [range], 3.30 h [1.39 to 7.83 h]) than in nonpregnant women (2.43 h [1.05 to 6.00 h]) (P=0.005). Pregnant women had lower exposures to artemether and dihydroartemisinin than nonpregnant women, resulting in 1.2% decreased exposure for each additional week of gestational age. By term, these exposures were reduced by 48% compared to nonpregnant patients. The overall exposure to lumefantrine was improved with the extended regimen, with no significant differences in exposures to lumefantrine or desbutyl-lumefantrine between pregnant and nonpregnant women. The extended artemether-lumefantrine regimen was well tolerated and safe and increased the overall antimalarial drug exposure and so could be a promising treatment option in pregnancy in areas with lower rates of malaria transmission and/or emerging drug resistance. (This study has been registered at ClinicalTrials.gov under identifier NCT01916954.).

Phase III, Multicenter Open-Label Study to Investigate the Efficacy of Elbasvir and Grazoprevir Fixed-Dose Combination for Eight Weeks in Treatment-Naïve, HCV GT1b-Infected Patients, with Non-Severe Fibrosis

Background: Genotype 1b is the most common HCV genotype worldwide, accounting for the largest proportion of infections in Europe, Russia, Latin America and Asia. Reducing treatment duration can improve adherence, reduce drug exposure and cost. Accordingly, we evaluated the efficacy of eight weeks fixed dose combination of grazoprevir-elbasvir in treatment-naive patients, with non-severe fibrosis. Methods: HCV mono-infected and treatment naive patients with non-severe fibrosis (Fibroscan®<9·5kPa and Fibrotest®<0·59) were enrolled in a study which included 117 patients. Genotyping by sequencing identified five patients with non-1b genotype (two GT1a, one GT1h, one GT1e and one GT1l). Thus, we included in the final analysis 112 GT1b patients. The primary end point was the proportion of patients with HCVRNA below the lower limit of quantification 12 weeks after treatment (SVR12). Findings: Mean age was 54 ± 13 years, 31% were male, viral load was higher than 800.000 IU/ml in 70 out of 112 patients (63%). Using Fibroscan®, 100 had F0-1 fibrosis score. FIB-4 lower than 1·45 and APRI less than one was found in 74/112 (66%) and 107/112 (95%) patients respectively. Relapse occurred in three patients by week 12. These three patients had a viral load higher than 6 million IU/mL and NS5A Y93H RAS (resistance associated substitution). Then, modified intention-to-treat SVR12 for patients with genotype 1b was 109/112 (97%). By week 24; five relapses were observed and all had the Y93H RAS at relapse. SVR12 was achieved in 100% of patients with a baseline viral load below 6 million and decreased to 98% (98/100) by follow-up week 24. Interpretation: Naive patients with genotype 1b and non-severe fibrosis can achieve an SVR12 of 97% and an SVR24 of 95%. Then, these patients can be treated with grazoprevir-elbasvir for eight weeks. Funding Statement: The CHU of Clermont-Ferrand has received a grant of MSD to conduct the study. MSD has financed the cost of the treatment. The data were managed by the research assistants and the delegation a la recherche Clinique all in Clermont-Ferrand. Declaration of Interests: A Abergel : Clinical Investigator/Speaker: AbbVie, Gilead Sciences, Merck Sharp & Dohme, Intercept; T Asselah : Clinical Investigator/Speaker/Consultant: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche; A Mallat : no conflict of interest; B Chanteranne : no conflict of interest; F Faure : no conflict of interest; D Larrey : Clinical Investigator/Speaker: AbbVie, Gilead Sciences, Merck Sharp & Dohme; J Gournay : personal fees from Gilead and Abbvie, grants and personal fees from Intercept; V Loustaud-Ratti : Clinical Investigator/Speaker: Abbvie, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme; V Di Martino : personal fees from Abbvie and MSD; I Fouchard-Hubert : grants from Gilead and Abbvie outside the submitted work; S Pol has received consulting and lecturing fees from Bristol-Myers Squibb, Janssen, Gilead, Roche, MSD, Myr Pharma, Shionogi, Biotest and Abbvie, and grants from Bristol-Myers Squibb, Gilead, Roche and MSD; F Bailly : personal fees and non-financial support from MSD; personal fees and non-financial support from Gilead; personal fees and non-financial support from Abbvie; personal fees and non-financial support from Intercept; D Samuel : personnal fees from Intercept, Biotest, Abbvie, Gilead Sciences; A Tran : Clinical Investigator/Speaker/Consultant: AbbVie, Gilead Sciences, Merck Sharp & Dohme; M Dodel : no conflict of interest; N Andant : no conflict of interest; G Lamblin : no conflict of interest; L Muti : no conflict of interest; M Reymond : no conflict of interest; C Teilhet : no conflict of interest; B Pereira : no conflict of interest; B Buchard : no conflict of interest. Ethics Approval Statement: The study was approved by the ethical committee (CPP Sud-Est) on September 26, 2016 and met the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provides written informed consent.